JPWO2007018273A1 - Diagnostic agent delivery composition containing sugar chain-modified liposome - Google Patents

Abstract

The present invention provides a diagnostic drug delivery composition containing a sugar chain-modified liposome useful for in-vivo delivery such as oral administration and a diagnostic drug. The sugar chain-modified liposome used in the diagnostic agent delivery composition of the present invention preferably has a sugar chain having at least one specific sequence bound via a linker such as human serum albumin.

Description

The present invention can be applied in the medical and pharmaceutical fields including pharmaceuticals and cosmetics, recognizes a target cell / tissue such as cancer, and locally delivers a drug or gene to an affected area. The present invention relates to a sugar chain-modified liposome that can be used as a cell / tissue sensing probe, and a diagnostic agent delivery composition in which a diagnostic agent to be delivered into the body is encapsulated.

As an example of a specific goal to be realized by the US National Nanotechnology Strategy (NNI), “Drug and gene delivery system (DDS: drug delivery system) that targets cancer cells and target tissues” was listed. In the Nanotechnology / Materials Promotion Strategy of the Japan Science and Technology Council, there is “Nanobiology that uses and controls the medical microsystems / materials / biological mechanisms” as one of the priority areas. One example is “Establishing basic seeds for biofunctional materials and pinpoint treatment for extending healthy life expectancy”. On the other hand, with the aging of society, the incidence and death rates of cancer are increasing year by year, and the development of target-oriented DDS, which is a novel therapeutic material, is awaited. The importance of target-oriented DDS nanomaterials with no side effects in other diseases is drawing attention, and the market size is predicted to exceed 10 trillion yen in the near future. These materials are also expected to be used for diagnosis as well as treatment.

The therapeutic effect of a drug is manifested by the drug reaching a specific target site and acting there. On the other hand, a side effect caused by a drug is that a drug acts on an unnecessary site. Therefore, development of a drug delivery system is also required in order to use the drug effectively and safely. Among them, in particular, targeting DDS is a concept of delivering a drug “to a necessary site in the body”, “a necessary amount”, and “only for a necessary time”. Liposomes, which are particulate carriers, are attracting attention as a representative material for that purpose. Passive targeting methods such as changing the lipid type, composition ratio, particle size, and surface charge of liposomes have been attempted in order to give these particles a target-directing function. There is a need for improvements.

On the other hand, active targeting methods have also been attempted to enable highly functional targeting. This is an ideal targeting method, also called “missile drug”, but it has not been completed in Japan and overseas, and future development is highly expected. In this method, a ligand is bound on the surface of the liposome membrane, and the receptor present on the cell membrane surface of the target tissue is specifically recognized, thereby enabling targeting actively. As a ligand for a receptor present on the cell membrane surface as a target in this active targeting method, an antigen, an antibody, a peptide, a glycolipid, a glycoprotein, or the like can be considered. Among these, glycolipids and glycoprotein sugar chains are information molecules in various cell-to-cell communications such as generation and morphogenesis of biological tissues, cell proliferation and differentiation, biological defense and fertilization mechanisms, canceration and metastasis mechanisms. It is becoming clear that it plays an important role.

In addition, research on various lectins (glycan recognition proteins) such as selectin, siglec, and galectin as receptors existing on the cell membrane surface of each target tissue has advanced, and thus has various molecular structures. Sugar chains have attracted attention as new DDS ligands (see Non-Patent Document 1 and Non-Patent Document 2).

Much research has been conducted on liposomes having a ligand bound to the outer membrane surface as a DDS material for selectively delivering drugs or genes to a target site such as cancer. However, most of them bind to target cells in vitro but are not targeted to target cells or tissues expected in vivo (see Non-Patent Document 3 and Non-Patent Document 4). In the research and development of DDS materials that utilize the molecular recognition function of sugar chains, some studies have been made on liposomes into which glycolipids having sugar chains have been introduced, but their functional evaluation is based on in vitro. However, little research has been conducted on liposomes into which glycoproteins having sugar chains have been introduced (see Non-Patent Document 5, Non-Patent Document 6, Non-Patent Document 7 and Non-Patent Document 8). Therefore, systematic research including preparation methods and in vivo analysis of liposomes with a wide variety of glycolipids and glycoproteins bound to glycolipids and glycoproteins has not been developed so far, and future progress is expected. This is an important issue. Furthermore, as a new type of DDS material research, the development of DDS materials that can be used by oral administration, which can be administered most simply and inexpensively, is also an important issue. For example, peptide drugs and the like are generally water-soluble and have a high molecular weight, and the gastrointestinal tract has a low permeability to the small intestinal mucosa, so that they are hardly absorbed in the intestinal tract even if administered orally due to enzymatic degradation. Thus, research on ligand-bound liposomes is drawing attention as a DDS material for delivering these high molecular weight pharmaceuticals and genes from the intestinal tract into the blood (see Non-Patent Document 9).

Patent Document 1 discloses a pharmaceutical composition having a pharmaceutically acceptable carrier and a compound containing a component that selectively binds to a selectin receptor. However, in this pharmaceutical composition, a sugar chain intended for oral administration is used as a medicine itself for inhibiting inflammatory diseases and other diseases mediated by cell adhesion. Is different.

The present inventors have developed a sugar chain-modified liposome in which a sugar chain is bound to a liposome via a linker protein (Patent Document 2). Furthermore, it discovered that the kind of sugar chain and the amount of sugar chain binding seem to be related to directivity to each target cell or target tissue (patent documents 3 to 5 and non-patent document 10). However, to date, no sugar chain-modified liposome optimal for delivery to the small intestine has been developed. In addition, there has been no systematic study on sugar chains useful in small intestine delivery, and it has remained unclear what kind of sugar chains should be used.

Therefore, there is a demand for efficiently designing a sugar chain-modified liposome optimal for in-vivo delivery such as oral administration and providing it as a material constituting a diagnostic drug delivery composition.
JP 5-507519 A JP 2003-226638 A JP 2003-226647 A WO2005 / 011632 WO2005 / 011633 Yamazaki, N .; , Kojima, S .; Bovin, N .; V. , Andre, S .; Gabius, S .; and Gabius, H .; -J. (2000) Adv. Drug Delivery Rev. 43, 225-244. Yamazaki, N .; , Jigami, Y .; Gabis, H .; -J. Kojima, S (2001) Trends in Glycoscience and Glycotechnology 13, 319-329. http: // www. gak. co. jp / TIGG / 71PDF / yamazaki. pdf Forssen, E .; and Willis, M .; (1998) Adv. Drug Delivery Rev. 29, 249-271. Toshio Takahashi and Mitsuru Hashida (1999), Today's DDS / Drug Delivery System, 159-167, Pharmaceutical Journal, Osaka) DeFreees, S.M. A. Phillips, L .; Guo, L .; and Zalipsky, S .; (1996) J. MoI. Am. Chem. Soc. 118, 6101-6104. Spevak, W.M. , Foxall, C.I. Charych, D .; H. Dasupta, F .; and Nagy, J .; O. (1996) J. MoI. Med. Chem. 39, 1018-1020. Stahn, R.A. Schaffer, H .; Kernchen, F .; and Schreiber, J. et al. (1998) Glycobiology 8, 311-319. Yamazaki, N .; , Jigami, Y .; Gabis, H .; -J. Kojima, S (2001) Trends in Glycoscience and Glycotechnology 13, 319-329. http: // www. gak. co. jp / TIGG / 71PDF / yamazaki. pdf Lehr, C.I. -M. (2000) J. Org. Controlled Release 65, 19-29 Noboru Yamazaki (2005), Development of Active Targeting DDS Nanoparticles, Bulletin of Nano Society, 3, 97-102

Therefore, an object of the present invention is to provide a diagnostic drug delivery composition in which a diagnostic drug is encapsulated in a sugar chain-modified liposome useful for in-vivo delivery such as oral administration.

In order to solve the above-mentioned problems, the present inventors have found that, as a result of diligent research, liposomes whose liposome surface is modified with a specific sugar chain are useful preparation constituent materials in the delivery of diagnostic agents. It has come to be completed.

In the present invention, the following configuration is adopted in order to solve the above problems. (1) A diagnostic drug delivery composition comprising a sugar chain-modified liposome to which at least one sugar chain selected from the following group is bound and a diagnostic drug:
Neu5Aca2,3Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Fuca1,2Galb1,4 (Fuca1,3) Glc,
Neu5Aca2,3Galb1,4Glc,
Galb1,3GalNAcb1,4 (Neu5Aca2,8Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Galb1,4GlcNAc,
GalNAca1,3 (Fuca1,2) Gal,
3 '-(O-SO3H) Galb1,4 (Fuca1,3) GlcNAc,
Fuca1,2Gal,
Mana1,2Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Fuca1,2Galb1,3GlcNAcb1,3Galb1,4Glc,
Mana1,2Mana1,6 (Mana1,2Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Neu5Aca2,6Galb1,4GlcNAc,
Galb1,3GalNAcb1,4Galb1,4Glcb1,1Cer + Neu5Aca2,3Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Galb1,3 (Fuca1,4) GlcNAcb1,3Galb1,4Glc,
Galb1,3GlcNAcb1,3Galb1,4Glc,
Gala1,3 (Fuca1,2) Gal,
Galb1,3GalNAc,
Galb1,6GlcNAc,
Mana1,6 (Mana1,3) Man,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Galb1,3GlcNAc,
Mana1,2Man,
Galb1,4 (Fuca1,3) GlcNAc,
Gala1,3Gal,
Fuca1,2Galb1,4Glc,
Mana1,6 (Mana1,3) Mana1,6Manb1,4GlcNAcb1,4GlcNAc,
Galb1,4 (Fuca1,3) Glc,
GalNAca1-OL-serine,
Neu5Aca2,3Galb1,4 (Fuca1,3) GlcNAc,
Fuca1,2Galb1,4 (Fuca1,3) GlcNAc,
Galb1,4Glc,
Mana1,6Man,
Neu5Aca2,6GalNAca1-OL-serine,
Mana1,6 (Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Fuca1,2Galb1,3 (Fuca1,4) GlcNAc,
Mana1,4Man,
Neu5Ac2,6GalNAca1-OL-serine,
Neu5Aca2,6Galb1,4Glc,
Fuca1,2Galb1,3 (Fuca1,4) GlcNAcb1,3Galb1,4Glc,
Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Mana1,3Man,
Neu5Aca2,3Galb1,3 (Fuca1,4) GlcNAc,
3 '-(O-SO3H) Galb1,3 (Fuca1,4) GlcNAc,
Neu5Aca2,3Galb1,4GlcNAc,
Galb1,3 (Fuca1,4) GlcNAc.
(2) The diagnostic drug delivery composition according to (1), wherein the modified bond density of the sugar chain is 0.0075 to 0.75 mg sugar chain / mg lipid. (3) The diagnostic drug delivery composition according to (1) or (2), wherein the sugar chain is bound to the liposome membrane via a linker. (4) The diagnostic agent delivery composition according to (3), wherein the linker is a biological protein. (5) The diagnostic agent delivery composition according to (4), wherein the linker is human serum albumin or bovine serum albumin. (6) The sugar chain-modified liposome is hydrophilized by binding a hydrophilic compound to at least one of the liposome membrane or the linker, according to any one of (1) to (5), Diagnostic agent delivery composition. (7) The diagnostic drug delivery composition according to any one of (1) to (6), wherein the liposome and the sugar chain are bound by a peptide bond. (8) The diagnostic drug delivery composition according to (3), wherein the ganglioside on the liposome membrane and the linker are covalently bonded, and the end of the linker is bonded by a peptide bond. (9) The hydrophilic compound is a low molecular weight hydrophilic compound, preferably a low molecular weight hydrophilic compound having at least one OH group, more preferably a low molecular weight hydrophilic compound having at least two OH groups. The diagnostic agent delivery composition according to (6) or (7), characterized in that it is a tris (hydroxyalkyl) aminoalkane. (10) The diagnostic agent delivery composition according to any one of (1) to (9), wherein the diagnostic agent is a cancer diagnostic agent or an anti-inflammatory diagnostic agent. (11) The diagnostic agent delivery composition according to any one of (1) to (10), wherein the diagnostic agent is a radioactive diagnostic agent. (12) The diagnostic agent delivery composition according to any one of claims 1 to 10, wherein the diagnostic agent is a fluorescent diagnostic agent. (13) The diagnostic agent delivery composition according to any one of (1) to (12), wherein the diagnostic agent delivery composition is orally administered. (14) The diagnostic agent delivery composition according to any one of (1) to (12), wherein the diagnostic agent delivery composition is administered intravenously.

The present invention makes it possible to develop and put into practical use a delivery system that effectively delivers a diagnostic agent in the body. Such a diagnostic agent delivery composition that is effectively delivered to a diagnostic site by oral administration or intravenous infusion is provided for the first time by the present invention.

FIG. 2 is a production schematic diagram of a sugar chain-modified liposome that can be used in the present invention. FIG. 2 is a graph showing the antitumor effect in tumor-bearing mice after intravenous dosing of doxorubicin-encapsulated liposome No. 155. FIG. 3 is a fluorescence micrograph showing the effect of doxorubicin accumulation from tumor blood vessels to tumor tissues in tumor-bearing mice after intravenous injection of doxorubicin-encapsulated liposome # 155. The left and right images are green and red fluorescence micrographs of the same tumor tissue, respectively. FIG. 4 is a diagram showing the anticancer effect in cancer-bearing mice by oral administration of doxorubicin-encapsulated liposome No. 237. FIG. 5 is a fluorescence micrograph showing the effect of doxorubicin accumulation from tumor blood vessels to tumor tissues in tumor-bearing mice after oral administration of doxorubicin-encapsulated liposome No. 237. The left and right images are green and red fluorescence micrographs of the same tumor tissue, respectively. FIG. 6 is a graph when calculating the IC50. The X-axis shows the concentration of the target drug, and the Y-axis shows the amount of bound ligand.

Hereinafter, the present invention will be described with reference to the best mode. Throughout this specification, it should be understood that the singular forms also include the plural concept unless specifically stated otherwise. Thus, it should be understood that singular articles (eg, “a”, “an”, “the”, etc. in the case of English) also include the plural concept unless otherwise stated. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the above field unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.

The embodiments provided below are provided for a better understanding of the present invention, and it is understood that the scope of the present invention should not be limited to the following description. Therefore, it is obvious that those skilled in the art can make appropriate modifications within the scope of the present invention with reference to the description in the present specification.

Hereinafter, definitions of terms particularly used in the present specification will be described as appropriate.

In the present specification, the “sugar chain” refers to a compound formed by connecting one or more unit sugars (monosaccharide and / or a derivative thereof). When two or more unit sugars are connected, each unit sugar is bound by dehydration condensation by a glycosidic bond. Examples of such sugar chains include polysaccharides (glucose, galactose, mannose, fucose, xylose, N-acetylglucosamine, N-acetylgalactosamine, sialic acid, and complexes and derivatives thereof) contained in the living body. Other examples include, but are not limited to, a wide range of sugar chains that are decomposed or derived from complex biomolecules such as degraded polysaccharides, glycoproteins, proteoglycans, glycosaminoglycans, and glycolipids. Therefore, in the present specification, the sugar chain can be used interchangeably with “polysaccharide”, “carbohydrate”, and “carbohydrate”. Further, unless otherwise specified, the “sugar chain” in the present specification may include both sugar chains and sugar chain-containing substances. Typically, a substance in which about 20 types of monosaccharides (glucose, galactose, mannose, fucose, xylose, N-acetylglucosamine, N-acetylgalactosamine, sialic acid, and complexes and derivatives thereof) are connected in a chain. It is attached to proteins and lipids inside and outside the body of cells. The functions differ depending on the sequence of monosaccharides, and they are usually branched in a complex manner. The human body is expected to have several hundreds of sugar chains with various structures, and there are tens of thousands of useful structures in the human body. It is believed that there are more than types. Although it is considered to be related to higher-order functions that proteins and lipids perform in vivo, such as intercellular molecular / cell recognition functions, there are many unexplained mechanisms. It is attracting attention in the current life science as a third life chain after nucleic acid and protein. In particular, the function of a sugar chain as a ligand (information molecule) in cell recognition is expected, and its application to the development of highly functional materials is being studied.

As used herein, “sugar” or “monosaccharide” refers to polyhydroxyaldehyde or polyhydroxyketone containing at least one hydroxyl group and at least one aldehyde group or ketone group, and constitutes the basic unit of a sugar chain. In this specification, sugar is also referred to as carbohydrate and both are used interchangeably. In this specification, when specifically mentioned, a sugar chain refers to a chain or a sequence in which one or more sugars are linked, and when referred to as a sugar or a monosaccharide, it refers to one unit constituting the sugar chain. Here, those in which n = 2, 3, 4, 5, 6, 7, 8, 9 and 10 are referred to as diose, triose, tetrose, pentose, hexose, heptose, octose, nonose and decourse, respectively. Generally, it corresponds to an aldehyde or ketone of a chain polyhydric alcohol. The former is called aldose and the latter is called ketose. In the present invention, any type can be used.

The nomenclature and abbreviations used to describe sugars in the present invention follow conventional nomenclature. For example, β-D-galactose

Is Gal; N-acetyl-α-D-galactosamine

Is GalNAc; α-D-mannose

Is Man; β-D-glucose

Is Glc; N-acetyl-β-D-glucosamine

Is GlcNAc; α-L-fucose

Is Fuc; α-N-acetylneuraminic acid

Neu5Ac; Ceramide

Is Cer; L-serine CH ₂ (OH) CH (COOH) NH ₂ is represented by Ser. Cer is usually classified as a lipid, but in the present specification, it is also treated as a sugar unless otherwise specified because it also falls within the definition of a kind of sugar constituting a sugar chain. In addition, Ser is usually classified as an amino acid, but in the present specification, it is also treated as a saccharide unless otherwise mentioned because it also falls within the definition of a kind of saccharide constituting a glycan. Two cyclic anomers are represented by α and β. It may be expressed as a or b for display reasons. Accordingly, in the present specification, α and a, and β and b are used interchangeably for the anomeric notation.

In this specification, galactose refers to any isomer, but is typically β-D-galactose, and is used to refer to β-D-galactose unless otherwise specified.

In this specification, acetylgalactosamine refers to any isomer, but is typically N-acetyl-α-D-galactosamine, and refers to N-acetyl-α-D-galactosamine unless otherwise specified. Used as a thing.

In this specification, mannose refers to any isomer, but is typically α-D-mannose, and is used to refer to α-D-mannose unless otherwise specified.

In this specification, glucose refers to any isomer, but is typically β-D-glucose, and is used to refer to β-D-glucose unless otherwise specified.

In this specification, acetylglucosamine refers to any isomer, but is typically N-acetyl-β-D-glucosamine, and unless otherwise specified, refers to N-acetyl-β-D-glucosamine. Used as a thing.

In this specification, fucose refers to any isomer, but is typically α-L-fucose, and is used to refer to α-L-fucose unless otherwise specified.

In this specification, acetylneuraminic acid refers to any isomer, but is typically α-N-acetylneuraminic acid, and unless otherwise specified refers to α-N-acetylneuraminic acid. Used as.

In the present specification, serine refers to any isomer, but is typically L-serine, and is used to refer to L-serine unless otherwise specified.

In this specification, it is noted that the symbol, designation, abbreviation (Glc, etc.), etc. of sugars are different when they represent monosaccharides and when used in sugar chains. In the sugar chain, the unit sugar exists in a form in which hydrogen or a hydroxyl group is removed from the other side because dehydration condensation occurs between the unit sugar and another unit sugar to be bound. Therefore, when these sugar abbreviations are used to represent monosaccharides, all hydroxyl groups are present, but when used in a sugar chain, the hydroxyl groups of the sugars to which the hydroxyl groups are bound are dehydrated. It is understood that only oxygen remains after condensation.

When a sugar is covalently bonded to albumin, the reducing end of the sugar is aminated and can be bound to other components such as albumin via its amine group, in which case the hydroxyl group at the reducing end is an amine group. Note that it has been replaced with.

Monosaccharides are generally joined by glycosidic bonds to form disaccharides and polysaccharides. The bond orientation with respect to the plane of the ring is indicated by α and β. Specific carbon atoms that form a bond between two carbons are also described.

In this specification, the sugar chain is

It is represented by Thus, for example, the β glycosidic bond between C-1 of galactose and C-4 of glucose is represented by Galβ1,4Glc.

The branch of the sugar chain is represented by parentheses and is described by being placed immediately to the left of the unit sugar to be bound. For example,

And in parentheses are

It is written. Thus, for example, when β-glycosidic bond is formed between C-1 of galactose and C-4 of glucose, and C-3 of glucose is further α-glycoside bonded to C-1 of fucose, Galβ1,4 ( It is expressed as Fucα1,3) Glc. Monosaccharides are represented on the basis of numbering as low as possible to (latent) carbonyl groups. Even when an atomic group superior to a (latent) carbonyl group is introduced into a molecule according to the general standard of organic chemical nomenclature, it is usually represented by the above numbering.

Examples of the sugar chain used in the present specification include a sugar chain having at least one unit sugar selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc, Fuc, Neu5Ac and Ser. As such a sugar chain, for example,
Neu5Aca2,3Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Fuca1,2Galb1,4 (Fuca1,3) Glc,
Neu5Aca2,3Galb1,4Glc,
Galb1,3GalNAcb1,4 (Neu5Aca2,8Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Galb1,4GlcNAc,
GalNAca1,3 (Fuca1,2) Gal,
3 '-(O-SO3H) Galb1,4 (Fuca1,3) GlcNAc,
Fuca1,2Gal,
Mana1,2Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Fuca1,2Galb1,3GlcNAcb1,3Galb1,4Glc,
Mana1,2Mana1,6 (Mana1,2Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Neu5Aca2,6Galb1,4GlcNAc,
Galb1,3GalNAcb1,4Galb1,4Glcb1,1Cer + Neu5Aca2,3Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Galb1,3 (Fuca1,4) GlcNAcb1,3Galb1,4Glc,
Galb1,3GlcNAcb1,3Galb1,4Glc,
Gala1,3 (Fuca1,2) Gal,
Galb1,3GalNAc,
Galb1,6GlcNAc,
Mana1,6 (Mana1,3) Man,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Galb1,3GlcNAc,
Mana1,2Man,
Galb1,4 (Fuca1,3) GlcNAc,
Gala1,3Gal,
Fuca1,2Galb1,4Glc,
Mana1,6 (Mana1,3) Mana1,6Manb1,4GlcNAcb1,4GlcNAc,
Galb1,4 (Fuca1,3) Glc,
GalNAca1-OL-serine,
Neu5Aca2,3Galb1,4 (Fuca1,3) GlcNAc,
Fuca1,2Galb1,4 (Fuca1,3) GlcNAc,
Galb1,4Glc,
Mana1,6Man,
Neu5Aca2,6GalNAca1-OL-serine,
Mana1,6 (Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Fuca1,2Galb1,3 (Fuca1,4) GlcNAc,
Mana1,4Man,
Neu5Ac2,6GalNAca1-OL-serine,
Neu5Aca2,6Galb1,4Glc,
Fuca1,2Galb1,3 (Fuca1,4) GlcNAcb1,3Galb1,4Glc,
Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Mana1,3Man,
Neu5Aca2,3Galb1,3 (Fuca1,4) GlcNAc,
3 '-(O-SO3H) Galb1,3 (Fuca1,4) GlcNAc,
Neu5Aca2,3Galb1,4GlcNAc,
Galb1,3 (Fuca1,4) GlcNAc,
And sugar chains selected from the group consisting of combinations of two or more thereof, but are not limited thereto. The reason why two or more combinations can be used is not limited by theory, but each of the sugar chains has specificity for a lectin localized in the tissue or cell of the target delivery site, and is mixed. This is because it is considered that the specificity is exhibited.

In the present specification, a combination of sugar chains is represented by inserting “+” between the sugar chains contained. For example, Galβ1,3GalNAcβ1,4Galβ1,4Glcβ1,1Cer + Neu5Acα2,3Galβ1,3GalNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer (liposome number 67) and Galβ1,3GalNAcβ1,4Gcβ1,4Gc , 3Galβ1,3GalNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer is included in a mixed manner.

(Liposome) In the present specification, the “liposome” usually means a closed vesicle composed of a lipid layer assembled in a film shape and an inner aqueous layer. In addition to phospholipids typically used, cholesterol, glycolipids and the like can also be incorporated. Since liposomes are closed vesicles containing water inside, it is possible to retain water-soluble drugs and the like in the vesicles. Therefore, such liposomes are used to deliver drugs and genes that cannot pass through the cell membrane into the cell. Moreover, since biocompatibility is good, the expectation as a nanoparticulate carrier material for DDS is great.

The liposome can be prepared by any technique known in the art. For example, among them, a method using a cholic acid dialysis method is exemplified. In the cholate dialysis method, production is carried out by a) preparation of mixed micelles of lipid and surfactant, and b) dialysis of mixed micelles. Next, in a preferred embodiment of the sugar chain liposome of the present invention, it is preferable to use a protein as a linker, and the coupling of a glycoprotein having a sugar chain bound to the protein to the liposome can be performed by the following two-step reaction. it can. a) periodate oxidation of the ganglioside moiety on the liposome membrane, and b) coupling of the glycoprotein to the oxidized liposome by reductive amination reaction. An example of the reaction flow is shown in FIG. By such a technique, a glycoprotein containing a desired sugar chain can be bound to the liposome, and a wide variety of glycoprotein / liposome conjugates having the desired sugar chain can be obtained. It is very important to examine the particle size distribution to see the purity and stability of the liposomes. As the method, gel filtration chromatography (GPC), scanning electron microscope (SEM), dynamic light scattering (DLS), or the like can be used. Liposomes of the type having a molar ratio of dipalmitoylphosphatidylcholine (DPPC), cholesterol, dicetyl phosphate (DCP), ganglioside 35: 45: 5: 15 can be produced. The liposome is stable even when stored at 4 ° C. for several months. The in vivo stability of liposomes can be examined using mice. Liposomes are intravenously injected into mice, blood is collected after 3 hours to prepare serum, and ultrafiltration is performed using a membrane having a pore size of 0.03 μm to purify and collect the liposomes. As a result of the SEM observation, it can be confirmed that the form of the liposome is not changed before and after the treatment and recovery for 3 hours in vivo.

Examples of the lipid constituting the sugar chain-modified liposome of the present invention include phosphatidylcholines, phosphatidylethanolamines, phosphatidic acids, long-chain alkyl phosphates, glycolipids (gangliosides, etc.), phosphatidylglycerols, sphingomyelins And cholesterols.

Examples of the phosphatidylcholines include dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, and the like.

Examples of the phosphatidylethanolamines include dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, and the like.

Examples of the phosphatidic acids include dimyristoyl phosphatidic acid, dipalmitoyl phosphatidic acid, and distearoyl phosphatidic acid. Examples of long chain alkyl phosphates include dicetyl phosphate.

Examples of glycolipids include galactosylceramide, glucosylceramide, lactosylceramide, phosphnatide, globoside, gangliosides and the like. Examples of gangliosides include ganglioside GM1 (Galβ1,3GalNAcβ1,4 (NeuAα2,3) Galβ1,4Glcβ1,1′Cer), ganglioside GDla, ganglioside GTlb, and the like.

As the phosphatidylglycerols, dimyristoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, distearoyl phosphatidylglycerol and the like are preferable.

Of these, phosphatidic acids, long-chain alkyl phosphates, glycolipids, and cholesterols have the effect of increasing the stability of liposomes, and are therefore preferably added as constituent lipids. For example, the lipid constituting the liposome of the present invention is selected from the group consisting of phosphatidylcholines (molar ratio 0 to 70%), phosphatidylethanolamines (molar ratio 0 to 30%), phosphatidic acids, and long-chain alkyl phosphates. One or more selected lipids (molar ratio 0-30%), one or more lipids selected from the group consisting of glycolipids, phosphatidylglycerols and sphingomyelin (molar ratio 0-40%), and What contains cholesterol (molar ratio 0-70%) is mentioned. It is preferred to include a glycolipid such as ganglioside. This is because a linker such as albumin is easily bonded.

In a preferred embodiment, the liposome according to the present invention can contain a ganglioside, to which a linker such as a peptide is bound, and to which a sugar chain is bound.

By combining the glycolipid when preparing the liposome, the sugar chain-modified liposome of the present invention containing the sugar chain contained in the glycolipid as a constituent component can be prepared.

(Sugar chain modified liposome) In one aspect, the present invention provides a sugar chain modified liposome. Conventionally, there has not been provided a target that sufficiently targets a desired target cell or tissue in vivo. The present invention has an effect that targeting that has been impossible with conventional DDS materials becomes possible by providing a sugar chain-modified liposome that is directed to a desired target cell or tissue in a living body. In a specific embodiment, such a sugar chain-modified liposome is bound with a sugar chain having at least one structure selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc, Fuc, Neu5Ac and Ser. Yes.

In the present specification, the “sugar chain-modified liposome” refers to a substance containing a sugar chain and a liposome, and preferably refers to a liposome that is modified by binding a sugar chain directly or indirectly. Specifically, the form in which the sugar chain is bound to the liposome is represented by S- (M) -L (S: sugar chain, M: linker (may or may not be present), L: liposome, −: covalent bond Such a linkage or cross-linking agent (eg, 3,3′-dithiobis (sulfosuccinimidyl propionate) (DTSSP)).

When ganglioside is put in a liposome, the sugar chain-modified liposome of the present invention is represented by SM-GS-L (GS: sugar chain part of ganglioside).

More specifically, in this specification, “the liposome proximal end of the sugar chain” of the sugar chain-modified liposome refers to the terminal part of the sugar chain that is most proximal to the liposome. When the sugar chain is branched, all the corresponding end portions are called proximal ends. The sugar at the liposome proximal end of the sugar chain is preferably Gal, GalNAc, Man, Glc, GlcNAc, Ser or Cer, and in certain preferred embodiments, Ser or Cer.

The “liposomal proximal end of the sugar chain” refers to the sugar (monosaccharide) that is most proximal to the liposome. Therefore, in the present specification, when “the sugar chain consisting of two or more disaccharides is included in the liposome proximal end of the sugar chain”, the liposome proximal end of the sugar chain is at the most proximal end of the sugar chain. In addition to sugars (monosaccharides), other sugars (monosaccharides, which may be the same as or different from the sugar at the most proximal end) contained in a sugar chain composed of the above disaccharides or more. It is understood that it is included.

In the present specification, the “liposome distal end of the sugar chain” of the sugar chain-modified liposome refers to the terminal portion of the sugar chain that is most distal to the liposome. When the sugar chain is branched, all the corresponding end portions are called the distal ends. The sugar at the liposome distal end of the sugar chain is preferably Gal, 3 ′-(O—SO ₃ H) Gal, GalNAc, Man and Fuc or Neu5Ac, and in certain preferred embodiments, 3 ′-(O a -SO ₃ H) Gal.

“The most distal end of the liposome of the sugar chain” refers to the sugar (monosaccharide) that is the most distal to the liposome. Therefore, in the present specification, when “the sugar chain consisting of two or more disaccharides is included in the liposome distal end of the sugar chain”, the liposome distal end of the sugar chain is located at the most distal end of the liposome of the sugar chain. In addition to a certain sugar (monosaccharide), the other sugar (monosaccharide; contained in the sugar chain consisting of the above-mentioned disaccharides or more) may be the same as or different from the most distal sugar. ) Is also included.

In certain preferred embodiments, the sugar chain-modified liposome of the present invention may have a specific sugar chain pattern regardless of location. “Sugar chain pattern” refers to a pattern determined by the type, bond, and anomer of a specific sugar chain. This sugar chain pattern is a preferable sugar chain pattern for passing through the intestinal mucosa. Without being bound by theory, it is believed that the inclusion of a specific “compatible” pattern of sugar chains somewhere makes it easier to get on the absorption pathway by the pumps present in the intestinal mucosa. In the present invention, as a result of systematic investigation, it was found that "the oral absorption is good" when the following sugar chain pattern is included.

Examples of sugar chain patterns that may have a specific sugar chain pattern regardless of the location include, but are not limited to, the following: The sugar chain of the sugar chain-modified liposome has the following structure: R ¹ -X ^1- X ² -R ² , wherein R ¹ and R ² are independently hydrogen or any sugar chain, and X ¹ is Fuc, GalNAc, Gal 3 ′-(O—SO ₃ H) Gal, GlcNAc, Man and Neu5Ac, and the X ² is selected from the group consisting of Gal, Glc, GlcNAc, Ser, GalNAc, Cer and Man The sugar chain of the sugar chain-modified liposome has the following structure: R ¹ -X ¹ -X ² -X ³ -R ² , where R ¹ and R ² are independently , Hydrogen, Other is any sugar chain, wherein ^{X 1} is Fuc, Gal, GalNAc, GlcNAc, is selected from the group consisting of Man and Neu5Ac, and said ^{X 2} are selected from the group consisting Gal, GlcNAc, from GalNAc and Man And X ³ is selected from the group consisting of Glc, GlcNAc, Gal, GalNAc, Ser, Cer and Man; the sugar chain of the sugar chain-modified liposome has the following structure: R ¹ -X ^1- X ² -X ³ -X ⁴ -R ² , wherein R ¹ and R ² are independently hydrogen or any sugar chain, and X ¹ is Fuc , Gal, is selected from the group consisting of Neu5Ac and Man, and said ^{X 2} is, Gal, GalNAc, is selected from the group consisting of GlcNAc and Man, X ³ is, GlcNAc, GalNAc, is selected from the group consisting of Gal and Man, and said ^{X 4} are, Gal, Glc, Man, is selected from the group consisting of Cer and GlcNAc, pattern; sugar carbohydrate-modified liposome Has the following structure: R ¹ -X ¹ -X ² -X ³ -X ⁴ -X ⁵ -R ² , wherein R ¹ and R ² are independently hydrogen , or any sugar chain, wherein ^{X 1} is Fuc, is selected from the group consisting of Neu5Ac and Man, the ^{X 2} is Gal or Man, the ^{X 3} is GlcNAc, the group consisting of GalNAc and Man The X ⁴ is selected from the group consisting of Gal, GlcNAc and Man, and the X ⁵ is selected from the group consisting of Glc, Cer and GlcNAc The sugar chain of the sugar chain-modified liposome has the following structure: R ¹ -X ¹ -X ² -X ³ -X ⁴ -X ⁵ -X ⁶ -R ^{2 1} and the R ² are independently hydrogen or any sugar chain, the X ¹ is Man or Neu5Ac, the X ² is Man or Gal, and the X ³ is , Man or GalNAc, the X ⁴ is Man or Gal, the X ⁵ is GlcNAc or Glc, and the X ⁶ is GlcNAc or Cer.

In certain preferred embodiments, the sugar chain-modified liposome of the present invention may have a specific sugar chain pattern on the distal end side of the liposome. Without being bound by theory, it is considered that the sugar chain structure on the distal end side of the liposome is characterized by being easily recognized by the intestinal mucosa because it exists outside the sugar chain-modified liposome. In the present invention, a systematic investigation revealed that the following sugar chain patterns are easily recognized by the intestinal mucosa and are suitable for oral administration.

Examples of the sugar chain pattern that can have a specific sugar chain pattern on the distal end side of the liposome include, but are not limited to, the following: The liposome distal end of the sugar chain of the sugar chain-modified liposome is from position end side, the following ^structure: Fuc 1 ^-A have 2 -R ^Z, wherein either said ^{a 2} is Gal, is selected from the group consisting of Glc and GlcNAc, and said ^{R Z} is hydrogen Or a sugar chain, a pattern; the liposome distal end of the sugar chain of the sugar chain-modified liposome has the following structure: Fuc ¹ -A ² -A ³ -R ^Z from the distal end side Where A ² is Gal or GlcNAc, A ³ is selected from the group consisting of Glc, Gal and GlcNAc, and the R ^Z is hydrogen or any sugar chain, Pattern; Glycosylation Liposomes distal end of the sugar chain of liposomes is from distal end side, the following ^structure: Fuc ¹ -A ² -A 3 has ^-A 4 -R ^Z, wherein said ^{A 2} are, Gal or GlcNA The A ³ is Gal or GlcNA, the A ⁴ is Gal or Glc, and the R ^Z is hydrogen or an arbitrary sugar chain; a sugar chain-modified liposome The liposome distal end of the sugar chain has the following structure: Fuc ¹ -A ² -A ³ -A ⁴ -A ⁵ -R ^Z from the distal end side, where A ² is Gal The A ³ is GlcNA, the A ⁴ is Gal, the A ⁵ is Glc, and the R ^Z is hydrogen or any sugar chain, The liposome distal end of the sugar chain of the sugar chain-modified liposome is ^Structure: Gal 1 ^-B has 2 -R ^Z, wherein the Gal ¹ may not be sulfated also be sulfated, the ^{B 2} is Gal, GalNAc, from GlcNAc and Glc A pattern selected from the group consisting of: ^RZ is hydrogen or any sugar; the liposome distal end of the sugar chain of the sugar chain-modified liposome has the following structure from the distal end side: : Gal ¹ -B ² -B ³ -R ^Z , wherein said Gal ¹ may be sulfated or non-sulfated, said B ² is GalNAc or GlcNAc, B ³ is Gal and the R ^Z is hydrogen or any sugar pattern; the liposome distal end of the sugar chain of the sugar chain-modified liposome is less than the distal end side Structure: Gal ¹ -B ² -B ^3- B ⁴ -R ^Z , where the Gal ¹ may be sulfated or unsulfated, the B ² is GalNAc or GlcNAc, and the B ³ is Gal , The B ⁴ is Glc, and the R ^Z is hydrogen or any sugar, the pattern; the liposome distal end of the sugar chain of the sugar chain-modified liposome is more than the distal end side And the following structure: Gal ¹ -B ² -B ³ -B ⁴ -B ⁵ -R ^Z , wherein Gal ¹ may be sulfated or non-sulfated, ² is GalNAc, the B ³ is Gal, the B ⁴ is Glc, the B ⁵ is Cer, and the R ^Z is hydrogen or any sugar A pattern; the liposome distal end of the sugar chain of the sugar chain-modified liposome is located on the distal end side Ri, the following structures: GalNAc ¹ -C have ² -R ^Z, wherein the ^{C 2} is Gal or Ser, and said ^{R Z} is hydrogen or is any sugar pattern The liposome distal end of the sugar chain of the sugar chain-modified liposome has the following structure from the distal end side: Man ¹ -D ² -R ^Z , where D ² is Man; The R ^Z is hydrogen or an arbitrary sugar pattern; the liposome distal end of the sugar chain of the sugar chain-modified liposome has the following structure from the distal end side: Man ¹ -D ^2- has a D ³ -R ^Z, wherein said ^{D 2} is a Man, the ^{D 3} is GlcNAc or Man, and wherein ^{R Z} is hydrogen or is any sugar pattern The liposome distal end of the sugar chain of the sugar chain-modified liposome is on the distal end side; Ri, the following ^{structure: Man 1 -D 2 -D 3 -D} 4 has a -R ^Z, wherein said ^{D 2} is a Man, the ^{D 3} is a Man or GlcNAc, the ^{D 4} is , Man or GlcNAc, and the R ^Z is hydrogen or any sugar pattern; the liposome distal end of the sugar chain of the sugar chain-modified liposome is It has the structure: Man ¹ -D ² -D ³ -D ⁴ -D ⁵ -R ^Z , where the D ² is Man, the D ³ is Man, and the D ⁴ is Man or GlcNAc, the D ⁵ is GlcNAc, and the R ^Z is hydrogen or any sugar pattern; the liposome distal end of the sugar chain of the sugar chain-modified liposome is the distal From the end side, the following structure: Man ¹ -D ² -D ³ -D ⁴ Has -D ⁵ -D ⁶ -R ^Z, wherein said ^{D 2} is a Man, the ^{D 3} is Man, the ^{D 4} is Man, the ^{D 5} is an GlcNAc , The D ⁶ is GlcNAc, and the R ^Z is hydrogen or any sugar, a pattern; the liposome distal end of the sugar chain of the sugar chain-modified liposome is more than the distal end side Having the following structure: Neu5Ac ¹ -E ² -R ^Z , wherein E ² is Gal or GalNAc and the R ^Z is hydrogen or any sugar, pattern; The liposome distal end of the sugar chain of the sugar chain-modified liposome has the following structure: Neu5Ac ¹ -E ² -E ³ -R ^Z from the distal end side, where E ² is Gal or GalNAc. , and the the ^{E 3} are, GlcNAc, Glc, GalN It is selected from the group consisting of c and Ser, and said R ^Z is hydrogen or is any sugar pattern; liposomes distal end of the sugar chains of sugar-modified liposome, than the distal end side Having the following structure: Neu5Ac ¹ -E ² -E ³ -E ⁴ -R ^Z , wherein E ² is Gal, and E ³ is selected from the group consisting of Glc and GalNAc, E ⁴ is selected from the group consisting of Gal and Cer, and the R ^Z is hydrogen or any sugar, the pattern; the liposome distal end of the sugar chain of the sugar chain-modified liposome is From the distal end side, it has the following structure: Neu5Ac ¹ -E ² -E ³ -E ⁴ -E ⁵ -R ^Z , where E ² is Gal, and E ³ is GalNAc, the ^{E 4} is Gal, the ^{E 5} is, G a c, and the R ^Z is hydrogen or is any sugar pattern; liposomes distal end of the sugar chains of sugar-modified liposome, from distal end side, the following structure: Neu5Ac ^{1 -E 2 -E 3 -E 4 -E} 5 -E have ⁶ -R ^Z, wherein the ^{E 2} is Gal, the ^{E 3} is a GalNAc, the ^{E 4} is a Gal Yes, the E ⁵ is Glc, the E ⁶ is Cer, and the R ^Z is hydrogen or any sugar.

In certain preferred embodiments, the sugar chain-modified liposome of the present invention may have a specific sugar chain pattern on the proximal end side of the liposome. Although this sugar chain pattern is on the liposome side and is not bound by theory, it is considered that the sugar chain pattern itself is fixed and the recognition by the intestinal mucosa is made stable, so that the absorbability is improved. Furthermore, it is considered that the stability of the liposomes by having these structural patterns also contributes to the improvement of oral absorption.

Examples of the sugar chain pattern that may have a specific sugar chain pattern on the proximal end side of the liposome include, but are not limited to, the following: The liposome proximal end of the sugar chain of the sugar chain-modified liposome is It has the structure R ¹ -F ² -GlcNAc ³ , where the R
¹ is independently hydrogen or any sugar chain, and the F ² is selected from the group consisting of Gal, Fuc, GlcNAc and 3 ′-(O—SO ₃ H) Gal, The GlcNAc ³ is present at the proximal end of the liposome, the pattern; the liposome proximal end of the sugar chain of the sugar chain-modified liposome has the following structure: R ¹ -F ² -F ³ -GlcNAc ⁴ Wherein R ¹ is independently hydrogen or any sugar chain, the F ² is a sugar selected from Man, Fuc and Neu5Ac, and the F ³ is Gal or GlcNAc Wherein the GlcNAc ⁴ is present at the most proximal end of the liposome, the pattern; the liposome proximal end of the sugar chain of the sugar chain modified liposome has the following structure: R ¹ -F ² -F ³ -F ⁴ -GlcNAc ⁵ And, wherein said ^{F 1} is independently a hydrogen, or any sugar chain, wherein ^{F 2} is a Man, the ^{F 3} is Man, the ^{F 4} is GlcNAc , and the wherein the GlcNAc ⁵ is present in the proximal-most end of the liposomes, the pattern; liposome proximal end of the sugar chains of sugar-modified liposome, the following ^{structure: R 1 -F 2 -F 3 -F} 4 - F ⁵ -GlcNAc ⁶ wherein R ¹ is independently hydrogen or any sugar chain, F ² is Man, and F ³ is Man The F ⁴ is Man and the F ⁵ is GlcNAc, where the GlcNAc ⁶ is present at the proximal end of the liposome; the liposome proximal end of the sugar chain of the sugar chain-modified liposome is the following ^{structure: R 1 -F 2 -F 3 -F} 4 -F 5 - Has ⁶ -GlcNAc ^7, wherein said ^{R 1} is independently a hydrogen, or any sugar chain, wherein ^{F 2} is a Man, the ^{F 3} is Man, The F ⁴ is Man, the F ⁵ is Man and the F ⁶ is GlcNAc, where the GlcNAc ⁷ is present at the proximal end of the liposome; The liposome proximal end of the chain has the following structure: R ¹ -G ² -Gal ³ where the R ¹ is independently hydrogen or any sugar chain and the G ² is selected from the group consisting of Fuc, Gal and GalNac, where Gal ³ is present at the proximal end of the liposome, the pattern; the liposome proximal end of the sugar chain of the sugar chain modified liposome has the following structure: R has ¹ -H ² -GalNAc ^3, Kode該^{R 1} is independently a hydrogen, or any sugar chain, and said ^{H 2} is Gal, where GalNAc ³ is present in the proximal-most end of the liposomes, the pattern; The liposome proximal end of the sugar chain of the sugar chain-modified liposome has the following structure: R ¹ -I ² -Ser ³ where R ¹ is independently hydrogen or any sugar A chain, and the I ² is GalNAc, where Ser ³ is present at the proximal end of the liposome, the pattern; the liposome proximal end of the sugar chain of the sugar chain-modified liposome has the following structure: R ¹ -I ² -I ³ -Ser ⁴ where R ¹ is independently hydrogen or any sugar chain, and the I ² is Neu5Ac, and the I ³ It is a GalNAc, here Ser ⁴ liposomes Present in the most proximal end, the pattern; liposome proximal end of the sugar chains of sugar-modified liposome, the following ^structure: have R ¹ -J 2 -Glc ^3, wherein said ^{R 1} is independently hydrogen or where is any sugar chains, and the J ² is Gal or Fuc, wherein Glc ³ is present in the proximal-most end of the liposomes, the pattern; sugar chain of liposomes sugar-modified liposome The proximal end has the following structure: R ¹ -J ² -J ³ -Glc ⁴ where R ¹ is independently hydrogen or any sugar chain, and J ² is selected from the group consisting of Fuc, GlcNAc and Neu5Ac, wherein J ³ is Gal, wherein Glc ⁴ is present at the proximal end of the liposome; the sugar chain of the sugar chain modified liposome The proximal end of the liposome is ^Structure: have ^{R 1 -J 2 -J 3 -J 4} -Glc 5, wherein said ^{R 1} is independently a hydrogen, or any sugar chain, and said ^{J 2} is , Fuc or Gal, wherein J ³ is GlcNAc, and J ⁴ is Gal, where Glc ⁵ is present at the most proximal end of the liposome; the liposome of the sugar chain of the sugar chain-modified liposome The proximal end has the following structure: R ¹ -J ² -J ³ -J ⁴ -J ⁵ -Glc ⁶ where R ¹ is independently hydrogen or any sugar The J ² is Fuc, the J ³ is Gal, the J ⁴ is GlcNAc or GalNAc, and the J ⁵ is Gal, where Glc ⁶ is the most recent of the liposome Pattern present at the distal end; liposo of sugar chain of sugar chain-modified liposome The proximal end of the helix has the following structure: R ¹ -K ² -Man ³ , where R ¹ is independently hydrogen or any sugar chain, and the K ² is Man, where Man ³ is present at the proximal end of the liposome, the pattern; the liposome proximal end of the sugar chain of the sugar chain modified liposome has the following structure: R ¹ -L ² -Cer ³ Wherein R ¹ is independently hydrogen or any sugar chain, and the L ² is Glc, where Cer ³ is present at the proximal end of the liposome , Pattern; the liposome proximal end of the sugar chain of the sugar chain-modified liposome has the following structure: R ¹ -L ² -L ³ -Cer ⁴ where R ¹ is independently hydrogen Or any sugar chain, and the L ² is Gal and the L ³ is Glc Yes, where Cer ⁴ is present at the proximal end of the liposome, pattern; the liposome proximal end of the sugar chain of the sugar chain modified liposome has the following structure: R ¹ -L ² -L ³ -L ⁴ -Cer ⁵ Where R ¹ is independently hydrogen or any sugar chain, and the L ² is GalNAc or Neu5Ac, the L ³ is Gal, and L ⁴ is Glc, where Cer ⁵ is present at the proximal end of the liposome, the pattern; the liposome proximal end of the sugar chain of the sugar chain modified liposome has the following structure: R ¹ -L ² -L ³ -L ⁴ -L ⁵ -Cer ⁶ wherein R ¹ is independently hydrogen or any sugar chain, the L ² is Gal, and the L ³ is a GalNAc, the ^{L 4} represents a Gal, the ^{L 5} represents, G a c, where Cer ⁶ is present in the most proximal end of the liposomes, the pattern; liposome proximal end of the sugar chains of sugar-modified liposome, the following ^{structure: R 1 -L 2 -L 3 -L} 4 - L ⁵ -L ⁶ -Cer ⁷ wherein R ¹ is independently hydrogen or any sugar chain, L ² is Neu5Ac, and L ³ is Gal, the L ⁴ is GalNac, the L ⁵ is Gal, the L ⁶ is Glc, where Cer ⁷ is at the proximal end of the liposome.

In certain preferred embodiments, the sugar chain-modified liposome of the present invention may have a specific sugar at both ends. Without being bound by theory, it is considered that the presence of a specific sugar increases the affinity of the sugar chain for the intestinal mucosa and improves the stability of the liposome, which also contributes to the improvement of oral absorption.

Examples of the pattern that may have a specific sugar at both ends include, but are not limited to, the following: The sugar at the most proximal end of the liposome of the sugar chain is Glc or GlcNAc, and A pattern in which the sugar at the distal end is Gal or Fuc; The sugar at the most proximal end of the liposome in the sugar chain is GlcNAc, and the sugar at the most distal end of the liposome in the sugar chain is Man.

Examples of the sugar chain-modified liposome used herein include, but are not limited to,
Neu5Aca2,3Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Fuca1,2Galb1,4 (Fuca1,3) Glc,
Neu5Aca2,3Galb1,4Glc,
Galb1,3GalNAcb1,4 (Neu5Aca2,8Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Galb1,4GlcNAc,
GalNAca1,3 (Fuca1,2) Gal,
3 '-(O-SO3H) Galb1,4 (Fuca1,3) GlcNAc,
Fuca1,2Gal,
Mana1,2Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Fuca1,2Galb1,3GlcNAcb1,3Galb1,4Glc,
Mana1,2Mana1,6 (Mana1,2Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Neu5Aca2,6Galb1,4GlcNAc,
Galb1,3GalNAcb1,4Galb1,4Glcb1,1Cer + Neu5Aca2,3Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Galb1,3 (Fuca1,4) GlcNAcb1,3Galb1,4Glc,
Galb1,3GlcNAcb1,3Galb1,4Glc,
Gala1,3 (Fuca1,2) Gal,
Galb1,3GalNAc,
Galb1,6GlcNAc,
Mana1,6 (Mana1,3) Man,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Galb1,3GlcNAc,
Mana1,2Man,
Galb1,4 (Fuca1,3) GlcNAc,
Gala1,3Gal,
Fuca1,2Galb1,4Glc,
Mana1,6 (Mana1,3) Mana1,6Manb1,4GlcNAcb1,4GlcNAc,
Galb1,4 (Fuca1,3) Glc,
GalNAca1-OL-serine,
Neu5Aca2,3Galb1,4 (Fuca1,3) GlcNAc,
Fuca1,2Galb1,4 (Fuca1,3) GlcNAc,
Galb1,4Glc,
Mana1,6Man,
Neu5Aca2,6GalNAca1-OL-serine,
Mana1,6 (Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Fuca1,2Galb1,3 (Fuca1,4) GlcNAc,
Mana1,4Man,
Neu5Ac2,6GalNAca1-OL-serine,
Neu5Aca2,6Galb1,4Glc,
Fuca1,2Galb1,3 (Fuca1,4) GlcNAcb1,3Galb1,4Glc,
Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Mana1,3Man,
Neu5Aca2,3Galb1,3 (Fuca1,4) GlcNAc,
3 '-(O-SO3H) Galb1,3 (Fuca1,4) GlcNAc,
Neu5Aca2,3Galb1,4GlcNAc,
Galb1,3 (Fuca1,4) GlcNAc,
And liposomes modified with a sugar chain selected from the group consisting of combinations of two or more in any ratio.

As used herein, “liposome number” refers to a number that refers to a sugar chain-modified liposome to which sugar chains are bound as shown in Table 1, Table 2, Table 3, and Table 4 below.

The sugar chain-modified liposome used in the present specification may contain, for example, the sugar chains shown in Table 1 at a density suitable for transferring from the intestinal tract into the blood.

As used herein, “modified bond density” is the amount of sugar chain used when preparing a sugar chain-modified liposome, and the density of sugar chains bound per mg of liposome lipid (mg sugar). Chain / mg lipid). The binding density of the sugar chain-modified liposome of the present invention is not desired to be bound by theory, but empirically, the amount of sugar chain used for preparation is almost proportional to the density of the sugar chain bound to the liposome. I know that Therefore, in this specification, unless otherwise stated, the bond density is determined by the amount used at the time of preparation. In vitro, for example, it can be determined indirectly using E-selectin. The sugar chain-modified liposome of the present invention can control the directivity with respect to the target delivery site by selecting the type of sugar chain to be bound to the liposome and the binding density. Table 1 below shows liposome numbers, sugar chain structures, modified bond densities, and their oral administration (enteral) directivity.

“++” indicates the average value of liposomes absorbed by the intestinal tract 10 minutes after administration when liposomes (reference liposomes) bound with tris (hydroxymethyl) aminomethane instead of sugar chains were orally administered. It represents 4 to 6 times the value.

“+” Means that when liposomes (reference liposomes) bound with tris (hydroxymethyl) aminomethane instead of sugar chains are orally administered, the average value of liposomes absorbed by the intestinal tract 10 minutes after administration is the average of reference liposomes. It represents 3 to 4 times the value.

Preferably, the sugar chain-modified liposomes suitable for oral administration of the present invention can be prepared using sugar chains and modified bond densities of the types shown in Table 1 above and combinations thereof. Although not bound by theory, once it is found that the target directivity is + or ++, the same effect can be expected even when two or more sugar chains are combined. This is because sugar chains that recognize lectins of target tissues or target cells are recognized as preferable even when combined.

The sugar chain-modified liposomes suitable for oral administration used in the present invention are preferably liposome numbers 27, 29, 40, 45, 50, 53, 56, 67, 68, 69, 70, 71, 87, 105, 117. , 120, 125, 139, 142, 150, 152, 153, 154, 175, 184, 186, 197, 204, 224, 225, 230, 237, 240, 273, 285, 288 or 290.

The sugar chain-modified liposome used in the present specification can contain, for example, the sugar chains shown in Table 2 at a density suitable for delivery to the liver.

As used herein, delivery to the liver refers to delivery to an area spanning the right season buttocks and upper epigastric region beneath the diaphragm.

As used herein, “modified bond density” is the amount of sugar chain used when preparing a sugar chain-modified liposome, and the density of sugar chains bound per mg of liposome lipid (mg sugar). Chain / mg lipid). The binding density of the sugar chain-modified liposome of the present invention is not desired to be bound by theory, but empirically, the amount of sugar chain used for preparation is almost proportional to the density of the sugar chain bound to the liposome. I know that Therefore, in this specification, unless otherwise stated, the bond density is determined by the amount used at the time of preparation. In vitro, for example, it can be determined indirectly using E-selectin. The sugar chain-modified liposome of the present invention can control the directivity with respect to the target delivery site by selecting the type of sugar chain to be bound to the liposome and the binding density. Table 2 below shows the liposome number, sugar chain structure, modified bond density, and liver directivity.

When a liposome to which tris (hydroxymethyl) aminomethane is bound is used as a reference liposome, “++” indicates that the average value of liposomes delivered to the liver 5 minutes after intravenous injection is 1.5 to 2 that is the average value of reference liposomes. This means that it will be 1 time.

When the liposome to which tris (hydroxymethyl) aminomethane is bound is used as the reference liposome, “+” indicates that the average value of the liposome delivered to the liver 5 minutes after intravenous injection is 1.2 to 1 that is the average value of the reference liposome. .5 times increase.

Since liposomes bound with tris (hydroxymethyl) aminomethane have a slight liver directivity, Galβ1,3GalNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer was used as a reference liposome.

Preferably, the sugar chain-modified liposomes suitable for intrahepatic delivery of the present invention can be prepared using the sugar chains and modified bond densities of the types shown in Table 1 above and combinations thereof. Although not bound by theory, once it is found that the target directivity is + or ++, the same effect can be expected even when two or more sugar chains are combined. This is because sugar chains that recognize lectins of target tissues or target cells are recognized as preferable even when combined.

  The sugar chain-modified liposomes suitable for intrahepatic delivery used in the present invention are preferably liposome numbers 3, 16, 22, 27, 29, 37, 38, 41, 53, 67, 70, 91, 96, 106, 111, 117, 130, 139, 146, 150, 151, 152, 154, 178, 183, 184, 195, 199, 209, 218, 225, 229, 230, 234, 236, 239, 240, 285, 290, Or 292.

The sugar chain-modified liposome used in the present specification can contain, for example, the sugar chains shown in Table 3 at a density suitable for delivery into the pancreas.

As used herein, delivery to the pancreas refers to a long lobulated gland with no capsule extending from the duodenal fold to the spleen, a flat head within the duodenum, and an elongated trihedral shape across the abdomen. Refers to delivery to the body and the region across the tail that contacts the spleen.

As used herein, “modified bond density” is the amount of sugar chain used when preparing a sugar chain-modified liposome, and the density of sugar chains bound per mg of liposome lipid (mg sugar). Chain / mg lipid). The binding density of the sugar chain-modified liposome of the present invention is not desired to be bound by theory, but empirically, the amount of sugar chain used for preparation is almost proportional to the density of the sugar chain bound to the liposome. I know that Therefore, in this specification, unless otherwise stated, the bond density is determined by the amount used at the time of preparation. In vitro, for example, it can be determined indirectly using E-selectin. The sugar chain-modified liposome of the present invention can control the directivity with respect to the target delivery site by selecting the type of sugar chain to be bound to the liposome and the binding density. Table 3 below shows the liposome number, sugar chain structure, modified bond density and pancreatic directionality.

.

“++” is delivered into the pancreas 5 minutes after intravenous injection when a liposome (reference liposome) conjugated with Galβ1,3GalNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer is used instead of the sugar chain. It means that the average value of the liposome is 2 to 4 times the average value of the reference liposome.

“+” Is delivered into the pancreas 5 minutes after intravenous injection when a liposome (reference liposome) conjugated with Galβ1,3GalNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer is used instead of the sugar chain. It means that the average value of the liposome is 1 to 2 times the average value of the reference liposome.

When a liposome to which tris (hydroxymethyl) aminomethane is bound is used as a reference liposome, “++” means that the average value of liposomes delivered into the pancreas 5 minutes after intravenous injection is 1.5 to 1.5 times the average value of reference liposomes. This represents a 2.2-fold increase.

When a liposome to which tris (hydroxymethyl) aminomethane is bound is used as a reference liposome, “+” indicates that the average value of liposomes delivered into the pancreas 5 minutes after intravenous injection is 1.2 to Represents a factor of 1.5.

Since liposomes to which tris (hydroxymethyl) aminomethane is bound have slight pancreatic directivity, Galβ1,3GalNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer was used as a reference liposome.

Preferably, the sugar chain-modified liposomes suitable for intrapancreatic delivery of the present invention can be prepared using the types of sugar chains and modified bond densities shown in Table 1 above and combinations thereof. Although not bound by theory, once it is found that the target directivity is + or ++, the same effect can be expected even when two or more sugar chains are combined. This is because sugar chains that recognize lectins of target tissues or target cells are recognized as preferable even when combined.

The sugar chain-modified liposomes suitable for intrapancreatic delivery used in the present invention are preferably liposome numbers 22, 27, 29, 38, 40, 56, 60, 68, 69, 70, 71, 76, 87, 91, 93, 96, 105, 106, 111, 116, 117, 120, 125, 127, 130, 137, 139, 142, 146, 150, 151, 152, 153, 154, 155, 175, 184, 191, 195, 197, 199, 204, 207, 209, 213, 218, 220, 224, 225, 229, 230, 233, 234, 235, 237, 249, 273, 292, or 295.

The sugar chain-modified liposome used in the present specification may contain, for example, the sugar chains shown in Table 4 at a density suitable for delivery into the brain.

As used herein, delivery to the brain refers to delivery throughout the central nervous system within the skull (cerebrum, cerebellum, medulla, etc.).

As used herein, “modified bond density” is the amount of sugar chain used when preparing a sugar chain-modified liposome, and the density of sugar chains bound per mg of liposome lipid (mg sugar). Chain / mg lipid). The binding density of the sugar chain-modified liposome of the present invention is not desired to be bound by theory, but empirically, the amount of sugar chain used for preparation is almost proportional to the density of the sugar chain bound to the liposome. I know that Therefore, in this specification, unless otherwise stated, the bond density is determined by the amount used at the time of preparation. In vitro, for example, it can be determined indirectly using E-selectin. The sugar chain-modified liposome of the present invention can control the directivity with respect to the target delivery site by selecting the type of sugar chain to be bound to the liposome and the binding density. Table 4 below shows the liposome number, sugar chain structure, modified bond density and brain directivity.

“++” is delivered into the brain 5 minutes after intravenous injection when liposomes (reference liposomes) conjugated with Galβ1,3GalNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer are used instead of sugar chains. The average value of the liposomes is 3 to 7 times the average value of the reference liposomes.

“+” Is delivered into the brain 5 minutes after intravenous injection when liposome (standard liposome) conjugated with Galβ1,3GalNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer is used instead of sugar chain. It means that the average value of the liposome is 2-3 times the average value of the reference liposome.

When a liposome to which tris (hydroxymethyl) aminomethane is bound is used as a reference liposome, “++” indicates that the average value of liposomes delivered into the brain 5 minutes after intravenous injection is 1.7 to Represents 3.7 times.

When a liposome to which tris (hydroxymethyl) aminomethane is bound is used as a reference liposome, “+” indicates that the average value of liposomes delivered into the brain 5 minutes after intravenous injection is 1.1 to 1.1 from the average value of reference liposomes. It means that it becomes 1.4 times.

Since liposomes to which tris (hydroxymethyl) aminomethane is bound have slight brain directivity, Galβ1,3GalNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer was used as a reference liposome.

Preferably, the sugar chain-modified liposomes suitable for intracerebral delivery of the present invention can be prepared using sugar chains and modified bond densities of the types shown in Table 1 above and combinations thereof. Although not bound by theory, once it is found that the target directivity is + or ++, the same effect can be expected even when two or more sugar chains are combined. This is because sugar chains that recognize lectins of target tissues or target cells are recognized as preferable even when combined.

  The sugar chain-modified liposomes suitable for intracerebral delivery used in the present invention are preferably liposome numbers 22, 29, 38, 40, 45, 50, 53, 56, 60, 67, 68, 69, 70, 71, 76, 80, 87, 93, 105, 106, 116, 120, 127, 129, 137, 141, 142, 146, 150, 151, 152, 154, 155, 175, 178, 184, 186, 189, 197, 207, 209, 213, 218, 224, 229, 230, 233, 235, 237, 249, 273, 290, 292, or 295.

Preferred sugar chain-modified liposomes of the present invention as described in the above table can be produced by the following method. Specifically, this method comprises (a) a step of providing a liposome; (b) a step of hydrophilizing the liposome; (c) a linker on the hydrophilized liposome, if necessary. A step of binding to form a linker-bonded liposome; and (d) a step of binding a sugar chain described in Table 3 to the liposome to generate a sugar chain-modified liposome.

Preferably, in this method, the step of hydrophilizing the liposome in step (b) is performed by binding a low molecular weight hydrophilic compound directly or indirectly on the lipid membrane or linker of the liposome. The linker used in step (c) is a human-derived protein, and in step (d), a glycan is bound to the liposome under conditions that allow a glycan to be bound directly or indirectly. Glycosylated liposomes are produced.

The liposome and the linker, and the linker and the sugar chain are preferably bonded using a bifunctional crosslinking agent (for example, DTSSP).

The sugar chain-modified liposome of the present invention can encapsulate or bind a drug or gene. Examples of the drug include biopharmaceuticals or biotherapeutic substances (eg, siRNA, shRNA, siRNA derivative, shRNA derivative, RNA, RNA derivative, DNA, DNA derivative, monoclonal antibody, vaccine, interferon, hormone, prostaglandin, transcription Factor, Recombinant Protein, Antibody Drug, Nucleic Acid>
Pharmaceuticals, gene therapy agents), alkylated anticancer agents, antimetabolites, plant-derived anticancer agents, anticancer antibiotics, biological response modifiers (BRM) / cytokines, platinum complex anticancer agents, immunotherapy Drugs, hormone anticancer drugs, tumor drugs such as monoclonal antibodies, central nervous system drugs, peripheral nervous system / sensory organ drugs, respiratory disease drugs, cardiovascular drugs, gastrointestinal drugs, hormone drugs, urology / Reproductive organ drugs, vitamins, nourishing tonics, metabolic drugs, antibiotics / chemotherapeutic drugs, testing drugs, anti-inflammatory drugs, eye disease drugs, central nervous system drugs, autoimmune drugs, cardiovascular drugs, diabetes, Lifestyle-related diseases such as hyperlipidemia, corticosteroids, immunosuppressants, antibacterial agents, antiviral agents, angiogenesis inhibitors, cytokines Chemokines, anti-cytokine antibodies, anti-chemokine antibodies, anti-cytokine / chemokine receptor antibodies, siRNA, shRNA, miRNA, smRNA, antisense RNA or gene therapy-related nucleic acid preparations such as ODN or DNA, neuroprotective factors, antibody drugs, Examples include, but are not limited to, molecular targeted drugs, osteoporosis / bone metabolism improving drugs, neuropeptides, and bioactive peptides / proteins.

As used herein, a “linker” is a molecule that mediates the binding between a sugar chain and the surface of a liposome. In the sugar chain-modified liposome of the present invention, the sugar chain may be bound to the liposome surface via a linker. The linker can be appropriately selected by those skilled in the art, but is preferably biocompatible, and more preferably pharmaceutically acceptable. The linker used in the present specification may be, for example, a biological protein, preferably a human protein, more preferably a human serum protein, and even more preferably human serum albumin or bovine serum albumin. In particular, when human serum albumin is used, it has been confirmed by experiments on mice that the uptake into each tissue is large.

In the present specification, the “crosslinking agent” means that a chemical bond is formed between molecules of a chain polymer so as to form a bridge. Typically, it acts between macromolecules such as lipids, proteins, peptides, and sugar chains and other molecules (eg, lipids, proteins, peptides, sugar chains), and is covalently linked within or between molecules. A drug that forms a covalent bond that connects places that did not exist. In the present specification, the liposome and the sugar chain may be covalently formed by this crosslinking agent, or via a linker, between the linker and the sugar chain, and between the linker and the liposome. May be bound by a crosslinking agent. The cross-linking agent varies depending on the target for cross-linking, and examples thereof include, but are not limited to, aldehydes (for example, glutaraldehyde), carbodiimides, and imide esters. When the amino group-containing substance is crosslinked, an aldehyde-containing group such as glutaraldehyde can be used. Specifically, for example, bissulfosuccinimidyl suberate, disuccinimidyl glutarate, dithiobissuccinimidyl propionate, disuccinimidyl suberate, 3,3′-dithiobis (sulfosuccinimidyl) Divalent reagents such as propionate), ethylene glycol bissuccinimidyl succinate, ethylene glycol bissulfostaginimidyl succinate, and the like can be used.

As used herein, the terms “protein”, “polypeptide”, “oligopeptide” and “peptide” are used interchangeably herein and refer to a polymer of amino acids of any length. This polymer may be linear, branched, or cyclic. The amino acid may be natural or non-natural and may be a modified amino acid. The term can also encompass one assembled into a complex of multiple polypeptide chains. The term also encompasses natural or artificially modified amino acid polymers. Such modifications include, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation or any other manipulation or modification (eg, conjugation with a labeling component). This definition also includes, for example, polypeptides containing one or more analogs of amino acids (eg, including unnatural amino acids, etc.), peptide-like compounds (eg, peptoids) and other modifications known in the art. Is included.

In this specification, “protein” refers to a polymer of amino acids having a relatively large molecular weight or a modification thereof, and “peptide” refers to a polymer of amino acids having a relatively small molecular weight or a modification thereof. It should be understood that it may refer to a variant. Examples of such molecular weight include, but are not limited to, about 30 kDa, preferably about 20 kDa, more preferably about 10 kDa.

As used herein, a “biological protein” refers to a protein derived from an organism, including any organism (eg, any type of multicellular organism (eg, animal (eg, vertebrate, invertebrate)). Animal), plant (for example, monocotyledonous plant, dicotyledonous plant, etc.))) or the like. Preferably, it is a protein derived from a vertebrate (for example, larvae, lampreys, cartilaginous fish, teleosts, amphibians, reptiles, birds, mammals, etc.), more preferably a mammal (for example, a single hole, marsupial) , Rodents, crustaceans, wings, carnivores, carnivores, long noses, odd hoofs, even hoofs, rodents, scales, sea cattle, cetaceans, primates, rodents And other proteins derived from the order of rabbits, etc.). More preferably, a protein derived from a primate (eg, chimpanzee, Japanese monkey, human) is used. Most preferably, a protein derived from a living body intended for administration is used.

As used herein, “human-derived serum protein” refers to a protein contained in a liquid portion that remains when human blood naturally coagulates.

As used herein, “human serum albumin” refers to albumin contained in human serum, and “bovine serum albumin” refers to albumin contained in bovine serum.

In the sugar chain-modified liposome in the present invention, at least one of the liposome membrane or the linker may be hydrophilized by binding a hydrophilic compound, preferably a tris (hydroxyalkyl) aminoalkane.

As used herein, “hydrophilization” refers to binding of a hydrophilic compound to the liposome surface. Examples of the compound used for hydrophilization include a low molecular weight hydrophilic compound, preferably a low molecular weight hydrophilic compound having at least one OH group, and more preferably a low molecular weight hydrophilic compound having at least two OH groups. Can be mentioned. Further, a low molecular weight hydrophilic compound having at least one amino group, that is, a hydrophilic compound having at least one OH group and at least one amino group in the molecule can be mentioned. Since the hydrophilic compound is a small molecule, it does not easily cause steric hindrance to the sugar chain, and does not hinder the progress of the sugar chain molecule recognition reaction by the lectin on the surface of the target cell membrane. Further, the hydrophilic compound does not include a sugar chain to which a lectin used for directing a specific target such as a lectin can be bound in the sugar chain-modified liposome of the present invention. Examples of such hydrophilic compounds include amino alcohols such as tris (hydroxyalkyl) aminoalkanes including tris (hydroxymethyl) aminomethane, and more specifically, tris (hydroxymethinore) aminoethane. , Tris (hydroxyethyl) aminoethane, tris (hydroxypropyl) aminoethane, tris (hydroxymethyl) aminomethane, tris (hydroxyethyl) aminomethane, tris (hydroxypropyl) aminomethane, tris (hydroxymethyl) aminopropane, tris (hydroxy) And ethyl) aminopropane and tris (hydroxypropyl) aminopropane. Furthermore, a compound obtained by introducing an amino group into a low molecular compound having an OH group can also be used as the hydrophilic compound of the present invention. Although this compound is not limited, For example, the compound which introduce | transduced the amino group into the sugar chain which lectins, such as cellobiose, do not couple | bond is mentioned. For example, the liposome surface is hydrophilized using a divalent reagent for crosslinking and tris (hydroxymethyl) aminomethane on the lipid phosphatidylethanolamine of the liposome membrane. The general formula of the hydrophilic compound is represented by the following formula (1), formula (2), formula (3), and the like.

X—R ¹ (R ² OH) _n Formula (1) H ₂ N—R ³ — (R ⁴ OH) _n Formula (2) H ₂ N—R ⁵ (OH) _n Formula (3) where R ¹ , R ³ and R ⁵ represent C ₁ to C ₄₀ , preferably C ₁ to C ₂₀ , more preferably C ₁ to C ₁₀ linear or branched hydrocarbon chains, and R ² and R ⁴ are present Or a C ₁ to C ₄₀ , preferably C ₁ to C ₂₀ , more preferably C ₁ to C ₁₀ straight or branched hydrocarbon chain. X represents a reactive functional group bonded to a bivalent reagent for a direct bond or a bridge and liposomal lipid, for _{example, COOH, NH, NH 2,} CHO, SH, NHS- ester, maleimide, imidoesters, active halogens, EDC, Examples include pyridyl disulfide, azidophenyl, hydrazide and the like. n represents a natural number. The surface of the liposome hydrophilized with such a hydrophilic compound is thinly covered with the hydrophilic compound. However, since the thickness of the cover of the hydrophilic compound is small, the reactivity of sugar chains and the like is not suppressed even when sugar chains are bound to liposomes.

Hydrophilization of liposomes is achieved by a conventionally known method, for example, a method of preparing liposomes using phospholipids obtained by covalently binding polyethylene glycol, polyvinyl alcohol, maleic anhydride copolymer or the like (Japanese Patent Laid-Open No. 2000-302585). (E.g. CNDAC-containing liposomal formulation dilauroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine; dipalmitoyl phosphatidylglycerol, distearoyl phosphatidylglycerol; sphingomyelin; cholesterol; N-monomethoxypolyethyleneglycol succinyl-distearoylphosphatidylethanolamine ( (Hereinafter referred to as PEG2000-DSPE)): Multiple layers were prepared by the method of Bangham et al. (See J. Mol. Biol. 8, 660-668 (1964)) using CNDAC hydrochloride, glucose aqueous solution and trehalose aqueous solution. It can be also performed by adopting a method such as “A rough dispersion of liposomes is obtained.”)). Among these, it is particularly preferable to make the liposome surface hydrophilic using tris (hydroxymethyl) aminomethane. The method using tris (hydroxymethyl) aminomethane of the present invention is preferable in several respects as compared with the conventional hydrophilization method using polyethylene glycol or the like. For example, in the case where a sugar chain is bound on a liposome as in the present invention and its molecular recognition function is utilized for target orientation, tris (hydroxymethyl) aminomethane is a low molecular weight substance, so that conventional polyethylene glycol or the like can be used. Compared to the method using a high molecular weight substance, it is particularly preferable because it is less likely to cause steric hindrance to the sugar chain and does not hinder the progress of the sugar chain molecule recognition reaction by the lectin (sugar chain recognition protein) on the target cell membrane surface.

In addition, the liposome according to the present invention has a good particle size distribution, component composition, and dispersion characteristics even after the hydrophilization treatment, and is excellent in long-term storage and in vivo stability. Is preferred. In order to hydrophilize the liposome surface using tris (hydroxymethyl) aminomethane, for example, lipids such as dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine were obtained by a conventional method. Bissulfosuccinimidyl suberate, disuccinimidyl glutarate, dithiobissuccinimidyl propionate, disuccinimidyl suberate, 3,3′-dithiobis (sulfosuccinimidyl propionate) Dipalmitoyl phosphatidyl ethanol on a liposome membrane by adding a divalent reagent such as ethylene glycol bissuccinimidyl succinate or ethylene glycol bissulfosuccinimidyl succinate A trivalent (hydroxymethyl) aminomethane is bound to the liposome surface by binding a divalent reagent to a lipid such as thiol, and then reacting tris (hydroxymethyl) aminomethane with the negative bond of the divalent reagent. Let me.

As described above, liposomes obtained by hydrophilizing liposomes are extremely stable in vivo, and have a long half-life in vivo without binding to a target-directed sugar chain as described later. It can be suitably used as a drug carrier in a delivery system. The present invention also includes liposomes whose surfaces are rendered hydrophilic with low molecular weight compounds.

As used herein, “delivery vehicle” refers to a carrier (vehicle) that mediates delivery of a desired substance. If the substance to be delivered is a drug, it is referred to as a “drug delivery vehicle”. The drug delivery system (Drug Delivery System, DDS) is also called a drug delivery system, and is sometimes classified into an absorption-controlled DDS, a controlled-release DDS, and a target-oriented DDS. An ideal DDS is a system that delivers a drug “to the necessary site in the body”, “a necessary amount”, and “for the required time”. Targeting DDS (written as Targeting DDS, translated into target-oriented DDS) is categorized as passive targeting (active) and active targeting (active). . The former is a method of controlling the behavior in the body using physicochemical properties such as the particle size and hydrophilicity of the carrier (drug carrier). The latter is a method in which a special mechanism is added to these to actively control the directivity to the target tissue. For example, an antibody having a specific molecule recognition function for a target molecule of a specific cell constituting the target tissue There is a method using a carrier to which a sugar chain or the like is bound, and it is sometimes called a “missile drug”.

As used herein, “drug delivery vehicle” refers to a vehicle for delivering a desired drug.

In another aspect, the present invention relates to a drug delivery vehicle for oral administration. The drug delivery vehicle for oral administration can further comprise a pharmaceutically acceptable carrier and the like. Pharmaceutically acceptable carriers include, for example, antioxidants, preservatives, colorants, flavors, and diluents, emulsifiers, suspending agents, solvents, fillers, extenders, buffers, delivery vehicles, diluents Examples include, but are not limited to, agents, excipients and / or pharmaceutical adjuvants. Typically, the drug delivery vehicle for oral administration of the present invention is administered in the form of a composition comprising a glycosylated liposome together with one or more physiologically acceptable carriers, excipients or diluents. . For example, a suitable vehicle can be water for injection, physiological solution, or artificial cerebrospinal fluid.

Acceptable carriers, excipients or stabilizers used herein are non-toxic to the recipient and are preferably inert at the dosages and concentrations used. Such non-toxic and inert carriers include, for example, phosphate, citrate, or other organic acids; ascorbic acid, α-tocopherol; low molecular weight polypeptides; proteins (eg, serum albumin, gelatin or Immunoglobulins); hydrophilic polymers (eg, polyvinylpyrrolidone); amino acids (eg, glycine, glutamine, asparagine, arginine or lysine); monosaccharides, disaccharides and other carbohydrates (including glucose, mannose, or dextrin); (Eg, EDTA); sugar alcohols (eg, mannitol or sorbitol); salt-forming counterions (eg, sodium); and / or non-ionic surfactants (eg, Tween, pluronic) Other things can be mentioned polyethylene glycol (PEG)) it is not limited thereto.

Exemplary suitable carriers include neutral buffered saline or saline mixed with serum albumin. Preferably, the product is formulated as a lyophilizer using a suitable excipient (eg, sucrose). Other standard carriers, diluents and excipients may be included as desired. Other exemplary compositions include pH 7.0-8.5 Tris buffer or pH 4.0-5.5 acetate buffer, which may further include sorbitol or a suitable substitute thereof. .

In one aspect, the present invention provides a drug delivery vehicle for oral administration comprising a sugar chain-modified liposome. The drug delivery vehicle of the present invention binds a sugar chain having at least one structure selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc, Fuc and Neu5Ac, preferably a sugar chain shown in Table 1 above Sugar chain-modified liposomes. This sugar chain-modified liposome may encapsulate or bind a drug or gene.

Examples of the drug encapsulated or bound to the sugar chain-modified liposome of the present invention include, but are not limited to, biopharmaceuticals or biotherapeutic substances (for example, siRNA, shRNA, siRNA derivatives, shRNA derivatives). , RNA, RNA derivatives, DNA, DNA derivatives, monoclonal antibodies, vaccines, interferons, hormones, prostaglandins, transcription factors, recombinant proteins, antibody drugs, nucleic acids>
Drugs, gene therapy drugs), alkylated anticancer drugs, antimetabolites, plant-derived anticancer drugs, anticancer antibiotics, BRM / cytokines, platinum complex anticancer drugs, immunotherapy drugs, hormone anticancer drugs, monoclonal antibodies, etc. Drugs, drugs for central nervous system, drugs for peripheral nervous system / sensory organs, drugs for treating respiratory diseases, drugs for cardiovascular system, drugs for digestive organs, drugs for hormonal system, drugs for urology / genital organs, vitamins / nutritional tonics, metabolic Drugs, antibiotics / chemotherapeutic drugs, test drugs, anti-inflammatory drugs, eye disease drugs, central nervous system drugs, autoimmune drugs, cardiovascular drugs, lifestyle-related drugs such as diabetes and hyperlipidemia, Corticosteroids, immunosuppressants, antibacterial agents, antiviral agents, angiogenesis inhibitors, cytokines, chemokines, anti-cytokine antibodies, anti-chemokine antibodies, anti-cytokine / chemokines Gene therapy-related nucleic acid preparations such as body antibodies, siRNA, shRNA, miRNA, smRNA, antisense RNA or ODN or DNA, neuroprotective factors, antibody drugs, molecular targeting drugs, osteoporosis / bone metabolism improving drugs, neuropeptides, physiology Drugs such as active peptides and proteins.

The drug delivery vehicle for oral administration of the present invention is for oral administration of a biological agent to a subject in need of the biological agent, and for the respiratory system, circulatory system, digestive system, urinary / genital system, It can also be used to treat mammals with central or peripheral nervous system disorders.

The drug delivery vehicle for oral administration of the present invention can enhance the absorption controllability in the intestinal tract by adjusting the type of sugar chain and the binding density of the sugar chain-modified liposome. By binding to the liposome both sugar chains that enhance intestinal absorption controllability and sugar chains that have directivity to specific tissues or organs, the characteristics of both directivity to specific tissues or organs and intestinal absorption controllability can be achieved. It is also possible to produce liposomes that have both.

The drug delivery vehicle for oral administration of the present invention can be easily prepared by those skilled in the art by considering pH, isotonicity, stability and the like. The drug delivery vehicle for oral administration of the present invention is blended with a pharmaceutically acceptable carrier, and is a liquid such as a solid preparation such as a tablet, capsule, granule, powder or powder, syrup, suspension or solution. It can be administered orally as a formulation.

The drug delivery vehicle for oral administration of the present invention may be a physiologically acceptable carrier, excipient or stabilizer as necessary (Japanese Pharmacopoeia 14th edition or its latest edition, Remington's Pharmaceutical Sciences, 18th Edition). , A. R. Gennaro, ed., Mack Publishing Company, 1990, etc.) and a sugar chain composition having a desired degree of purity, and prepared in the form of a lyophilized cake or an aqueous solution. And can be stored.

The amount of the drug delivery vehicle for oral administration used in the treatment method of the present invention is the purpose of use, target disease (type, severity, etc.), patient age, weight, sex, medical history, cell morphology or type, etc. Can be easily determined by those skilled in the art. The frequency with which the treatment method of the present invention is applied to a subject (or patient) also depends on the purpose of use, target disease (type, severity, etc.), patient age, weight, sex, medical history, treatment course, etc. In view of this, it can be easily determined by those skilled in the art. Examples of the frequency include administration every day to once every several months (for example, once a week to once a month). It is preferable to administer once a week to once a month while observing the course.

Drug delivery vehicles for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosage forms suitable for administration. Such carriers allow drug delivery vehicles to be formulated into liquids, gels, syrups, slurries, suspensions, etc. suitable for ingestion by patients.

The drug delivery vehicle of the present invention comprises a composition in which the drug or biological agent is contained in a sugar chain-modified liposome in an amount effective to achieve the intended purpose. “An amount effective to treat” is a term well recognized by those skilled in the art and refers to an amount of an agent effective to produce an intended pharmacological result (eg, prevention, treatment, prevention of recurrence, etc.). Say. Thus, a therapeutically effective amount is an amount sufficient to reduce the symptoms of the disease to be treated. One useful assay to ascertain an effective amount (eg, a therapeutically effective amount) for a given application is to measure the extent of recovery of the target disease. The amount actually administered will depend on the individual to whom the treatment is to be applied, and is preferably an amount optimized to achieve the desired effect without significant side effects. The determination of an effective dose is well within the ability of those skilled in the art.

Therapeutically effective amount, prophylactically effective amount and the like and toxicity are standard pharmaceutical procedures in cell cultures or experimental animals (eg ED ₅₀ , therapeutically effective dose in 50% of the population; and LD ₅₀ , 50% of the population. The dose that is lethal to). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as ratio ED 50 _/ LD _50. Drug delivery vehicles that exhibit large therapeutic indices are preferred. Data obtained from cell culture assays and animal experiments are used to formulate a range of quantities for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED ₅₀ with little or no toxicity. This dose will vary within this range depending on the mode of administration used, the sensitivity of the patient, and the route of administration. As an example, the dose is appropriately selected depending on the age and other patient conditions, the type of disease, the type of cells used, and the like.

The drug delivery vehicle of the present invention can be manufactured in a manner similar to that known in the art (eg, mixing, dissolving, etc.).

In the present specification, the “instruction” refers to a method for administering the sugar chain-modified liposome of the present invention or a drug delivery vehicle for oral administration, etc., a person who administers, such as a doctor, a patient, etc. Is described. This instruction manual describes a word indicating a procedure for administering the sugar chain-modified liposome of the present invention or a drug delivery vehicle for oral administration. This instruction is prepared in accordance with the format prescribed by the national supervisory authority (for example, the Ministry of Health, Labor and Welfare in Japan and the Food and Drug Administration (FDA) in the United States, etc. in the United States) where the present invention is implemented, and is approved by the supervisory authority. It is clearly stated that it has been received. The instruction sheet is a so-called package insert, and is usually provided as a paper medium, but is not limited thereto. For example, an electronic medium (for example, a home page (web site) or e-mail provided on the Internet) It can also be provided in such a form.

As used herein, “subject” refers to an organism to which the treatment of the present invention is applied, and is also referred to as a “patient”. The patient or subject may preferably be a human.

(Use of glycosylated liposome as a medicine) In another aspect, the present invention treats a disorder of the respiratory system, circulatory system, digestive system, urinary / genital system, central nervous system, or peripheral nervous system. Use of a sugar chain-modified liposome for the manufacture of a medicament for the purpose is provided. Here, as the sugar chain-modified liposome, any form described in the above (Sugar chain-modified liposome) can be used.

(Treatment Method) In another aspect, the present invention provides a method for treating a subject having a disorder of the respiratory system, circulatory system, digestive system, urinary / genital system, central nervous system, or peripheral nervous system. I will provide a. The method includes administering to a subject an oral drug delivery vehicle for treating a disorder, the oral drug delivery vehicle comprising a sugar chain-modified liposome and a pharmaceutically acceptable carrier; The sugar chain-modified liposome contains an amount of the drug effective to treat the disorder. Here, as the sugar chain-modified liposome, any form described in the above (Sugar chain-modified liposome) can be used.

(Delivery method) In another aspect, the present invention provides a method for delivering a biological agent to a target site in a subject in need thereof. This method includes the step of orally administering the sugar chain-modified liposome of the present invention, wherein the sugar chain-modified liposome contains an effective amount of the biological factor. Here, as the sugar chain-modified liposome, any form described in the above (Sugar chain-modified liposome) can be used.

(Production Method) In another aspect, the present invention provides a method for producing a sugar chain-modified liposome. In this method, (a) a step of providing a liposome; (b) a step of hydrophilizing the liposome; (c) a linker is bound to the hydrophilized liposome, if necessary, to form a linker A step of producing a bound liposome; and (d) a step of producing a sugar chain-modified liposome by binding a sugar chain to the liposome. Preferably, in this method, the step of hydrophilizing the liposome in step (b) is performed on the lipid membrane of the liposome or on the linker directly or indirectly with a low molecular weight hydrophilic compound (for example, tris (hydroxyalkyl). And the linker used in step (c) is a human-derived protein (eg, human serum albumin) and in step (d), Under the condition of directly or indirectly binding the sugar chain, the sugar chain is bound to produce a sugar chain-modified liposome.

In another aspect, the present invention provides a method for producing a sugar chain-modified liposome for delivering a drug to a target delivery site. This method comprises (a) providing a sugar chain-modified liposome having various sugar chain densities to achieve delivery to the intended delivery site; (b) for the sugar chain density on the sugar chain-modified liposome; Determining the density to achieve optimal delivery to the delivery site; and (c) incorporating the drug into the determined optimal glycosylated liposome to produce a drug-containing liposome.

(Production of liposome) The liposome itself can be produced according to a known method, and examples thereof include a thin film method, a reverse layer evaporation method, an ethanol injection method, and a dehydration-rehydration method.

Moreover, it is also possible to adjust the particle diameter of the liposome using an ultrasonic irradiation method, an extrusion method, a French press method, a homogenization method, or the like. The production method of the liposome itself of the present invention will be specifically described. For example, first, a lipid and an interface containing phosphatidylcholines, cholesterol, phosphatidylethanolamines, phosphatidic acids, gangliosides, glycolipids or phosphatidylglycerols as a blending component. Prepare mixed micelles with the activator sodium cholate. In particular, the formulation of long-chain alkyl phosphates such as phosphatidic acids or dicetyl phosphate is essential for negatively charging the liposomes, and the formulation of phosphatidylethanolamines is used as a hydrophilization reaction site as gangliosides or sugars. Formulation of lipids or phosphatidylglycerols is essential as a linker binding site. At least one lipid selected from the group consisting of gangliosides, glycolipids, phosphatidylglycerols, sphingomyelins and cholesterols assembles in the liposome and functions as a scaffold (raft) to which the linker is bound. The liposome of the present invention is further stabilized by forming a raft capable of binding such a protein. That is, the liposome of the present invention is a liposome in which at least one raft of lipid selected from the group consisting of ganglioside, glycolipid, phosphatidylglycerols, sphingomyelins and cholesterols for binding a linker is formed. Including. And a liposome is produced by performing ultrafiltration of the mixed micelle obtained by this. The liposome used in the present invention may be a normal one, but it is desirable that its surface be made hydrophilic. After the liposome is produced as described above, the liposome surface is made hydrophilic.

The present invention also includes liposomes that are not bound to sugar chains that have been rendered hydrophilic using the above-mentioned hydrophilic compound. Such hydrophilic liposomes have the advantage that the stability of the liposome itself is enhanced, and that the sugar chain is recognizable when the sugar chain is bound. In the liposome of the present invention, for example, the constituent lipids of the liposome are phosphatidylcholines (molar ratio 0 to 70%), phosphatidylethanolamines (molar ratio 0 to 30%), phosphatidic acids, long chain alkyl phosphates and dicetyl phosphates. One or more lipids (molar ratio 0-30%) selected from the group consisting of: gangliosides, glycolipids, phosphatidylglycerols and sphingomyelins (molar ratio) 0 to 40%), as well as cholesterol (molar ratio 0 to 70%).

The present invention further includes a method of making the liposome hydrophilic by binding the hydrophilic compound to the liposome. Further, hydrophilic liposomes to which sugar chains are not bonded are also included. The target-directed liposome or intestinal absorbable liposome of the present invention can be produced by binding a sugar chain to a liposome to which no sugar chain is bound.

(Synthesis of sugar chain) The sugar chain that can be used in the sugar chain-modified liposome of the present invention can be synthesized by a general sugar chain synthesis method. These methods include (1) chemical synthesis, (2) fermentation using genetically modified cells or microorganisms, (3) synthesis using sugar hydrolase (glycosidase), (4) glycosyltransferase And a method of synthesis using (glycosyltransferase). (WO 2002/081723, JP-A-9-31095, JP-A-11-42096, JP-A-2004-180676, Kenichi Hatanaka, Shinichiro Nishimura, Goro Ouchi and Kazuyoshi Kobayashi (1997) Glucose Science and Industry, Kodansha See Tokyo etc.).

The sugar chain used in the sugar chain-modified liposome of the present invention may be a sugar chain synthesized by the above method or a commercially available sugar chain.

(Binding of sugar chain to liposome) In the present invention, any of the above sugar chains may be directly bonded to the liposome prepared as described above, and further, the sugar chain is bonded via a linker. You may let them. At this time, the type of sugar chain to be bound to the liposome is not limited to one, and a plurality of sugar chains may be bound. In this case, the plurality of sugar chains may be a plurality of sugar chains having binding activity for different lectins that are commonly present on the cell surface of the same tissue or organ, or may be present on the cell surface of different tissues or organs. It may be a sugar chain having binding activity for different lectins. By selecting a plurality of sugar chains such as the former, it is possible to reliably direct a specific target tissue or organ, and by selecting a plurality of sugar chains such as the latter, a single type of liposome has a plurality of sugar chains. Targets can be directed, and multipurpose target-directed liposomes can be obtained.

In order to bind the sugar chain to the liposome, it is possible to mix the linker and / or sugar chain at the time of manufacturing the liposome and to bond the sugar chain to the surface while manufacturing the liposome. It is desirable to prepare a glycan and a sugar chain separately, and bind a linker and / or a glycan to a liposome that has been manufactured. This is because the density of the sugar chain to be bound can be controlled by binding the linker and / or sugar chain to the liposome. Direct binding of sugar chains to liposomes can be performed by the method described below.

A liposome is produced by mixing a sugar chain as a glycolipid, or the sugar chain is bound to the phospholipid of the liposome after production and the sugar chain density is controlled. When a sugar chain is bound using a linker, it is preferable to use a biological protein, particularly a human-derived protein, as the linker. The protein derived from the living body is not limited, and examples include proteins existing in blood such as albumin, and other physiologically active substances existing in the living body. Examples include animal serum albumins such as human serum albumin (HSA) and bovine serum albumin (BSA). Particularly when human serum albumin is used, it has been confirmed by experiments on mice that the uptake into each tissue is large. It has been. The liposome of the present invention is very stable, and can be post-treated by binding a protein, binding a linker, or binding a sugar chain after the liposome is formed. Therefore, it is possible to produce various liposomes according to the purpose by producing a large amount of liposomes and then binding different proteins according to the purpose or by binding a linker or sugar chain.

In the liposome of the present invention, a sugar chain is directly bonded to a lipid constituting the liposome via a linker. The liposome of the present invention is a liposome having a complex carbohydrate type ligand such as glycolipid or glycoprotein and hydrophilized with a low molecular weight compound.

Moreover, as described later, when the target-directed liposome of the present invention is used as a medicine, the liposome needs to contain a compound having a pharmaceutical effect. The compound having a pharmaceutical effect may be encapsulated in the liposome or bound to the surface of the liposome, but a protein having a pharmaceutical effect may be used as a linker. In this case, the protein may also serve as a linker for binding the liposome and the sugar chain and a protein having a medicinal effect. Examples of proteins having medicinal effects include physiologically active proteins.

In the preparation of the sugar chain-modified liposome of the present invention, a crosslinking agent can be used when the liposome and the linker are bound.

What is necessary is just to perform by the method described below in order to couple | bond a sugar chain to a liposome via a linker.

First, a protein is bound to the liposome surface. The liposome is treated with an oxidizing agent such as NaIO ₄ , Pb (O ₂ CCH ₃ ) ₄ or NaBiO ₃ to oxidize the ganglioside present on the membrane surface of the liposome, and then using a test drive such as NaBH ₃ CN or NaBH _4. The linker and the ganglioside on the liposome membrane surface are bound by a reductive amination reaction. This linker is also preferably made hydrophilic, in which a compound having a hydroxy group is bound to Ringer protein. For example, bissulfosuccinimidyl suberate, disuccinimidyl glutarate, dithiobissuccinimi Zirpropionate, disuccinimidyl suberate, 3,3′-dithiobis (sulfosuccinimidyl propionate), ethylene glycol bissuccinimidyl succinate, ethylene glycol bissulfosuccinimidyl succinate, etc. What is necessary is just to couple | bond the compound used for the above-mentioned hydrophilization, such as a tris (hydroxymethyl) aminomethane, with the linker on a liposome using a bivalent reagent.

Specifically, first, one end of the divalent reagent for crosslinking is bonded to all amino groups of the linker. A sugar chain glycosylamine compound obtained by subjecting the reducing end of each sugar chain to a glycosyl amination reaction is prepared, and the amino group of this sugar chain and another part of the cross-linked divalent reagent bonded above on the liposome are prepared. Join the unreacted end. The covalent bond between the sugar chain and / or the hydrophilic compound and the liposome, or the covalent bond between the sugar chain and / or the hydrophilic compound and the linker can be cleaved when the liposome is taken into the cell. For example, when a linker and a sugar chain are covalently bonded via a disulfide bond, the sugar chain is cleaved by reduction in the cell. When the sugar chain is cleaved, the liposome surface becomes hydrophobic, binds to the biological membrane, disturbs the membrane stability, and releases the drug contained in the liposome.

Next, hydrophilic treatment is carried out using the unreacted end of most of the divalent reagent remaining unreacted with no sugar chain attached to the surface of the protein on the sugar chain-bound liposome membrane thus obtained. Do. That is, the unreacted end of the divalent reagent bound to the protein on the liposome is bound to the above-described hydrophilic compound such as tris (hydroxymethyl) aminomethane to make the entire liposome surface hydrophilic. To do. Hydrophilization of the liposome surface and the linker improves transferability to various tissues, retention in blood, and transferability to various tissues. This is because when the liposome surface and the linker surface are rendered hydrophilic, the portions other than sugar chains appear to be water in the body in each tissue, etc. This is probably due to the fact that only the sugar chain is not recognized by the target tissue lectin (sugar chain recognition protein).

The sugar chain is then bound to a linker on the liposome. For this purpose, the reducing end of the saccharide constituting the sugar chain is glycosylated with an ammonium salt such as NH ₄ HCO ₃ or NH ₂ COONH ₄ and then bissulfosuccinimidyl suberate, disuccinimidyl glutarate is used. Rate, dithiobissuccinimidyl propionate, disuccinimidyl suberate, 3,3′-dithiobis (sulfosuccinimidyl propionate), ethylene glycol bissuccinimidyl succinate, ethylene glycol bissulfostasis Using a divalent reagent such as nimidyl succinate, a linker bound on the surface of the liposome membrane and the glycosylated amino sugar are bound to obtain a liposome. These sugar chains are commercially available.

The particle size of the liposome of the present invention, such as a sugar chain-bound liposome, is 30 to 500 nm, preferably 50 to 350 nm. The liposome of the present invention is desirably negatively charged. By being negatively charged, the interaction with negatively charged cells in the living body can be prevented. The zeta potential of the liposome surface of the present invention is −50 to 10 mV, preferably −40 to 0 mV, more preferably −30 to −10 mV at 37 ° C. in physiological saline.

Examples of the drug contained in the sugar chain-modified liposome of the present invention include biopharmaceuticals or biotherapeutic substances (eg, siRNA, shRNA, siRNA derivatives, shRNA derivatives, RNA, RNA derivatives, DNA, DNA derivatives, monoclonal antibodies, vaccines, interferons) , Hormones, prostaglandins, transcription factors, recombinant proteins, antibody drugs, nucleic acids>
Drugs, gene therapy drugs), alkylated anticancer drugs, antimetabolites, plant-derived anticancer drugs, anticancer antibiotics, BRM / cytokines, platinum complex anticancer drugs, immunotherapy drugs, hormone anticancer drugs, monoclonal antibodies, etc. Drugs, drugs for central nervous system, drugs for peripheral nervous system / sensory organs, drugs for treating respiratory diseases, drugs for cardiovascular system, drugs for digestive organs, drugs for hormonal system, drugs for urology / genital organs, vitamins / nutritional tonics, metabolic Drugs, antibiotics / chemotherapeutic drugs, test drugs, anti-inflammatory drugs, eye disease drugs, central nervous system drugs, autoimmune drugs, cardiovascular drugs, lifestyle-related drugs such as diabetes and hyperlipidemia, Corticosteroids, immunosuppressants, antibacterial agents, antiviral agents, angiogenesis inhibitors, cytokines, chemokines, anti-cytokine antibodies, anti-chemokine antibodies, anti-cytokine / chemokines Gene therapy-related nucleic acid preparations such as body antibodies, siRNA, shRNA, miRNA, smRNA, antisense RNA or ODN or DNA, neuroprotective factors, antibody drugs, molecular targeting drugs, osteoporosis / bone metabolism improving drugs, neuropeptides, physiology Examples include active peptides and proteins. For example, as a tumor drug, alkylation of nitrogen mustard-N-oxide, cyclophosphamide, ifosfamide, pulsphan, nimustine hydrochloride, mitoblonitol, melphalan, dacarbazine, ranimustine, estramustine phosphate sodium, etc. Agents, mercaptopurine, thioinosine (mercaptopurine riboside), methotrexate, enositabine, cytarabine, ancitabine hydrochloride (cyclocytidine hydrochloride), fluorouracil, 5-FU, tegafur, doxyfluridine, carmofur and other antimetabolites, etoposide, bin plastin sulfate , Plant-derived anticancer agents such as pinklistin sulfate, vindesine sulfate, paclitaxel, taxol, irinotecan hydrochloride, nogitecan hydrochloride and other alkaloids, actinomycin Anticancer antibiotics such as mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride (acracinomycin A), pirarubicin hydrochloride, epirubicin hydrochloride, neocarinostatin In addition, there are mitoxantrone hydrochloride, carboplatin, cisplatin, L-asparaginase, acegraton, procarbazine hydrochloride, tamoxifen citrate, ubenimex, lentinan, schizophyllan, medroxyprogesterone acetate, phosfestol, mepithiostane, epithiostanol and the like. In the present invention, the above-mentioned drugs include derivatives thereof.

By including the drug as described above, the liposome of the present invention can be used for treatment of diseases such as cancer and inflammation. Here, cancer includes all neoplastic diseases such as tumors and leukemias. When these drugs are contained in the sugar chain-modified liposome of the present invention and administered, the drugs accumulate at cancer and inflammation sites as compared to when the drug is administered alone. Compared to the case of single administration, it can accumulate 2 times or more, preferably 5 times or more, more preferably 10 times or more, and particularly preferably 50 times or more. Compared with oral administration of liposomes to which tris (hydroxymethyl) aminomethane is bound (reference liposomes), they can accumulate 3 to 4 times, preferably 4 to 6 times.

The sugar chain-modified liposome of the present invention can be used for treatment of various diseases by encapsulating a drug as described above. The drug-encapsulated sugar chain-modified liposome can be administered by intravenous injection or oral administration. In the sugar chain-modified liposome of the present invention, the medium transferred to the blood by oral administration shows the same tendency as intravenous injection for delivery to the organ when orally administered. It may be encapsulated inside or bound to the liposome surface. For example, a protein can be bound to the surface in the same manner as the above linker binding method, and other compounds can be bound by a known method by using a functional group of the compound. . In addition, the encapsulation inside the liposome is performed by the following method. Well-known methods may be used to encapsulate drugs in liposomes, including phosphatidylethanolamines, phosphatidic acids or long-chain alkyl phosphates, gangliosides, glycolipids or phosphatidylglycerols and lipids including cholesterols. By using them to form liposomes, drugs and the like are encapsulated in the liposomes.

Therefore, the liposome preparation obtained by encapsulating a drug or gene that can be used for treatment or diagnosis in the liposome of the present invention has selectively controlled migration to cancer tissue, inflammatory tissue, and various tissues. It is possible to enhance the efficacy by concentrating therapeutic drugs or diagnostic agents on target cells and tissues, or to reduce side effects by reducing the uptake of drugs to other cells and tissues.

When the drug delivery vehicle for intravenous administration and oral administration of the present invention is used for diagnosis, a labeling compound such as a fluorescent dye or a radioactive compound is encapsulated or bound to the liposome. The labeled compound-bound liposome binds to the affected area, the labeled compound is taken into the affected area cells, and the disease can be detected and diagnosed using the presence of the labeled compound as an index.

When the present invention is used as a diagnosis, for example, a DNA probe diagnostic agent, an X-ray contrast agent, a radioactive reagent, a radioactive contrast agent, a radioactive diagnostic agent, a fluorescent reagent, a fluorescent contrast agent, a fluorescent diagnostic agent, a CT contrast agent, for PET Contrast agent, SPECT contrast agent, MRI contrast agent, AIDS diagnostic agent, hematology test reagent, functional test reagent, microbial test reagent, molecular imaging, in vivo imaging, fluorescence imaging, luminescence imaging, cell sorter, PET and It can be used for SPECT or the like. Examples of research reagents include reagents used in recombinant DNA techniques, immunoassays, hybridization methods, and enzyme assays.

As a result of the present invention, for example, Example 9, Example 10, Example 24, and Example 25, this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand, so that a drug or fluorescent substance can be applied to a diseased part or various organs. And radiolabeled substances can be efficiently integrated and delivered by active targeting. Therefore, since the sugar chain-modified liposome of the present invention can visualize the accumulation in a target tissue such as a tumor, it also provides a delivery medium for use as a research reagent or a diagnostic agent as well as a therapeutic drug delivery medium. To do.

(Health / Food) The present invention can also be used in the field of health / food. In such a case, the points to be noted when used as an oral medicine as described above should be considered as necessary. In particular, when used as a functional food / health food such as a specific health food, it is preferable to treat it according to a medicine. Preferably, a food composition in which a functional food, a nutritional supplement or a health supplement is encapsulated or bound to the sugar chain-modified liposome of the present invention can be used. There is no limitation on the functional food, nutritional supplement or health supplement that can be used in the present invention, and any food that has been designed and processed and converted so as to effectively express the food function is included.

For example, Ginkgo biloba, Echinasia, Saw Palmetto, St. John's Wort, Valerian, Black Cohosh, Milk Thistle, Evening Primrose, Grape Seed Extract, Bil Perry, Feverfew, Tochigi, Soybean, French Coastal Pine, Garlic, Ginseng, Tea, Ginger, Agaricus, Meshimakobu , Purple Ipe, AHCC, Yeast Beta Glucan, Maitake, Propolis, Beer Yeast, Cereals, Plum, Chlorella, Barley Leaves, Green Juice, Vitamins, Collagen, Glucosamine, Mulberry Leaves, Rooibos Tea, Amino Acid, Royal Jelly, Shiitake Mycelium Extract , Spirulina, Tabuchi Carrot, Watercress, Plant Fermented Food, DHA, EPA, ARA, Kelp, Cabbage, Aloe, Megsurino Wood, Hops, Oyster Meat Extract, Pikudienol, Sesame, etc. Functional Food, Nutritional Supplement It can be exemplified as the goods or health supplements. These may be included in the liposome as they are, or a processed product such as an extract may be included. A food composition containing liposomes is taken orally. The liposome to be used may not have a sugar chain bound thereto, and may have a sugar chain that enhances intestinal absorption or a sugar chain targeted to a specific tissue or organ bound thereto. When the liposome of the present invention is administered as a food composition, it may be processed into a food such as a liquid beverage, a gel food, or a solid food. Moreover, you may process into a tablet, a granule, etc. The food composition of the present invention can be used as a functional food, a nutritional supplement or a health supplement depending on the type of food contained in the liposome.

For example, the liposome containing DHA can be used as a functional food, nutritional supplement or health supplement effective for mild senile dementia and memory improvement.

References such as scientific literature, patents and patent applications cited herein are hereby incorporated by reference in their entirety to the same extent as if each was specifically described.

In order to achieve the object of the present invention, preferred embodiments include the following items. (Item 1) Galactose (Gal), N-acetylgalactosamine (GalNAc), mannose (Man), glucose (Glc), N-acetylglucosamine (GlcNAc), fucose (Fuc), N-acetylneuraminic acid (Neu5Ac), galactose 3-sulfuric acid (3- (O-SO₃H) A sugar chain-modified liposome comprising a sugar chain containing at least one sugar selected from the group consisting of Gal), ceramide (Cer) and serine (Ser), and a liposome. (Item 2) The sugar chain has the following structure: R¹-X¹-X²-R²Where R¹And the R²Are independently hydrogen or any sugar chain, and the X¹Are Fuc, GalNAc, Gal, 3 '-(O-SO₃H) selected from the group consisting of Gal, GlcNAc, Man and Neu5Ac and the X²The sugar chain-modified liposome according to item 1, wherein is selected from the group consisting of Gal, Glc, GlcNAc, Ser, GalNAc, Cer and Man. (Item 3) The sugar chain is R²Item 3. The sugar chain-modified liposome according to item 2, which binds to the liposome directly on the side or indirectly like a hydrophobic interaction. (Item 4) X¹And X²Are α1,2 bond, α1,3 bond, α1,4 bond, α1,6 bond, α1-O-bond, α2,3 bond, α2,6 bond, β1,1 bond, β1, Selected from the group consisting of three bonds, β1,4 bonds and β1,6 bonds, wherein the α1-O-linkage is X²Item 3. The sugar chain-modified liposome according to Item 2, which exists when Ser is Ser. (Item 5) X¹-X²Is 3 '-(O-SO₃H) Gal-GlcNAc, Fuc-Gal, Fuc-Glc, Fuc-GlcNAc, Gal-Gal, Gal-GalNAc, Gal-Glc, Gal-GlcNAc, GalNAc-Gal, GalNAc-Ser, Glc-Cer, GlcNAc-Gal Item 3. The sugar chain-modified liposome according to Item 2, having a structure selected from the group consisting of GlcNAc-GlcNAc, Neu5Ac-GalNeu5Ac-GalNAcMan-Man, and Man-GlcNAc. (Item 6) X¹-X²Fucα1,2Gal, Fucα1,3Glc, Fucα1,3GlcNAc, Fucα1,4GlcNAc, 3 ′-(O—SO₃H) Galβ1, 3GlcNAc, Galα1,3Gal, Galβ1,3GalNAc, Galβ1,3GlcNAc, Galβ1,4Glc, Galβ1,4GlcNAc, Galβ1,6GlcNAc, GalNAcα1,3Gal, GalNAcα1-O-Lcβ GlcNAcβ1,4GlcNAc, Glcβ1,1CerNeu5Acα2,3Gal, Neu5Acα2,6GalNAcManα1,2ManManα1,3ManManα1,4ManManαα, 6Man and Manβ1,4GlcNAc, a structure selected from the group consisting of the saccharides and a structure selected from the liposomes selected from the group 5 (Item 7) The sugar chain has the following structure: R¹-X¹-X²-X³-R²Where R¹And the R²Are independently hydrogen or any sugar chain, and the X¹Is selected from the group consisting of Fuc, Gal, GalNAc, GlcNAc, Man and Neu5Ac, and said X²Is selected from the group consisting of Gal, GlcNAc, GalNAc and Man, and said X³The sugar chain-modified liposome according to item 1, wherein is selected from the group consisting of Glc, GlcNAc, Gal, GalNAc, Ser, Cer and Man. (Item 8) The sugar chain is R²8. The sugar chain-modified liposome according to item 7, which binds to the liposome directly on the side or indirectly like a hydrophobic interaction. (Item 9) X¹And X²Between X and X²And X³And at least one sugar chain bond selected from the group consisting of the bonds between¹And X²Are α1,2 bond, α1,3 bond, α1,4 bond, β1,3 bond, β1,4 bond, α2,3 bond, α2,6 bond, α1,6 bond and α1,3. Selected from the group consisting of a bond and the X²And X³The bond between and is composed of β1,1 bond, β1,3 bond, β1,4 bond, α1,2 bond, α1-O-bond, α1,6 bond, α1,3 bond and β1,4 bond Where the α1-O-bond is X³8. The sugar chain-modified liposome according to item 7, wherein is present in Ser. (Item 10) X¹And X²Between X and X²And X³And all of the sugar chain bonds selected from the group consisting of the bonds between¹And X²Are α1,2 bond, α1,3 bond, α1,4 bond, β1,3 bond, β1,4 bond, α2,3 bond, α2,6 bond, α1,6 bond and α1,3. Selected from the group consisting of a bond and the X²And X³The bond between and is composed of β1,1 bond, β1,3 bond, β1,4 bond, α1,2 bond, α1-O-bond, α1,6 bond, α1,3 bond and β1,4 bond Where, α
1-O-linkage is X³8. The sugar chain-modified liposome according to item 7, wherein is present in Ser. (Item 11) X¹-X²-X³Are Fuc-Gal-Glc, Fuc-Gal-GlcNAc, Fuc-GlcNAc-Gal, Gal-GalNAc-Gal, Gal-GlcNAc-Gal, Gal-GlcNAc-Gal, Gal-Glc-Cer, GlcNAc-Glc, A structure selected from the group consisting of Neu5Ac-Gal-GalNAc, Neu5Ac-Gal-Glc, Neu5Ac-Gal-GlcNAc, Neu5Ac-GalNAc-Ser, Man-Man-Man, Man-Man-GlcNAc, and Man-GlcNAc-GlcNAc 8. The sugar chain-modified liposome according to item 7, which has (Item 12) X¹-X²-X³Are Fucα1,2Galβ1,3GlcNAc, Fucα1,2Galβ1,4Glc, Fucα1,2Galβ1,4GlcNAc, Fucα1,4GlcNAcβ1,3Gal, Galβ1,3GalNAcβ1,4Gal, Galβ1,4GalNAc1, Gal3c, Gal3 GlcNAcβ1,3Galβ1,4Glc, Neu5Acα2,3Galβ1,3GalNAc, Neu5Acα2,3Galβ1,3GlcNAc, Neu5Acα2,3Galβ1,4Glc, Ne5Acα2,3Galβ1,4GlcNAc, N6 2Man, Manα1,2Manα1,3Man, Manα1,2Manα1,6Man, Manα1,3Manα1,6Man, Manα1,3Manβ1,4GlcNAc, Manα1,6Manβ1,4GlcNAc, and a structure having the structure 11 selected from the group consisting of Manβ1,4GlcNAcβ1,4GlcNAc The sugar chain-modified liposome described. (Item 13) The sugar chain has the following structure: R¹-X¹-X²-X³-X⁴-R²Where R¹And the R²Are independently hydrogen or any sugar chain, and the X¹Is selected from the group consisting of Fuc, Gal, Neu5Ac and Man, and the X²Is selected from the group consisting of Gal, GalNAc, GlcNAc and Man;³Is selected from the group consisting of GlcNAc, GalNAc, Gal and Man, and the X⁴The sugar chain-modified liposome according to item 1, wherein is selected from the group consisting of Gal, Glc, Man, Cer and GlcNAc. (Item 14) The sugar chain is R²13. The sugar chain-modified liposome according to item 12, which binds to the liposome directly on the side or indirectly like a hydrophobic interaction. (Item 15) X¹And X²The bond between and X²And X³Between X and X³And X⁴And at least one sugar chain bond selected from the group consisting of¹And X²Is selected from the group consisting of α1,2 bond, α1,3 bond, α2,3 bond, β1,3 bond and α1,6 bond,²And X³Is selected from the group consisting of β1,3 bond, β1,4 bond, α1,2 bond, α1,3 bond, and α1,6 bond,³And X⁴14. The sugar chain-modified liposome according to item 13, wherein the bond between and is selected from the group consisting of β1,1 bond, β1,3 bond, β1,4 bond, α1,3 bond and α1,6 bond. (Item 16) X¹And X²The bond between and X²And X³Between X and X³And X⁴And at least two sugar chain bonds selected from the group consisting of bonds between¹And X²Is selected from the group consisting of α1,2 bond, α1,3 bond, α2,3 bond, β1,3 bond and α1,6 bond,²And X³Is selected from the group consisting of β1,3 bond, β1,4 bond, α1,2 bond, α1,3 bond, and α1,6 bond,³And X⁴14. The sugar chain-modified liposome according to item 13, wherein the bond between and is selected from the group consisting of β1,1 bond, β1,3 bond, β1,4 bond, α1,3 bond and α1,6 bond. (Item 17) X¹And X²The bond between and X²And X³Between X and X³And X⁴And all of the sugar chain bonds selected from the group consisting of the bonds between¹And X²Is selected from the group consisting of α1,2 bond, α1,3 bond, α2,3 bond, β1,3 bond and α1,6 bond,²And X³Is selected from the group consisting of β1,3 bond, β1,4 bond, α1,2 bond, α1,3 bond, and α1,6 bond,³And X⁴14. The sugar chain-modified liposome according to item 13, wherein the bond between and is selected from the group consisting of β1,1 bond, β1,3 bond, β1,4 bond, α1,3 bond and α1,6 bond. (Item 18) X¹-X²-X³-X⁴Is Fuc-Gal-GlcNAc-Gal, Fuc-GlcNAc-Gal-Glc, GalNAc-Gal-Glc-Cer, Gal-GalNAc-Gal-Glc, Gal-GlcNAc-Gal-Glc, Neu5Ac-Gal-GalNAc-Gal 14. The sugar chain according to item 13, having a structure selected from the group consisting of Neu5Ac-Gal-Glc-Cer, Man-Man-Man-Man, Man-Man-Man-GlcNAc, and Man-Man-GlcNAc-GlcNAc. Modified liposomes. (Item 19) X¹-X²-X³-X⁴Are Fucα1,2Galβ1,3GlcNAcβ1,3Gal, Fucα1,4GlcNAcβ1,3Galβ1,4Glc, GalNAcβ1,4Galβ1,4Glcβ1,1Cer, Galβ1,3GalNAβ1,4Galβ1,4Glc, Galβ1,3Glc3GG3β Neu5Acα2,3Galβ1,4Glcβ1,4Cer, Manα1,2Manα1,2Manα1,3Man, Manα1,2Manα1,3Manα1,6Man, Manα1,2Manα1,3Manβ1,4GlcNAc, Manα1,2Manα1,6Manα1,6Man, Man4 3Manβ1,4 Item 19. The sugar chain-modified liposome according to Item 18, having a structure selected from the group consisting of GlcNAcβ1,4GlcNAc, Manα1,6Manα1,6Manβ1,4GlcNAc and Manα1,6Manβ1,4GlcNAcβ1,4GlcNAc. (Item 20) The sugar chain has the following structure: R¹-X¹-X²-X³-X⁴-X⁵-R²Where R¹And the R²Are independently hydrogen or any sugar chain, and the X¹Is selected from the group consisting of Fuc, Neu5Ac and Man;²Is Gal or Man, and the X³Is selected from the group consisting of GlcNAc, GalNAc and Man;⁴Is selected from the group consisting of Gal, GlcNAc and Man, and the X⁵The sugar chain-modified liposome according to item 1, wherein is selected from the group consisting of Glc, Cer and GlcNAc. (Item 21) The sugar chain is R²Item 21. The sugar chain-modified liposome according to item 20, which binds to the liposome directly on the side or indirectly like a hydrophobic interaction. (Item 22) X¹And X²The bond between and X²And X³The bond between and X³And X⁴Between X and X⁴And X⁵Wherein at least one sugar chain bond selected from the group consisting of bonds between and is defined, wherein X¹And X²Are selected from the group consisting of β1,3 bond, α1,2 bond, α2,3 bond, α1,3 bond and α1,6 bond,²And X³Are selected from the group consisting of β1,3 bond, α1,2 bond, α1,3 bond and α1,6 bond,³And X⁴Is selected from the group consisting of β1,3 bond, β1,4 bond, α1,3 bond and α1,6 bond,⁴And X⁵Item 21. The sugar chain-modified liposome according to Item 20, wherein the bond between and is a β1,1 bond or a β1,4 bond. (Item 23) X¹And X²The bond between and X²And X³The bond between and X³And X⁴Between X and X⁴And X⁵Wherein at least two sugar chain bonds selected from the group consisting of bonds between and are defined, wherein X¹And X²Are selected from the group consisting of β1,3 bond, α1,2 bond, α2,3 bond, α1,3 bond and α1,6 bond,²And X³Are selected from the group consisting of β1,3 bond, α1,2 bond, α1,3 bond and α1,6 bond,³And X⁴Is selected from the group consisting of β1,3 bond, β1,4 bond, α1,3 bond and α1,6 bond,⁴And X⁵Item 21. The sugar chain-modified liposome according to Item 20, wherein the bond between and is a β1,1 bond or a β1,4 bond. (Item 24) X¹And X²The bond between and X²And X³The bond between and X³And X⁴Between X and X⁴And X⁵Wherein at least three sugar chain bonds selected from the group consisting of bonds between and are defined, wherein X¹And X²Are selected from the group consisting of β1,3 bond, α1,2 bond, α2,3 bond, α1,3 bond and α1,6 bond,²And X³Are selected from the group consisting of β1,3 bond, α1,2 bond, α1,3 bond and α1,6 bond,³And X⁴Is selected from the group consisting of β1,3 bond, β1,4 bond, α1,3 bond and α1,6 bond,⁴And X⁵Item 21. The sugar chain-modified liposome according to Item 20, wherein the bond between and is a β1,1 bond or a β1,4 bond. (Item 25) X¹And X²The bond between and X²And X³The bond between and X³And X⁴Between X and X⁴And X⁵All of the sugar chain bonds selected from the group consisting of the bonds between¹And X²Are selected from the group consisting of β1,3 bond, α1,2 bond, α2,3 bond, α1,3 bond and α1,6 bond,²And X³Are selected from the group consisting of β1,3 bond, α1,2 bond, α1,3 bond and α1,6 bond,³And X⁴Is selected from the group consisting of β1,3 bond, β1,4 bond, α1,3 bond and α1,6 bond,⁴And X⁵Item 21. The sugar chain-modified lipo of Item 20, wherein the bond between and is a β1,1 bond or β1,4 bond
Some. (Item 26) X¹-X²-X³-X⁴-X⁵Are Fuc-Gal-GlcNAc-Gal-Glc, Gal-GalNAc-Gal-Glc-Cer, Neu5Ac-Gal-GalNAc-Gal-Glc, Man-Man-Man-Man-GlcNAc and Man-Man-Man-GlcNAc- Item 21. The sugar chain-modified liposome according to Item 20, having a structure selected from the group consisting of GlcNAc. (Item 27) X¹-X²-X³-X⁴-X⁵Are Fucα1,2Galβ1,3GlcNAcβ1,3Galβ1,4Glc, Galβ1,3GalNAcβ1,4Glcβ1,1Cer, Neu5Acα2,3Galβ1,3GalNAcβ1,4Galβ1,4Glcβ, Manα1,2Manα1, M3,4Glcβ Selected from 4GlcNAc, Manα1,2Manα1,3Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,2Manα1,6Manα1,6Manβ1,4GlcNAc, Manα1,3Manα1,6Manβ1,4GlcNAcβ1,4GlcNAc1,4GlcNAc1,4GlcNAc1,4GlcNAc1,4GlcNAc, 4 The To, liposome modified by a sugar chain according to claim 26. (Item 28) The sugar chain has the following structure: R¹-X¹-X²-X³-X⁴-X⁵-X⁶-R²Where R¹And the R²Are independently hydrogen or any sugar chain, and the X¹Is Man or Neu5Ac and the X²Is Man or Gal and the X³Is Man or GalNAc, and the X⁴Is Man or Gal and the X⁵Is GlcNAc or Glc and the X⁶Is a sugar chain-modified liposome according to item 1, which is GlcNAc or Cer. (Item 29) The sugar chain is R²29. The sugar chain-modified liposome according to item 28, which binds to the liposome directly on the side or indirectly like a hydrophobic interaction. (Item 30) X¹And X²The bond between and X²And X³The bond between and X³And X⁴The bond between and X⁴And X⁵Between X and X⁵And X⁶Wherein at least one sugar chain bond selected from the group consisting of bonds between and is defined, wherein X¹And X²Is a α1,2 bond or α2,3 bond,²And X³Is a α1,2 bond, α1,3 bond, α1,6 bond or β1,3 bond,³And X⁴Is a α1,3 bond or an α1,6 bond, and the X⁴And X⁵Is a β1,4 bond, and the X⁵And X⁶Item 29. The sugar chain-modified liposome according to Item 28, wherein the bond between and is a β1,1 bond or β1,4 bond. (Item 31) X¹And X²The bond between and X²And X³The bond between and X³And X⁴The bond between and X⁴And X⁵Between X and X⁵And X⁶Wherein at least two sugar chain bonds selected from the group consisting of bonds between and are defined, wherein X¹And X²Is a α1,2 bond or α2,3 bond,²And X³Is a α1,2 bond, α1,3 bond, α1,6 bond or β1,3 bond,³And X⁴Is a α1,3 bond or an α1,6 bond, and the X⁴And X⁵Is a β1,4 bond, and the X⁵And X⁶Item 29. The sugar chain-modified liposome according to Item 28, wherein the bond between and is a β1,1 bond or β1,4 bond. (Item 32) X¹And X²The bond between and X²And X³The bond between and X³And X⁴The bond between and X⁴And X⁵Between X and X⁵And X⁶Wherein at least three sugar chain bonds selected from the group consisting of bonds between and are defined, wherein X¹And X²Is a α1,2 bond or α2,3 bond,²And X³Is a α1,2 bond, α1,3 bond, α1,6 bond or β1,3 bond,³And X⁴Is a α1,3 bond or an α1,6 bond, and the X⁴And X⁵Is a β1,4 bond, and the X⁵And X⁶Item 29. The sugar chain-modified liposome according to Item 28, wherein the bond between and is a β1,1 bond or β1,4 bond. (Item 33) X¹And X²The bond between and X²And X³The bond between and X³And X⁴The bond between and X⁴And X⁵Between X and X⁵And X⁶And at least four sugar chain bonds selected from the group consisting of the bonds between¹And X²Is a α1,2 bond or α2,3 bond,²And X³Is a α1,2 bond, α1,3 bond, α1,6 bond or β1,3 bond,³And X⁴Is a α1,3 bond or an α1,6 bond, and the X⁴And X⁵Is a β1,4 bond, and the X⁵And X⁶Item 29. The sugar chain-modified liposome according to Item 28, wherein the bond between and is a β1,1 bond or β1,4 bond. (Item 34) X¹And X²The bond between and X²And X³The bond between and X³And X⁴The bond between and X⁴And X⁵Between X and X⁵And X⁶All of the sugar chain bonds selected from the group consisting of the bonds between¹And X²Is a α1,2 bond or α2,3 bond,²And X³Is a α1,2 bond, α1,3 bond, α1,6 bond or β1,3 bond,³And X⁴Is a α1,3 bond or an α1,6 bond, and the X⁴And X⁵Is a β1,4 bond, and the X⁵And X⁶Item 29. The sugar chain-modified liposome according to Item 28, wherein the bond between and is a β1,1 bond or β1,4 bond. (Item 35) X¹-X²-X³-X⁴-X⁵-X⁶30. The sugar chain-modified liposome according to Item 28, which is Man-Man-Man-Man-GlcNAc-GlcNAc or Neu5Ac-Gal-GalNAc-Gal-Glc-Cer. (Item 36) X¹-X²-X³-X⁴-X⁵-X⁶Are Manα1,2Manα1,3Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,2Manα1,3Manα1,6Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,2Manα1,6Manα1,6G3NAc1,4GlcNAc 36. The sugar chain-modified liposome according to item 35, which has a structure selected from the group consisting of: (Item 37) The sugar chain-modified liposome according to item 1, wherein the sugar at the most proximal end of the liposome of the sugar chain is selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc and Ser, and combinations thereof. (Item 38) The sugar at the most distal end of the liposome of the sugar chain is Gal, 3 '-(O-SO₃H) The sugar chain-modified liposome according to item 1, selected from the group consisting of Gal, GalNAc, Man, Fuc and Neu5Ac and combinations thereof. (Item 39) The sugar at the most proximal end of the liposome of the sugar chain is selected from the group consisting of Gal, GalNAc, Man, Glc, GlcNAc and Ser, and combinations thereof, and the sugar at the most distal end of the liposome of the sugar chain Is Gal, GalNAc, 3 ′-(O—SO₃H) The sugar chain-modified liposome according to item 1, selected from the group consisting of Gal, Man, Fuc and Neu5Ac and combinations thereof. (Item 40) The sugar chain-modified liposome according to item 37, wherein the sugar at the most proximal end of the liposome of the sugar chain is Ser or Cer. (Item 41) The sugar at the most distal end of the liposome of the sugar chain is 3 '-(O-SO₃H) The sugar chain-modified liposome according to Item 38, which is Gal. (Item 42) The liposome distal end of the sugar chain has the following structure: Fuc from the distal end side.¹-A²-R^ZWhere A²Is selected from the group consisting of Gal, Glc and GlcNAc, and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 43) Fuc¹And A²43. The sugar chain-modified liposome according to Item 42, wherein the bond between and is selected from the group consisting of α1,2 bond, α1,3 bond and α1,4 bond. (Item 44) The sugar chain modification according to item 42, wherein the liposome distal end of the sugar chain has a structure selected from the group consisting of Fuc-Gal, Fuc-Glc and Fuc-GlcNAc from the distal end side. Liposome. (Item 45) The liposome distal end of the sugar chain has a structure selected from the group consisting of Fucα1,2Gal, Fucα1,3Glc, Fucα1,3GlcNAc and Fucα1,4GlcNAc from the distal end side. The sugar chain-modified liposome. (Item 46) The liposome distal end of the sugar chain has the following structure: Fuc from the distal end side.¹-A²-A³-R^ZWhere A²Is Gal or GlcNAc, and the A³Is selected from the group consisting of Glc, Gal and GlcNAc, and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 47) Fuc¹And A²Between and A²And A³At least one sugar chain bond selected from the group consisting of a bond between and wherein Fuc¹And A²Is a α1,2 bond or α1,4 bond,²And A³47. The sugar chain-modified liposome according to item 46, wherein the bond between and is a β1,3 bond or β1,4 bond. (Item 48) Fuc¹And A²Between and A²And A³All of the sugar chain bonds selected from the group consisting of the bonds between and wherein Fuc¹And A²Is a α1,2 bond or α1,4 bond,²And A³47. The sugar chain-modified liposome according to item 46, wherein the bond between and is a β1,3 bond or β1,4 bond. (Item 49) The liposome distal end of the sugar chain has a structure selected from the group consisting of Fuc-Gal-Glc, Fuc-Gal-GlcNAc and Fuc-GlcNAc-Gal from the distal end side. The sugar chain-modified liposome according to 1. (Item 50) The liposome distal end of the sugar chain is F from the distal end side.
50. The sugar chain-modified liposome according to Item 49, having a structure selected from the group consisting of ucα1,2Galβ1,4Glc, Fucα1,2Galβ1,3GlcNAc, Fucα1,2Galβ1,4GlcNAc and Fucα1,4GlcNAcβ1,3Gal. (Item 51) The liposome distal end of the sugar chain has the following structure: Fuc from the distal end side.¹-A²-A³-A⁴-R^ZWhere A²Is Gal or GlcNA, and the A³Is Gal or GlcNA, and the A⁴Is Gal or Glc and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 52) Fuc¹And A²The bond between and A²And A³Between and A³And A⁴At least one sugar chain bond selected from the group consisting of a bond between and wherein Fuc¹And A²Is a α1,2 bond or α1,4 bond,²And A³Is a β1,3 bond, and the A³And A⁴Item 52. The sugar chain-modified liposome according to Item 51, wherein the bond between and is a β1,3 bond or β1,4 bond. (Item 53) Fuc¹And A²The bond between and A²And A³Between and A³And A⁴And at least two sugar chain bonds selected from the group consisting of bonds between and wherein Fuc¹And A²Is a α1,2 bond or α1,4 bond,²And A³Is a β1,3 bond, and the A³And A⁴Item 52. The sugar chain-modified liposome according to Item 51, wherein the bond between and is a β1,3 bond or β1,4 bond. (Item 54) Fuc¹And A²The bond between and A²And A³Between and A³And A⁴All of the sugar chain bonds selected from the group consisting of the bonds between and wherein Fuc¹And A²Is a α1,2 bond or α1,4 bond,²And A³Is a β1,3 bond, and the A³And A⁴Item 52. The sugar chain-modified liposome according to Item 51, wherein the bond between and is a β1,3 bond or β1,4 bond. (Item 55) The sugar chain-modified liposome according to item 51, wherein the liposome distal end of the sugar chain has a structure of Fuc-Gal-GlcNAc-Gal or Fuc-GlcNAc-Gal-Glc from the distal end side. (Item 56) The sugar chain modification according to item 55, wherein the liposome distal end of the sugar chain has a structure of Fucα1,2Galβ1,3GlcNAcβ1,3, Gal or Fucα1,4GlcNAcβ1,3Galβ1,4Glc from the distal end side. Liposome. (Item 57) The liposome distal end of the sugar chain has the following structure: Fuc from the distal end side.¹-A²-A³-A⁴-A⁵-R^ZWhere A²Is Gal and the A³Is GlcNA and the A⁴Is Gal and the A⁵Is Glc and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 58) Fuc¹And A²The bond between and A²And A³The bond between and A³And A⁴Between and A⁴And A⁵At least one sugar chain bond selected from the group consisting of a bond between and wherein Fuc¹And A²Is a α1,2 bond, and the A²And A³Is a β1,3 bond, and the A³And A⁴Is a β1,3 bond, and the A⁴And A⁵58. The sugar chain-modified liposome according to item 57, wherein the bond between and is a β1,4 bond. (Item 59) Fuc¹And A²The bond between and A²And A³The bond between and A³And A⁴Between and A⁴And A⁵And at least two sugar chain bonds selected from the group consisting of bonds between and wherein Fuc¹And A²Is a α1,2 bond, and the A²And A³Is a β1,3 bond, and the A³And A⁴Is a β1,3 bond, and the A⁴And A⁵58. The sugar chain-modified liposome according to item 57, wherein the bond between and is a β1,4 bond. (Item 60) Fuc¹And A²The bond between and A²And A³The bond between and A³And A⁴Between and A⁴And A⁵And at least three sugar chain bonds selected from the group consisting of bonds between and wherein Fuc¹And A²Is a α1,2 bond, and the A²And A³Is a β1,3 bond, and the A³And A⁴Is a β1,3 bond, and the A⁴And A⁵58. The sugar chain-modified liposome according to item 57, wherein the bond between and is a β1,4 bond. (Item 61) Fuc¹And A²The bond between and A²And A³The bond between and A³And A⁴Between and A⁴And A⁵And at least four sugar chain bonds selected from the group consisting of bonds between and wherein Fuc¹And A²Is a α1,2 bond, and the A²And A³Is a β1,3 bond, and the A³And A⁴Is a β1,3 bond, and the A⁴And A⁵58. The sugar chain-modified liposome according to item 57, wherein the bond between and is a β1,4 bond. (Item 62) Fuc¹And A²The bond between and A²And A³The bond between and A³And A⁴Between and A⁴And A⁵All of the sugar chain bonds selected from the group consisting of the bonds between and wherein Fuc¹And A²Is a α1,2 bond, and the A²And A³Is a β1,3 bond, and the A³And A⁴Is a β1,3 bond, and the A⁴And A⁵58. The sugar chain-modified liposome according to Item 57, wherein the bond between and is a β1,4 bond. (Item 63) The sugar chain-modified liposome according to item 57, wherein a liposome distal end of the sugar chain has a structure of Fuc-Gal-GlcNAc-Gal-Glc from the distal end side. (Item 64) The sugar chain-modified liposome according to item 63, wherein a liposome distal end of the sugar chain has a structure of Fucα1,2Galβ1,3GlcNAcβ1,3Galβ1,4Glc from the distal end side. (Item 65) The liposome distal end of the sugar chain has the following structure: Gal from the distal end side.¹-B²-R^ZWhere the Gal¹May be sulfated or unsulfated, and the B²Is selected from the group consisting of Gal, GalNAc, GlcNAc and Glc, and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 66) Gal¹And B²66. The sugar chain-modified liposome according to item 65, wherein the bond between and is selected from the group consisting of α1,3 bond, β1,3 bond, β1,4 bond and β1,6 bond. (Item 67) The liposome distal end of the sugar chain has a structure selected from the group consisting of Gal-Gal, Gal-GalNAc, Gal-Glc and Gal-GlcNAc from the distal end side. The sugar chain-modified liposome. (Item 68) The liposome distal end of the sugar chain is selected from the group consisting of Galα1,3Gal, Galβ1,3GalNAc, Galβ1,3GlcNAc, Galβ1,4Glc, Galβ1,4GlcNAc and Galβ1,6GlcNAc from the distal end side. 68. The sugar chain-modified liposome according to item 65, which has a structure. (Item 69) The liposome distal end of the sugar chain has the following structure: Gal from the distal end side.¹-B²-B³-R^ZWhere the Gal¹May be sulfated or unsulfated, and the B²Is GalNAc or GlcNAc, and the B³Is Gal and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 70) Gal¹And B²Between B and B²And B³At least one sugar chain bond selected from the group consisting of a bond between¹And B²Is a β1,3 bond, and B²And B³Item 70. The sugar chain-modified liposome according to Item 69, wherein the bond between and is a β1,4 bond or β1,3 bond. (Item 71) Gal¹And B²Between B and B²And B³All of the glycan linkages selected from the group consisting of the linkages between and wherein the Gal¹And B²Is a β1,3 bond, and B²And B³Item 70. The sugar chain-modified liposome according to Item 69, wherein the bond between and is a β1,4 bond or β1,3 bond. (Item 72) The sugar chain-modified liposome according to item 69, wherein a liposome distal end of the sugar chain has a Gal-GalNAc-Gal or Gal-GlcNAc-Gal structure from the distal end side. (Item 73) The liposome distal end of the sugar chain has a structure selected from the group consisting of Galβ1,3GalNAcβ1,4Gal, Galβ1,3GlcNAcβ1,3Gal and Galβ1,3GlcNAcβ1,3Gal from the distal end side. The sugar chain-modified liposome according to 1. (Item 74) The liposome distal end of the sugar chain has the following structure: Gal from the distal end side.¹-B²-B³-B⁴-R^ZWhere the Gal¹May be sulfated or unsulfated, and the B²Is GalNAc or GlcNAc, and the B³Is Gal and the B⁴Is Glc and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 75) Gal¹And B²Bond between and B²And B³Between B and B³And B⁴At least one sugar chain bond selected from the group consisting of a bond between¹And B²Is a β1,3 bond, and B²And B³Is a β1,4 bond or β1,3 bond,³And B⁴75. The sugar chain-modified liposome according to item 74, wherein the bond between and is a β1,4 bond. (Item 76) Gal¹And B²Bond between and B²And B³Between B and B³And B⁴And at least two sugar chain bonds selected from the group consisting of bonds between¹And B²The bond between
1, 3 bonds, and the B²And B³Is a β1,4 bond or β1,3 bond,³And B⁴75. The sugar chain-modified liposome according to item 74, wherein the bond between and is a β1,4 bond. (Item 77) Gal¹And B²Bond between and B²And B³Between B and B³And B⁴All of the sugar chain bonds selected from the group consisting of the bonds between¹And B²Is a β1,3 bond, and B²And B³Is a β1,4 bond or β1,3 bond,³And B⁴75. The sugar chain-modified liposome according to item 74, wherein the bond between and is a β1,4 bond. (Item 78) The sugar chain-modified liposome according to item 74, wherein a liposome distal end of the sugar chain has a structure of Gal-GalNAc-Gal-Glc or Gal-GlcNAc-Gal-Glc from the distal end side. (Item 79) The sugar chain-modified liposome according to item 79, wherein the liposome distal end of the sugar chain has a structure of Galβ1,3GalNAcβ1,4Galβ1,4Glc or Galβ1,3GlcNAcβ1,3Galβ1,4Glc from the distal end side. (Item 80) The liposome distal end of the sugar chain has the following structure: Gal from the distal end side.¹-B²-B³-B⁴-B⁵-R^ZWhere the Gal¹May be sulfated or unsulfated, and the B²Is GalNAc and the B³Is Gal and the B⁴Is Glc and the B⁵Is Cer and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 81) Gal¹And B²The bond between and B²And B³The bond between and B³And B⁴Between B and B⁴And B⁵At least one sugar chain bond selected from the group consisting of a bond between¹And B²Is a β1,3 bond, and B²And B³Is a β1,4 bond, and B³And B⁴Is a β1,4 bond, and B⁴And B⁵Item 91. The sugar chain-modified liposome according to Item 80, wherein the bond between and is a β1,1 bond. (Item 82) Gal¹And B²Bond between and B²And B³Bond between and B³And B⁴Between B and B⁴And B⁵And at least two sugar chain bonds selected from the group consisting of bonds between¹And B²Is a β1,3 bond, and B²And B³Is a β1,4 bond, and B³And B⁴Is a β1,4 bond, and B⁴And B⁵Item 91. The sugar chain-modified liposome according to Item 80, wherein the bond between and is a β1,1 bond. (Item 83) Gal¹And B²The bond between and B²And B³The bond between and B³And B⁴Between B and B⁴And B⁵And at least three sugar chain bonds selected from the group consisting of bonds between¹And B²Is a β1,3 bond, and B²And B³Is a β1,4 bond, and B³And B⁴Is a β1,4 bond, and B⁴And B⁵Item 91. The sugar chain-modified liposome according to Item 80, wherein the bond between and is a β1,1 bond. (Item 84) Gal¹And B²The bond between and B²And B³The bond between and B³And B⁴Between B and B⁴And B⁵All of the sugar chain bonds selected from the group consisting of the bonds between¹And B²Is a β1,3 bond, and B²And B³Is a β1,4 bond, and B³And B⁴Is a β1,4 bond, and B⁴And B⁵Item 91. The sugar chain-modified liposome according to Item 80, wherein the bond between and is a β1,1 bond. (Item 85) The sugar chain-modified liposome according to item 80, wherein the liposome distal end of the sugar chain has a structure of Gal-GalNAc-Gal-Glc-Cer from the distal end side. (Item 86) The sugar chain-modified liposome according to item 85, wherein the liposome distal end of the sugar chain has a structure of Galβ1,3GalNAcβ1,4Galβ1,4Glcβ1,1Cer from the distal end side. (Item 87) The liposome distal end of the sugar chain has the following structure: GalNAc from the distal end side.¹-C²-R^ZWhere C²Is Gal or Ser and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 88) GalNAc¹And C²Is a α1,3 bond or a 1-O— bond, where the α1-O— bond is C 1²Item 81. The sugar chain-modified liposome according to Item 80, which exists when Ser is Ser. (Item 89) The sugar chain-modified liposome according to item 87, wherein the liposome distal end of the sugar chain has a structure of GalNAc-Gal or GalNAc-Ser from the distal end side. (Item 90) The sugar chain-modified liposome according to item 89, wherein a liposome distal end of the sugar chain has a structure of GalNAcα1,3Gal or GalNAcα1-OL-Ser from the distal end side. (Item 91) The liposome distal end of the sugar chain has the following structure: Man from the distal end side.¹-D²-R^ZWhere D²Is Man and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 92) Man¹And D²92. The sugar chain-modified liposome according to Item 91, wherein the bond between and is selected from the group consisting of α1,2 bond, α1,3 bond, α1,4 bond and α1,6 bond. (Item 93) The sugar chain-modified liposome according to item 91, wherein the liposome distal end of the sugar chain has a Man-Man structure from the distal end side. (Item 94) The liposome distal end of the sugar chain has a structure selected from the group consisting of Manα1,2Man, Manα1,3Man, Manα1,4Man and Manα1,6Man from the distal end side. The sugar chain-modified liposome. (Item 95) The liposome distal end of the sugar chain has the following structure: Man from the distal end side.¹-D²-D³-R^ZWhere D²Is Man and the D³Is GlcNAc or Man and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 96) Man¹And D²The bond between and D²And D³And at least one sugar chain bond selected from the group consisting of bonds between¹And D²Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,²And D³96. The sugar chain-modified liposome according to item 95, wherein the bond between and is selected from the group consisting of α1,2 bond, α1,3 bond, α1,6 bond and β1,4 bond. (Item 97) Man¹And D²The bond between and D²And D³And all of the sugar chain bonds selected from the group consisting of the bonds between¹And D²Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,²And D³96. The sugar chain-modified liposome according to item 95, wherein the bond between and is selected from the group consisting of α1,2 bond, α1,3 bond, α1,6 bond and β1,4 bond. (Item 98) The sugar chain-modified liposome according to item 95, wherein the liposome distal end of the sugar chain has a Man-Man-Man or Man-Man-GlcNAc structure from the distal end side. (Item 99) The liposome distal end of the sugar chain is Manα1,2Manα1,2Man, Manα1,2Manα1,3Man, Manα1,2Manα1,6Man, Manα1,3Manα1,6Man, Manα1,3Manβ1,4GlcNAc, 99. The sugar chain-modified liposome according to item 98, having a structure selected from the group consisting of Manα1,6Manα1,6Man and Manα1,6Manβ1,4GlcNAc. (Item 100) The liposome distal end of the sugar chain has the following structure: Man from the distal end side.¹-D²-D³-D⁴-R^ZWhere D²Is Man and the D³Is Man or GlcNAc, and the D⁴Is Man or GlcNAc and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 101) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴And at least one sugar chain bond selected from the group consisting of bonds between¹And D²Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond, α1,6 bond and β1,4 bond,³And D⁴101. The sugar chain-modified liposome according to item 100, wherein the bond between and is selected from the group consisting of α1,3 bond, α1,6 bond and β1,4 bond. (Item 102) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴And at least two sugar chain bonds selected from the group consisting of bonds between and¹And D²Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond, α1,6 bond and β1,4 bond,³And D⁴101. The sugar chain-modified liposome according to item 100, wherein the bond between and is selected from the group consisting of α1,3 bond, α1,6 bond and β1,4 bond. (Item 103) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴And all of the sugar chain bonds selected from the group consisting of the bonds between¹And D²Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond, α1,6 bond and β1,4 bond,³And D⁴101. The sugar chain-modified liposome according to item 100, wherein the bond between and is selected from the group consisting of α1,3 bond, α1,6 bond and β1,4 bond. (Item 104) The liposome distal end of the sugar chain is selected from the group consisting of Man-Man-Man-Man, Man-Man-Man-GlcNAc and Man-Man-GlcNAc-GlcNAc from the distal end side.
101. The sugar chain-modified liposome according to item 100, which has a structure as described above. (Item 105) The liposome distal end of the sugar chain is Manα1,2Manα1,2Manα1,3Man, Manα1,2Manα1,3Manα1,6Man, Manα1,2Manα1,3Manβ1,4GlcNAc, Manα1,2Manα1,6Manα1, from the distal end side. A group consisting of 6Man, Manα1,3Manα1,6Manβ1,4GlcNAc, Manα1,3Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,6Manα1,6Manβ1,4GlcNAc and a group consisting of the sugars of Manα1,6Manβ1,4GlcNAcβ1,4GlcNAc Chain-modified liposomes. (Item 106) The liposome distal end of the sugar chain has the following structure: Man from the distal end side.¹-D²-D³-D⁴-D⁵-R^ZWhere D²Is Man and the D³Is Man and the D⁴Is Man or GlcNAc, and the D⁵Is GlcNAc and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 107) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴The bond between and D⁴And D⁵And at least one sugar chain bond selected from the group consisting of bonds between¹And D²Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And D⁴Is selected from the group consisting of α1,3 bond, α1,6 bond and β1,4 bond,⁴And D⁵109. The sugar chain-modified liposome according to item 106, wherein the bond between and is a β1,4 bond. (Item 108) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴The bond between and D⁴And D⁵And at least two sugar chain bonds selected from the group consisting of bonds between and¹And D²Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And D⁴Is selected from the group consisting of α1,3 bond, α1,6 bond and β1,4 bond,⁴And D⁵109. The sugar chain-modified liposome according to item 106, wherein the bond between and is a β1,4 bond. (Item 109) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴The bond between and D⁴And D⁵And at least three sugar chain bonds selected from the group consisting of bonds between¹And D²Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And D⁴Is selected from the group consisting of α1,3 bond, α1,6 bond and β1,4 bond,⁴And D⁵109. The sugar chain-modified liposome according to item 106, wherein the bond between and is a β1,4 bond. (Item 110) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴The bond between and D⁴And D⁵And all of the sugar chain bonds selected from the group consisting of the bonds between¹And D²Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And D⁴Is selected from the group consisting of α1,3 bond, α1,6 bond and β1,4 bond,⁴And D⁵109. The sugar chain-modified liposome according to item 106, wherein the bond between and is a β1,4 bond. (Item 111) The sugar according to item 106, wherein the liposome distal end of the sugar chain has a structure of Man-Man-Man-Man-GlcNAc or Man-Man-Man-GlcNAc-GlcNAc from the distal end side. Chain-modified liposomes. (Item 112) The liposome distal end of the sugar chain is Manα1,2Manα1,2Manα1,3Manβ1,4GlcNAc, Manα1,2Manα1,3Manα1,6Manβ1,4GlcNAc, Manα1,2Manα1,3Manβ1,4GlcNAcβ1,4GlcNAc, 4GlcNAc from the distal end side. Item 116. The modified liposome of item 111, which has a structure selected from the group consisting of Manα1,2Manα1,6Manα1,6Manβ1,4GlcNAc, Manα1,6Manα1,6Manβ1,4GlcNAcβ1,4GlcNAc and Manα1,3Manα1,6Manβ1,4GlcNAcβ1,4GlcNAc. (Item 113) The liposome distal end of the sugar chain has the following structure: Man from the distal end side.¹-D²-D³-D⁴-D⁵-D⁶-R^ZWhere D²Is Man and the D³Is Man and the D⁴Is Man and the D⁵Is GlcNAc and the D⁶Is GlcNAc and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 114) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴The bond between and D⁴And D⁵The bond between and D⁵And D⁶And at least one sugar chain bond selected from the group consisting of bonds between¹And D²Is a α1,2 bond, and D²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And D⁴Is a α1,3 bond or α1,6 bond, and D⁴And D⁵Is a β1,4 bond, the D⁵And D⁶114. The sugar chain-modified liposome according to item 113, wherein the bond between and is a β1,4 bond. (Item 115) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴The bond between and D⁴And D⁵The bond between and D⁵And D⁶And at least two sugar chain bonds selected from the group consisting of bonds between and¹And D²Is a α1,2 bond, and D²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And D⁴Is a α1,3 bond or α1,6 bond, and D⁴And D⁵Is a β1,4 bond, the D⁵And D⁶114. The sugar chain-modified liposome according to item 113, wherein the bond between and is a β1,4 bond. (Item 116) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴The bond between and D⁴And D⁵The bond between and D⁵And D⁶And at least three sugar chain bonds selected from the group consisting of bonds between¹And D²Is a α1,2 bond, and D²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And D⁴Is a α1,3 bond or α1,6 bond, and D⁴And D⁵Is a β1,4 bond, the D⁵And D⁶114. The sugar chain-modified liposome according to item 113, wherein the bond between and is a β1,4 bond. (Item 117) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴The bond between and D⁴And D⁵The bond between and D⁵And D⁶And at least four sugar chain bonds selected from the group consisting of bonds between¹And D²Is a α1,2 bond, and D²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And D⁴Is a α1,3 bond or an α1,6 bond, and D⁴And D⁵Is a β1,4 bond, the D⁵And D⁶114. The sugar chain-modified liposome according to item 113, wherein the bond between and is a β1,4 bond. (Item 118) Man¹And D²The bond between and D²And D³The bond between and D³And D⁴The bond between and D⁴And D⁵The bond between and D⁵And D⁶And a sugar chain bond is defined between the¹And D²Is a α1,2 bond, and D²And D³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And D⁴Is a α1,3 bond or an α1,6 bond, and D⁴And D⁵Is a β1,4 bond, the D⁵And D⁶114. The sugar chain-modified liposome according to item 113, wherein the bond between and is a β1,4 bond. (Item 119) The sugar chain-modified liposome according to item 113, wherein a liposome distal end of the sugar chain has a structure of Man-Man-Man-Man-GlcNAc-GlcNAc from the distal end side. (Item 120) The liposome distal end of the sugar chain is Manα1,2Manα1,2Manα1,3Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,2Manα1,3Manα1,6Manβ1,4GlcNAcβ1,4GlcNAc and Manα1,2Manα1,6Manα1, from the distal end side. 120. The sugar chain-modified liposome according to Item 119, which has a structure selected from the group consisting of 6Manβ1,4GlcNAcβ1,4GlcNAc. (Item 121) The liposome distal end of the sugar chain has the following structure: Neu5Ac from the distal end side.¹-E²-R^ZWhere E²Is Gal or GalNAc and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 122) Neu5Ac¹And E²122. The sugar chain-modified liposome according to Item 121, wherein the bond between and is an α2,3 bond or an α2,6 bond. (Item 123) The liposome distal end of the sugar chain is on the distal end side.
122. The sugar chain-modified liposome according to Item 121, which has a structure of Neu5Ac-Gal or Neu5Ac-GalNAc. (Item 124) The sugar chain-modified liposome according to item 123, wherein a liposome distal end of the sugar chain has a structure of Neu5Acα2,3Gal or Neu5Acα2,6GalNAc from the distal end side. (Item 125) The liposome distal end of the sugar chain has the following structure: Neu5Ac from the distal end side.¹-E²-E³-R^ZWhere E²Is Gal or GalNAc, and the E³Is selected from the group consisting of GlcNAc, Glc, GalNAc and Ser, and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 126) Neu5Ac¹And E²Between E and E²And E³Wherein at least one sugar chain bond selected from the group consisting of a bond between and Neu5Ac is defined.¹And E²Is an α2,3 bond or an α2,6 bond, and the E²And E³Is selected from the group consisting of a β1,3 bond, a β1,4 bond and an α1-O— bond, where the α1-O— bond is E³126. The sugar chain-modified liposome according to claim 125, which is present when Ser is Ser. (Item 127) Neu5Ac¹And E²Between E and E²And E³And all of the sugar chain bonds selected from the group consisting of the bonds between¹And E²Is an α2,3 bond or an α2,6 bond, and the E²And E³Is selected from the group consisting of a β1,3 bond, a β1,4 bond and an α1-O— bond, where the α1-O— bond is E³126. The sugar chain-modified liposome according to Item 125, which exists when Ser is Ser. (Item 128) The liposome distal end of the sugar chain is selected from the group consisting of Neu5Ac-Gal-GalNAc, Neu5Ac-Gal-GlcNAc, Neu5Ac-Gal-Glc and Neu5Ac-GalNAc-Ser from the distal end side. 126. The sugar chain-modified liposome according to item 125, which has a structure. (Item 129) The liposome distal end of the sugar chain is Neu5Acα2,3Galβ1,3GalNAc, Neu5Acα2,3Galβ1,3GlcNAc, Neu5Acα2,3Galβ1,4Glc, Neu5Acα2,3Galβ1,4GlcNAc1,4GlcNAcNe4 129. The sugar chain-modified liposome according to item 128, which has a structure selected from the group consisting of L-Ser. (Item 130) The liposome distal end of the sugar chain has the following structure: Neu5Ac from the distal end side.¹-E²-E³-E⁴-R^ZWhere E²Is Gal and the E³Is selected from the group consisting of Glc and GalNAc;⁴Is selected from the group consisting of Gal and Cer and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 131) Neu5Ac¹And E²The bond between and E²And E³Between E and E³And E⁴Wherein at least one sugar chain bond selected from the group consisting of a bond between and Neu5Ac is defined.¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond or β1,4 bond, and the E³And E⁴131. The sugar chain-modified liposome according to Item 130, wherein the bond between and is selected from the group consisting of β1,4 bond or β1,1 bond. (Item 132) Neu5Ac¹And E²The bond between and E²And E³Between E and E³And E⁴And at least two sugar chain bonds selected from the group consisting of the bonds between and Neu5Ac¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond or β1,4 bond, and the E³And E⁴131. The sugar chain-modified liposome according to Item 130, wherein the bond between and is selected from the group consisting of β1,4 bond or β1,1 bond. (Item 133) Neu5Ac¹And E²The bond between and E²And E³Between E and E³And E⁴And all the sugar chain linkages selected from the group consisting of the linkages between and Neu5Ac¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond or β1,4 bond, and the E³And E⁴131. The sugar chain-modified liposome according to Item 130, wherein the bond between and is selected from the group consisting of β1,4 bond or β1,1 bond. (Item 134) The liposome distal end of the sugar chain has a structure selected from the group consisting of Neu5Ac-Gal-GalNAc-Gal and Neu5Ac-Gal-Glu-Cer from the distal end side. The sugar chain-modified liposome. (Item 135) The item 134, wherein the liposome distal end of the sugar chain has a structure selected from the group consisting of Neu5Acα2,3Galβ1,3GalNAcβ1,4Gal and Neu5Acα2,3Galβ1,4Gluβ1,1Cer from the distal end side. The sugar chain-modified liposome. (Item 136) The liposome distal end of the sugar chain has the following structure: Neu5Ac from the distal end side.¹-E²-E³-E⁴-E⁵-R^ZWhere E²Is Gal and the E³Is GalNAc and the E⁴Is Gal and the E⁵Is Glc and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 137) Neu5Ac¹And E²The bond between and E²And E³The bond between and E³And E⁴Between E and E⁴And E⁵Wherein at least one sugar chain bond selected from the group consisting of a bond between and Neu5Ac is defined.¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond, and the E³And E⁴Is a β1,4 bond, and the E⁴And E⁵137. The sugar chain-modified liposome according to item 136, wherein the bond between and is β1,4. (Item 138) Neu5Ac¹And E²The bond between and E²And E³The bond between and E³And E⁴Between E and E⁴And E⁵And at least two sugar chain bonds selected from the group consisting of the bonds between and Neu5Ac¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond, and the E³And E⁴Is a β1,4 bond, and the E⁴And E⁵137. The sugar chain-modified liposome according to item 136, wherein the bond between and is β1,4. (Item 139) Neu5Ac¹And E²The bond between and E²And E³The bond between and E³And E⁴Between E and E⁴And E⁵And at least three sugar chain bonds selected from the group consisting of bonds between and Neu5Ac¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond, and the E³And E⁴Is a β1,4 bond, and the E⁴And E⁵137. The sugar chain-modified liposome according to item 136, wherein the bond between and is β1,4. (Item 140) Neu5Ac¹And E²The bond between and E²And E³The bond between and E³And E⁴Between E and E⁴And E⁵All the glycan bonds of the bond between and are defined in this Neu5Ac¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond, and the E³And E⁴Is a β1,4 bond, and the E⁴And E⁵137. The sugar chain-modified liposome according to item 136, wherein the bond between and is β1,4. (Item 141) The sugar chain-modified liposome according to item 136, wherein a liposome distal end of the sugar chain has a structure of Neu5Ac-Gal-GalNAc-Gal-Clc from the distal end side. (Item 142) The sugar chain-modified liposome according to item 141, wherein a liposome distal end of the sugar chain has a structure of Neu5Acα2,3Galβ1,3GalNAcβ1,4Galβ1,4Clc from the distal end side. (Item 143) The liposome distal end of the sugar chain has the following structure: Neu5Ac from the distal end side.¹-E²-E³-E⁴-E⁵-E⁶-R^ZWhere E²Is Gal and the E³Is GalNAc and the E⁴Is Gal and the E⁵Is Glc and the E⁶Is Cer and the R^ZItem 2. The sugar chain-modified liposome according to item 1, which is hydrogen or any sugar. (Item 144) Neu5Ac¹And E²The bond between and E²And E³The bond between and E³And E⁴The bond between and E⁴And E⁵Between E and E⁵And E⁶Wherein at least one sugar chain bond selected from the group consisting of a bond between and Neu5Ac is defined.¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond, and the E³And E⁴Is a β1,4 bond, and the E⁴And E⁵Is a bond between β1 and 4, and the E⁵And E⁶144. The sugar chain-modified liposome according to Item 143, wherein the bond between and is β1,1. (Item 145) Neu5Ac¹And E²The bond between and E²And E³The bond between and E³And E⁴The bond between and E⁴And E⁵Between E and E⁵And E⁶And at least two sugar chain bonds selected from the group consisting of the bonds between and Neu5Ac¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond, and the E³And E⁴Is a β1,4 bond, and the E⁴And E⁵Is a bond between β1 and 4, and the E⁵And E⁶144. The sugar chain-modified liposome according to Item 143, wherein the bond between and is β1,1. (Item 146) Neu5Ac¹And E²The bond between and E²And E³The bond between and E³And E⁴The bond between and E⁴And E⁵Between E and E⁵And E⁶
And at least three sugar chain bonds selected from the group consisting of bonds between and Neu5Ac¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond, and the E³And E⁴Is a β1,4 bond, and the E⁴And E⁵Is a bond between β1 and 4, and the E⁵And E⁶144. The sugar chain-modified liposome according to Item 143, wherein the bond between and is β1,1. (Item 147) Neu5Ac¹And E²The bond between and E²And E³The bond between and E³And E⁴The bond between and E⁴And E⁵Between E and E⁵And E⁶And at least four sugar chain bonds selected from the group consisting of bonds between and Neu5Ac¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond, and the E³And E⁴Is a β1,4 bond, and the E⁴And E⁵Is a bond between β1 and 4, and the E⁵And E⁶144. The sugar chain-modified liposome according to Item 143, wherein the bond between and is β1,1. (Item 148) Neu5Ac¹And E²The bond between and E²And E³The bond between and E³And E⁴The bond between and E⁴And E⁵Between E and E⁵And E⁶And all of the sugar chain bonds selected from the group consisting of the bonds between¹And E²Is an α2,3 bond, and E²And E³Is a β1,3 bond, and the E³And E⁴Is a β1,4 bond, and the E⁴And E⁵Is a bond between β1 and 4, and the E⁵And E⁶144. The sugar chain-modified liposome according to Item 143, wherein the bond between and is β1,1. (Item 149) The sugar chain-modified liposome according to item 143, wherein the liposome distal end of the sugar chain has a structure of Neu5Ac-Gal-GalNAc-Gal-Clc-Cer from the distal end side. (Item 150) The sugar chain-modified liposome according to item 149, wherein a liposome distal end of the sugar chain has a structure of Neu5Acα2,3Galβ1,3GalNAcβ1,4Galβ1,4Clcβ1,1Cer from the distal end side. (Item 151) The liposome proximal end of the sugar chain has the following structure: R¹-F²-GlcNAc³Where R¹Are independently hydrogen or any sugar chain, and the F²Are Gal, Fuc, GlcNAc and 3 '-(O-SO₃H) selected from the group consisting of Gal, wherein the GlcNAc³Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 152) F²And GlcNAc³152. The sugar chain-modified liposome according to Item 151, wherein the bond between and is selected from the group consisting of α1,3 bond, α1,4 bond, β1,3 bond, β1,4 bond and β1,6 bond. (Item 153) The liposome proximal end of the sugar chain is 3 '-(O-SO₃H) The sugar chain-modified liposome according to Item 151, having a structure selected from the group consisting of Gal-GlcNAc, Fuc-GlcNAc, Gal-GlcNAc and GlcNAc-GlcNAc. (Item 154) The liposome proximal end of the sugar chain is 3 '-(O-SO₃H) Description of item 153, which has a structure selected from the group consisting of Galβ1,3GlcNAc, Fucα1,3GlcNAc, Fucα1,4GlcNAc, Galβ1,3GlcNAc, Galβ1,4GlcNAc, Galβ1,6GlcNAc and GlcNAcβ1,4GlcNAc. (Item 155) The liposome proximal end of the sugar chain has the following structure: R¹-F²-F³-GlcNAc⁴Where R¹Are independently hydrogen or any sugar chain, and the F²Is selected from the group consisting of Man, Fuc and Neu5Ac;³Is Gal or GlcNAc, where the GlcNAc⁴Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 156) F³And F²Between F and F³And GlcNAc⁴Wherein at least one sugar chain bond selected from the group consisting of a bond between³And F²Is selected from the group consisting of α1,2 bond, β1,4 bond and α2,3 bond,³And GlcNAc⁴155. The sugar chain-modified liposome according to Item 155, wherein the bond between and is a β1,3 bond or a β1,4 bond. (Item 157) F³And F²Between F and F³And GlcNAc⁴All of the sugar chain bonds selected from the group consisting of the bonds between and³And F²Is selected from the group consisting of α1,2 bond, β1,4 bond and α2,3 bond,³And GlcNAc⁴155. The sugar chain-modified liposome according to Item 155, wherein the bond between and is a β1,3 bond or a β1,4 bond. (Item 158) The sugar chain modification according to item 155, wherein the liposome proximal end of the sugar chain has a structure selected from the group consisting of Fuc-Gal-GlcNAc, Man-GlcNAc-GlcNAc and Neu5Ac-Gal-GlcNAc. Liposome. (Item 159) The structure wherein the liposome proximal end of the sugar chain has a structure selected from the group consisting of Fucα1,2Galβ1,4GlcNAc, Manβ1,4GlcNAcβ1,4GlcNAc, Neu5Acα2,3Galβ1,3GlcNAc and Neu5Acα2,3Galβ1,4GlcNAc The sugar chain-modified liposome according to 1. (Item 160) The liposome proximal end of the sugar chain has the following structure: R¹-F²-F³-F⁴-GlcNAc⁵Where F¹Are independently hydrogen or any sugar chain, and the F²Is Man and the F³Is Man and the F⁴Is GlcNAc, where the GlcNAc⁵Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 161) F²And F³The bond between and F³And F⁴Between F and F⁴And GlcNAc⁵Wherein at least one sugar chain bond selected from the group consisting of a bond between²And F³Is a α1,3 bond or an α1,6 bond, and the F³And F⁴Is a β1,4 bond, and the F⁴And GlcNAc⁵161. The sugar chain-modified liposome according to item 160, wherein the bond between and is a β1,4 bond. (Item 162) F²And F³The bond between and F³And F⁴Between F and F⁴And GlcNAc⁵And at least two sugar chain bonds selected from the group consisting of bonds between²And F³Is a α1,3 bond or an α1,6 bond, and the F³And F⁴Is a β1,4 bond, and the F⁴And GlcNAc⁵161. The sugar chain-modified liposome according to item 160, wherein the bond between and is a β1,4 bond. (Item 163) F²And F³The bond between and F³And F⁴The bond between and F⁴And GlcNAc⁵All of the sugar chain bonds selected from the group consisting of the bonds between and²And F³Is a α1,3 bond or an α1,6 bond, and the F³And F⁴Is a β1,4 bond, and the F⁴And GlcNAc⁵161. The sugar chain-modified liposome according to item 160, wherein the bond between and is a β1,4 bond. (Item 164) The sugar chain-modified liposome according to item 160, wherein the liposome proximal end of the sugar chain has a structure of Man-Man-GlcNAc-GlcNAc. (Item 165) The sugar chain-modified liposome according to item 164, wherein the liposome proximal end of the sugar chain has a structure of Manα1,3Manβ1,4GlcNAcβ1,4GlcNAc or Manα1,6Manβ1,4GlcNAcβ1,4GlcNAc. (Item 166) The liposome proximal end of the sugar chain has the following structure: R¹-F²-F³-F⁴-F⁵-GlcNAc⁶Where R¹Are independently hydrogen or any sugar chain, and the F²Is Man and the F³Is Man and the F⁴Is Man and the F⁵Is GlcNAc, where the GlcNAc⁶Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 167) F²And F³The bond between and F³And F⁴The bond between and F⁴And F⁵Between F and F⁵And GlcNAc⁶Wherein at least one sugar chain bond selected from the group consisting of a bond between²And F³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And F⁴Is a α1,3 bond or an α1,6 bond, and the F⁴And F⁵Is a β1,4 bond, and the F⁵And GlcNAc⁶170. The sugar chain-modified liposome according to item 166, wherein the bond between and is a β1,4 bond. (Item 168) F²And F³The bond between and F³And F⁴The bond between and F⁴And F⁵Between F and F⁵And GlcNAc⁶And at least two sugar chain bonds selected from the group consisting of bonds between²And F³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And F⁴Is a α1,3 bond or an α1,6 bond, and the F⁴And F⁵Is a β1,4 bond, and the F⁵And GlcNAc⁶170. The sugar chain-modified liposome according to item 166, wherein the bond between and is a β1,4 bond. (Item 169) F²And F³The bond between and F³And F⁴The bond between and F⁴And F⁵Between F and F⁵And GlcNAc⁶And at least three sugar chain bonds selected from the group consisting of the bonds between²And F³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And F⁴Is a α1,3 bond or an α1,6 bond, and the F⁴And F⁵Is a β1,4 bond, and the F⁵And GlcNAc⁶170. The sugar chain-modified liposome according to item 166, wherein the bond between and is a β1,4 bond. (Item 170) F²And F³Between
Bond, F³And F⁴The bond between and F⁴And F⁵Between F and F⁵And GlcNAc⁶All of the sugar chain bonds selected from the group consisting of the bonds between and²And F³Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,³And F⁴Is a α1,3 bond or an α1,6 bond, and the F⁴And F⁵Is a β1,4 bond, and the F⁵And GlcNAc⁶170. The sugar chain-modified liposome according to item 166, wherein the bond between and is a β1,4 bond. (Item 171) The sugar chain-modified liposome according to item 166, wherein the liposome proximal end of the sugar chain has a structure of Man-Man-Man-GlcNAc-GlcNAc. (Item 172) The liposome proximal end of the sugar chain is selected from the group consisting of Manα1,3Manα1,6Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,2Manα1,3Manβ1,4GlcNAcβ1,4GlcNAc and Manα1,6Manα1,6Manβ1,4GlcNAcβ1,4GlcNAcβ1,4GlcNA 181. The sugar chain-modified liposome according to item 171, having a structure. (Item 173) The liposome proximal end of the sugar chain has the following structure: R¹-F²-F³-F⁴-F⁵-F⁶-GlcNAc⁷Where R¹Are independently hydrogen or any sugar chain, and the F²Is Man and the F³Is Man and the F⁴Is Man and the F⁵Is Man and the F⁶Is GlcNAc, where the GlcNAc⁷Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 174) F²And F³The bond between and F³And F⁴The bond between and F⁴And F⁵The bond between and F⁵And F⁶Between F and F⁶And GlcNAc⁷Wherein at least one sugar chain bond selected from the group consisting of a bond between²And F³Is a α1,2 bond, and the F³And F⁴Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,⁴And F⁵Is a α1,3 bond or an α1,6 bond, and the F⁵And F⁶Is a β1,4 bond, and the F⁶And GlcNAc⁷172. The sugar chain-modified liposome according to item 173, wherein the bond between and is a β1,4 bond. (Item 175) F²And F³The bond between and F³And F⁴The bond between and F⁴And F⁵The bond between and F⁵And F⁶Between F and F⁶And GlcNAc⁷And at least two sugar chain bonds selected from the group consisting of bonds between²And F³Is a α1,2 bond, and the F³And F⁴Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,⁴And F⁵Is a α1,3 bond or an α1,6 bond, and the F⁵And F⁶Is a β1,4 bond, and the F⁶And GlcNAc⁷172. The sugar chain-modified liposome according to item 173, wherein the bond between and is a β1,4 bond. (Item 176) F²And F³The bond between and F³And F⁴The bond between and F⁴And F⁵The bond between and F⁵And F⁶Between F and F⁶And GlcNAc⁷And at least three sugar chain bonds selected from the group consisting of the bonds between²And F³Is a α1,2 bond, and the F³And F⁴Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,⁴And F⁵Is a α1,3 bond or an α1,6 bond, and the F⁵And F⁶Is a β1,4 bond, and the F⁶And GlcNAc⁷172. The sugar chain-modified liposome according to item 173, wherein the bond between and is a β1,4 bond. (Item 177) F²And F³The bond between and F³And F⁴The bond between and F⁴And F⁵The bond between and F⁵And F⁶Between F and F⁶And GlcNAc⁷And at least four sugar chain bonds selected from the group consisting of the bonds between²And F³Is a α1,2 bond, and the F³And F⁴Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,⁴And F⁵Is a α1,3 bond or an α1,6 bond, and the F⁵And F⁶Is a β1,4 bond, and the F⁶And GlcNAc⁷172. The sugar chain-modified liposome according to item 173, wherein the bond between and is a β1,4 bond. (Item 178) F²And F³The bond between and F³And F⁴The bond between and F⁴And F⁵The bond between and F⁵And F⁶Between F and F⁶And GlcNAc⁷All of the sugar chain bonds selected from the group consisting of the bonds between and²And F³Is a α1,2 bond, and the F³And F⁴Is selected from the group consisting of α1,2 bond, α1,3 bond and α1,6 bond,⁴And F⁵Is a α1,3 bond or an α1,6 bond, and the F⁵And F⁶Is a β1,4 bond, and the F⁶And GlcNAc⁷172. The sugar chain-modified liposome according to item 173, wherein the bond between and is a β1,4 bond. (Item 179) The sugar chain-modified liposome according to item 173, wherein the liposome proximal end of the sugar chain has a structure of Man-Man-Man-Man-GlcNAc-GlcNAc. (Item 180) The liposome proximal end of the sugar chain is Manα1,2Manα1,2Manα1,3Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,2Manα1,3Manα1,6Manβ1,4GlcNAcβ1,4GlcNAc and Manα1,6Manα1,4Manc1,4Manc1,4Manc1,4Manc1,4Manc1,4Manc1,4 179. The sugar chain-modified liposome according to item 178, having a structure selected from the group consisting of: (Item 181) The liposome proximal end of the sugar chain has the following structure: R¹-G²-Gal³Where R¹Are independently hydrogen or any sugar chain, and the G²Is selected from the group consisting of Fuc, Gal and GalNac, wherein Gal³Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 182) G²And Gal³181. The sugar chain-modified liposome according to Item 181, wherein the bond between and is an α1,2 bond or an α1,3 bond. (Item 183) The sugar chain-modified liposome according to item 181, wherein the liposome proximal end of the sugar chain has a structure selected from the group consisting of Fuc-Gal, Gal-Gal and GalNAc-Gal. (Item 184) The sugar chain-modified liposome according to Item 183, wherein the liposome proximal end of the sugar chain has a structure selected from the group consisting of Fucα1,2Gal, Galα1,3Gal and GalNAcα1,3Gal. (Item 185) The liposome proximal end of the sugar chain has the following structure: R¹-H²-GalNAc³Where R¹Are independently hydrogen or any sugar chain and the H²Is Gal, where GalNAc³Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 186) H²And GalNAc³184. The sugar chain-modified liposome according to Item 184, wherein the bond between and is a β1,3 bond. (Item 187) The sugar chain-modified liposome according to item 184, wherein the liposome proximal end of the sugar chain has a structure of Gal-GalNAc. (Item 188) The sugar chain-modified liposome according to item 187, wherein the liposome proximal end of the sugar chain has a structure of Galβ1,3GalNAc. (Item 189) The liposome proximal end of the sugar chain has the following structure: R¹-I²-Ser³Where R¹Are independently hydrogen or any sugar chain and the I²Is GalNAc, where Ser³Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 190) I²And Ser³189. The sugar chain-modified liposome according to item 189, wherein the bond between and is an α1-O-bond. (Item 191) The sugar chain-modified liposome according to item 189, wherein the liposome proximal end of the sugar chain has a GalNAc-Ser structure. (Item 192) The sugar chain-modified liposome according to item 191, wherein the liposome proximal end of the sugar chain has a structure of GalNAcα1-OL-Ser. (Item 193) The liposome proximal end of the sugar chain has the following structure: R¹-I²-I³-Ser⁴Where R¹Are independently hydrogen or any sugar chain and the I²Is Neu5Ac and the I³Is GalNAc, where Ser⁴Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 194) I²And I³Between I and I³And Ser⁴And at least one sugar chain bond selected from the group consisting of the bonds between²And I³Is a α2,6 bond, and I³And Ser⁴194. The sugar chain-modified liposome according to Item 193, wherein the bond between and is an α1-O— bond. (Item 195) I²And I³Between I and I³And Ser⁴All of the sugar chain bonds selected from the group consisting of the bonds between²And I³Is a α2,6 bond, and I³And Ser⁴194. The sugar chain-modified liposome according to Item 193, wherein the bond between and is an α1-O— bond. (Item 196) The sugar chain-modified liposome according to item 193, wherein the liposome proximal end of the sugar chain has a structure of Neu5Ac-GalNAc-Ser. (Item 197) The sugar chain-modified liposome according to item 196, wherein the liposome proximal end of the sugar chain has a structure of Neu5Acα2,6GalNAcα1-OL-Ser. (Item 198) The liposome proximal end of the sugar chain has the following structure: R¹-J²-Glc³Where R¹Are independently hydrogen or any sugar chain, and the J²Is Gal or Fuc, where Glc³Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 199) J²And Glc³Bond between and α1,3 bond or β1,4
199. The sugar chain-modified liposome according to item 198, which is a bond. (Item 200) The sugar chain-modified liposome according to item 199, wherein the liposome proximal end of the sugar chain has a structure of Fuc-Glc or Gal-Glc. (Item 201) The sugar chain-modified liposome according to item 200, wherein the liposome proximal end of the sugar chain has a structure of Fucα1,3Glc or Galβ1,4Glc. (Item 202) The liposome proximal end of the sugar chain has the following structure: R¹-J²-J³-Glc⁴Where R¹Are independently hydrogen or any sugar chain, and the J²Is selected from the group consisting of Fuc, GlcNAc and Neu5Ac, wherein the J³Is Gal, where Glc⁴Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 203) J²And J³Between J and J³And Glc⁴At least one sugar chain bond selected from the group consisting of a bond between²And J³Is selected from the group consisting of α1,2 bond, α2,3 bond and β1,3 bond,³And Glc⁴201. The sugar chain-modified liposome according to Item 202, wherein the bond between and is a β1,4 bond. (Item 204) J²And J³Between J and J³And Glc⁴All of the sugar chain bonds selected from the group consisting of the bonds between²And J³Is selected from the group consisting of α1,2 bond, α2,3 bond and β1,3 bond,³And Glc⁴201. The sugar chain-modified liposome according to Item 202, wherein the bond between and is a β1,4 bond. (Item 205) The sugar chain modification according to item 202, wherein the liposome proximal end of the sugar chain has a structure selected from the group consisting of Fuc-Gal-Glc, GlcNAc-Gal-Glc and Neu5Ac-Gal-Glc. Liposome. (Item 206) The sugar chain modification according to item 203, wherein the liposome proximal end of the sugar chain has a structure selected from the group consisting of Fucα1,2Galβ1,4Glc, GlcNAcβ1,3Galβ1,4Glc and Neu5Acα2,3Galβ1,4Glc. Liposome. (Item 207) The liposome proximal end of the sugar chain has the following structure: R¹-J²-J³-J⁴-Glc⁵Where R¹Are independently hydrogen or any sugar chain, and the J²Is Fuc or Gal and the J³Is GlcNAc, and J⁴Is Gal, where Glc⁵Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 208) J²And J³Bond between and J³And J⁴Between J and J⁴And Glc⁵At least one sugar chain bond selected from the group consisting of a bond between²And J³Is a α1,4 bond or β1,3 bond,³And J⁴Is a β1,3 bond or β1,4 bond,⁴And Glc⁵209. The sugar chain-modified liposome according to item 207, wherein the bond between and is a β1,4 bond. (Item 209) J²And J³Bond between and J³And J⁴Between J and J⁴And Glc⁵And at least two sugar chain bonds selected from the group consisting of the bonds between²And J³Is a α1,4 bond or β1,3 bond,³And J⁴Is a β1,3 bond or β1,4 bond,⁴And Glc⁵209. The sugar chain-modified liposome according to item 207, wherein the bond between and is a β1,4 bond. (Item 210) J²And J³Bond between and J³And J⁴Between J and J⁴And Glc⁵All of the sugar chain bonds selected from the group consisting of the bonds between²And J³Is a α1,4 bond or β1,3 bond,³And J⁴Is a β1,3 bond or β1,4 bond,⁴And Glc⁵209. The sugar chain-modified liposome according to item 207, wherein the bond between and is a β1,4 bond. (Item 211) The sugar chain-modified liposome according to item 207, wherein the liposome proximal end of the sugar chain has a structure of Fuc-GlcNAc-Gal-Glc or Gal-GlcNAc-Gal-Glc. (Item 212) The sugar chain-modified liposome according to item 211, wherein the liposome proximal end of the sugar chain has a structure of Fucα1,4GlcNAcβ1,3Galβ1,4Glc or Galβ1,3GlcNAcβ1,3Galβ1,4Glc. (Item 213) The liposome proximal end of the sugar chain has the following structure: R¹-J²-J³-J⁴-J⁵-Glc⁶Where R¹Are independently hydrogen or any sugar chain;²Is Fuc and the J³Is Gal and the J⁴Is GlcNAc or GalNAc, and the J⁵Is Gal, where Glc⁶Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 214) J²And J³Bond between and J³And J⁴Bond between and J⁴And J⁵Between J and J⁵And Glc⁶At least one sugar chain bond selected from the group consisting of a bond between²And J³Is a α1,2 bond, and J³And J⁴Is a β1,3 bond,⁴And J⁵Is a β1,3 bond,⁵And Glc⁶213. The sugar chain-modified liposome according to item 213, wherein the bond between and is a β1,4 bond. (Item 215) J²And J³Bond between and J³And J⁴Bond between and J⁴And J⁵Between J and J⁵And Glc⁶And at least two sugar chain bonds selected from the group consisting of the bonds between²And J³Is a α1,2 bond, and J³And J⁴Is a β1,3 bond,⁴And J⁵Is a β1,3 bond,⁵And Glc⁶213. The sugar chain-modified liposome according to item 213, wherein the bond between and is a β1,4 bond. (Item 216) J²And J³Bond between and J³And J⁴Bond between and J⁴And J⁵Between J and J⁵And Glc⁶And at least three sugar chain bonds selected from the group consisting of the bonds between²And J³Is a α1,2 bond, and J³And J⁴Is a β1,3 bond,⁴And J⁵Is a β1,3 bond,⁵And Glc⁶213. The sugar chain-modified liposome according to item 213, wherein the bond between and is a β1,4 bond. (Item 217) J²And J³Bond between and J³And J⁴Bond between and J⁴And J⁵Between J and J⁵And Glc⁶All of the sugar chain bonds selected from the group consisting of the bonds between²And J³Is a α1,2 bond, and J³And J⁴Is a β1,3 bond,⁴And J⁵Is a β1,3 bond,⁵And Glc⁶213. The sugar chain-modified liposome according to item 213, wherein the bond between and is a β1,4 bond. (Item 218) The sugar chain-modified liposome according to item 213, wherein the liposome proximal end of the sugar chain has a structure of Fuc-Gal-GlcNAc-Gal-Glc. (Item 219) The sugar chain-modified liposome according to item 218, wherein the liposome proximal end of the sugar chain has a structure of Fucα1,2Galβ1,3GlcNAcβ1,3Galβ1,4Glc. (Item 220) The liposome proximal end of the sugar chain has the following structure: R¹-K²-Man³Where R¹Are independently hydrogen or any sugar chain and the K²Is Man, where Man³Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 221) K²And Man³220. The sugar chain-modified liposome according to Item 220, wherein the bond between and is selected from the group consisting of an α1,2 bond, an α1,3 bond, and an α1,4 bond. (Item 222) The sugar chain-modified liposome according to item 220, wherein the liposome proximal end of the sugar chain has a Man-Man structure. (Item 223) The sugar chain-modified liposome according to item 222, wherein the liposome proximal end of the sugar chain has a structure selected from the group consisting of Manα1,2Man, Manα1,3Man and Manα1,4Man. (Item 224) The liposome proximal end of the sugar chain has the following structure: R¹-L²-Cer³Where R¹Are independently hydrogen or any sugar chain, and the L²Is Glc, where Cer³Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 225) L²And Cer³227. The sugar chain-modified liposome according to Item 224, wherein the bond between and is a β1,1 bond. (Item 226) The sugar chain-modified liposome according to item 224, wherein the liposome proximal end of the sugar chain has a Glc-Cer structure. (Item 227) The sugar chain-modified liposome according to item 226, wherein the liposome proximal end of the sugar chain has a structure of Glcβ1,1Cer. (Item 228) The liposome proximal end of the sugar chain has the following structure: R¹-L²-L³-Cer⁴Where R¹Are independently hydrogen or any sugar chain, and the L²Is Gal and the L³Is Glc, where Cer⁴Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 229) L²And L³Between L and L³And Cer⁴At least one sugar chain bond selected from the group consisting of a bond between²And L³Is a β1,4 bond, and the L³And Cer⁴227. The sugar chain-modified liposome according to item 228, wherein the bond between and is a β1,1 bond. (Item 230) L²And L³Between L and L³And Cer⁴All of the sugar chain bonds selected from the group consisting of the bonds between and²And L³Is a β1,4 bond, and the L³And Cer⁴227. The sugar chain-modified liposome according to item 228, wherein the bond between and is a β1,1 bond. (Item 231) The liposome proximal end of the sugar chain has a Gal-Glc-Cer structure.
228. The sugar chain-modified liposome according to item 228. (Item 232) The sugar chain-modified liposome according to item 231, wherein the liposome proximal end of the sugar chain has a structure of Galβ1,4Glcβ1,1Cer. (Item 233) The liposome proximal end of the sugar chain has the following structure: R¹-L²-L³-L⁴-Cer⁵Where R¹Are independently hydrogen or any sugar chain, and the L²Is GalNAc or Neu5Ac, and the L³Is Gal and the L⁴Is Glc, where Cer⁵Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 234) L²And L³The bond between and³And L⁴Between L and L⁴And Cer⁵At least one sugar chain bond selected from the group consisting of a bond between²And L³Is a α2,3 bond or a β1,4 bond,³And L⁴Is a β1,4 bond, and the L⁴And Cer⁵234. The sugar chain-modified liposome according to Item 233, wherein the bond between and is a β1,1 bond. (Item 235) L²And L³The bond between and³And L⁴Between L and L⁴And Cer⁵And at least two sugar chain bonds selected from the group consisting of bonds between²And L³Is a α2,3 bond or a β1,4 bond,³And L⁴Is a β1,4 bond, and the L⁴And Cer⁵234. The sugar chain-modified liposome according to Item 233, wherein the bond between and is a β1,1 bond. (Item 236) L²And L³The bond between and³And L⁴Between L and L⁴And Cer⁵All of the sugar chain bonds selected from the group consisting of the bonds between and²And L³Is a α2,3 bond or a β1,4 bond,³And L⁴Is a β1,4 bond, and the L⁴And Cer⁵234. The sugar chain-modified liposome according to Item 233, wherein the bond between and is a β1,1 bond. (Item 237) The sugar chain-modified liposome according to item 233, wherein the liposome proximal end of the sugar chain has a structure selected from the group consisting of GalNAc-Gal-Glc-Cer and Neu5Ac-Gal-Glu-Cer. (Item 238) The sugar chain modification according to item 237, wherein the liposome proximal end of the sugar chain has a structure selected from the group consisting of GalNAcβ1,4Galβ1,4Glcβ1,1Cer and Neu5Acα2,3Galβ1,4Gluβ1,1Cer Liposome. (Item 239) The liposome proximal end of the sugar chain has the following structure: R¹-L²-L³-L⁴-L⁵-Cer⁶Where R¹Are independently hydrogen or any sugar chain, and the L²Is Gal and the L³Is GalNAc and the L⁴Is Gal and the L⁵Is Glc, where Cer⁶Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 240) L²And L³The bond between and³And L⁴The bond between and⁴And L⁵Between L and L⁵And Cer⁶At least one sugar chain bond selected from the group consisting of a bond between²And L³Is a β1,3 bond, and the L³And L⁴Is a β1,4 bond, and the L⁴And L⁵Is a β1,4 bond, and the L⁵And Cer⁶240. The sugar chain-modified liposome according to Item 239, wherein the bond between and is a β1,1 bond. (Item 241) L²And L³The bond between and³And L⁴The bond between and⁴And L⁵Between L and L⁵And Cer⁶And at least two sugar chain bonds selected from the group consisting of bonds between²And L³Is a β1,3 bond, and the L³And L⁴Is a β1,4 bond, and the L⁴And L⁵Is a β1,4 bond, and the L⁵And Cer⁶240. The sugar chain-modified liposome according to Item 239, wherein the bond between and is a β1,1 bond. (Item 242) L²And L³The bond between and³And L⁴The bond between and⁴And L⁵Between L and L⁵And Cer⁶And at least three sugar chain bonds selected from the group consisting of bonds between²And L³Is a β1,3 bond, and the L³And L⁴Is a β1,4 bond, and the L⁴And L⁵Is a β1,4 bond, and the L⁵And Cer⁶240. The sugar chain-modified liposome according to Item 239, wherein the bond between and is a β1,1 bond. (Item 243) L²And L³The bond between and³And L⁴The bond between and⁴And L⁵Between L and L⁵And Cer⁶All of the sugar chain bonds selected from the group consisting of the bonds between and²And L³Is a β1,3 bond, and the L³And L⁴Is a β1,4 bond, and the L⁴And L⁵Is a β1,4 bond, and the L⁵And Cer⁶240. The sugar chain-modified liposome according to Item 239, wherein the bond between and is a β1,1 bond. (Item 244) The sugar chain-modified liposome according to item 239, wherein the liposome proximal end of the sugar chain has a structure of Gal-GalNAc-Gal-Glc-Cer. (Item 245) The sugar chain-modified liposome according to item 244, wherein the liposome proximal end of the sugar chain has a structure of Galβ1, 3GalNAcβ1, 4Galβ1, 4Glcβ1, 1Cer. (Item 246) The liposome proximal end of the sugar chain has the following structure: R¹-L²-L³-L⁴-L⁵-L⁶-Cer⁷Where R¹Are independently hydrogen or any sugar chain, and the L²Is Neu5Ac and the L³Is Gal and the L⁴Is GalNac and the L⁵Is Gal and the L⁶Is Glc, where Cer⁷Item 2. The sugar chain-modified liposome according to Item 1, present at the most proximal end of the liposome. (Item 247) L²And L³The bond between and³And L⁴The bond between and⁴And L⁵The bond between and⁵And L⁶Between L and L⁶And Cer⁷At least one sugar chain bond selected from the group consisting of a bond between²And L³Is a α2,3 bond, and L³And L⁴Is a β1,3 bond, and the L⁴And L⁵Is a β1,4 bond, and the L⁵And L⁶Is a bond between β1 and 4, and the L⁶And Cer⁷247. The sugar chain-modified liposome according to Item 246, wherein the bond between and is a β1,1 bond. (Item 248) L²And L³The bond between and³And L⁴The bond between and⁴And L⁵The bond between and⁵And L⁶Between L and L⁶And Cer⁷And at least two sugar chain bonds selected from the group consisting of bonds between²And L³Is a α2,3 bond, and L³And L⁴Is a β1,3 bond, and the L⁴And L⁵Is a β1,4 bond, and the L⁵And L⁶Is a bond between β1 and 4, and the L⁶And Cer⁷247. The sugar chain-modified liposome according to Item 246, wherein the bond between and is a β1,1 bond. (Item 249) L²And L³The bond between and³And L⁴The bond between and⁴And L⁵The bond between and⁵And L⁶Between L and L⁶And Cer⁷And at least three sugar chain bonds selected from the group consisting of bonds between²And L³Is a α2,3 bond, and L³And L⁴Is a β1,3 bond, and L⁴And L⁵Is a β1,4 bond, and the L⁵And L⁶Is a bond between β1 and 4, and the L⁶And Cer⁷247. The sugar chain-modified liposome according to Item 246, wherein the bond between and is a β1,1 bond. (Item 250) L²And L³The bond between and³And L⁴The bond between and⁴And L⁵The bond between and⁵And L⁶Between L and L⁶And Cer⁷And at least four sugar chain bonds selected from the group consisting of bonds between²And L³Is a α2,3 bond, and L³And L⁴Is a β1,3 bond, and L⁴And L⁵Is a β1,4 bond, and the L⁵And L⁶Is a bond between β1 and 4, and the L⁶And Cer⁷247. The sugar chain-modified liposome according to Item 246, wherein the bond between and is a β1,1 bond. (Item 251) L²And L³The bond between and³And L⁴The bond between and⁴And L⁵The bond between and⁵And L⁶Between L and L⁶And Cer⁷And at least four sugar chain bonds selected from the group consisting of bonds between²And L³Is a α2,3 bond, and L³And L⁴Is a β1,3 bond, and L⁴And L⁵Is a β1,4 bond, and the L⁵And L⁶Is a bond between β1 and 4, and the L⁶And Cer⁷247. The sugar chain-modified liposome according to Item 246, wherein the bond between and is a β1,1 bond. (Item 252) L²And L³The bond between and³And L⁴The bond between and⁴And L⁵The bond between and⁵And L⁶Between L and L⁶And Cer⁷All of the sugar chain bonds selected from the group consisting of the bonds between and²And L³Is a α2,3 bond, and L³And L⁴Is a β1,3 bond, and L⁴And L
⁵Is a β1,4 bond, and the L⁵And L⁶Is a bond between β1 and 4, and the L⁶And Cer⁷247. The sugar chain-modified liposome according to Item 246, wherein the bond between and is a β1,1 bond. (Item 253) The sugar chain-modified liposome according to item 246, wherein the liposome proximal end of the sugar chain has a structure of Neu5Ac-Gal-GalNAc-Gal-Glc-Cer. (Item 254) The sugar chain-modified liposome according to item 253, wherein the liposome proximal end of the sugar chain has a structure of Neu5Acα2, 3Galβ1, 3GalNAcβ1,4Galβ1,4Glcβ1,1Cer. (Item 255) The sugar chain-modified liposome according to item 1, wherein the sugar at the most proximal end of the liposome of the sugar chain is Glc or GlcNAc, and the sugar at the most distal end of the liposome of the sugar chain is Gal or Fuc. . (Item 256) The sugar chain-modified liposome according to item 1, wherein the sugar at the most proximal end of the liposome of the sugar chain is GlcNAc and the sugar at the most distal end of the liposome of the sugar chain is Man. (Item 257) The following: Fucα1,2Galβ1,3GlcNAcβ1,3Galβ1,4Glc, Fucα1,2Galβ1,4 (Fucα1,3) GlcNAc, Galα1,3 (Fucα1,2) Gal, Galβ1,3 (Fucα1,4) GlcNAc, Galβ1, 3 (Fucα1,4) GlcNAcβ1,3Galβ1,4Glc, Galβ1,4 (Fucα1,3) GlcNAc, Galβ1,4Glc, Neu5Acα2,6GalNAcα1-OL-Ser, 3 ′-(O—SO₃H) Galβ1,3 (Fucα1,4) GlcNAc, Fucα1,2Galβ1,4 (Fucα1,3) Glc, Galβ1,3GlcNAcβ1,3Galβ1,4Glc, Galβ1,6GlcNAc, GalNAcα1-OL-Ser1, Neu5Acα3 Fucα1,4) GlcNAc, Neu5Acα2,3Galβ1,4 (Fucα1,3) GlcNAc, Neu5Acα2,3Galβ1,4Glc, Galα1,3Gal, Fucα1,2Gal, Galβ1,3GalNAc, Galβ1,4 (Fuc4G1) GalNAcα1,3 (Fucα1,2) Gal, Galβ1,3GalNAcβ1,4Galβ1,4Glcβ1,1Cer + Neu5Acα2,3Galβ1,3G alNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer, Manα1,2Man, Manα1,2Manα1,6 (Manα1,2Manα1,3) Manα1,6 (Manα1,2Manα1, Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc, 2Manα1,6 (Manα1,3) Manα1,6 (Manα1,2Manα1,2Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,3Man, Manα1,4Man, Manα1,6 (Manα1,3) Manα1,6 (Manα1,2Manα1, 2Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,6 (Manα1,3) Manα1,6 (Manα1,2Manα1,3) Manβ , 4GlcNAcβ1,4GlcNAc, Manα1,6 (Manα1,3) Manα1,6 (Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc and Manα1,6 (Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc and combinations of two or more thereof A sugar chain-modified liposome to which a sugar chain selected from the group is bound. (Item 258) The sugar chain-modified liposome according to any one of items 1 to 257, wherein the sugar chain is contained at a modified bond density suitable for oral administration. (Item 259) The sugar chain-modified liposome according to item 258, wherein the modified binding density is at least 0.0075 mg sugar chain / mg lipid. (Item 260) Fucα1,2Galβ1,3GlcNAcβ1,3Galβ1,4Glc, Fucα1,2Galβ1,4 (Fucα1,3) GlcNAc, Galα1,3 (Fucα1,2) Gal, Galβ1,3 (Fucα1,4) GlcNAc, Galβ1,3 ( Fucα1,4) GlcNAcβ1,3Galβ1,4Glc, Galβ1,4 (Fucα1,3) GlcNAc, Galβ1,4Glc, Neu5Acα2,6GalNAcα1-OL-Ser, 3 ′-(O—SO₃H) Galβ1,3 (Fucα1,4) GlcNAc, Fucα1,2Galβ1,4 (Fucα1,3) Glc, Galβ1,3GlcNAcβ1,3Galβ1,4Glc, Galβ1,6GlcNAc, GalNAcα1-OL-Ser1, Neu5Acα3 Fucα1,4) GlcNAc, Neu5Acα2,3Galβ1,4 (Fucα1,3) GlcNAc, Neu5Acα2,3Galβ1,4Glc, Galα1,3Gal, Fucα1,2Gal, Galβ1,3GalNAc, Galβ1,4 (Fuc4G1) GalNAcα1,3 (Fucα1,2) Gal, Galβ1,3GalNAcβ1,4Galβ1,4Glcβ1,1Cer + Neu5Acα2,3Galβ1,3G alNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer, Manα1,2Man, Manα1,2Manα1,6 (Manα1,2Manα1,3) Manα1,6 (Manα1,2Manα1, Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc, 2Manα1,6 (Manα1,3) Manα1,6 (Manα1,2Manα1,2Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,3Man, Manα1,4Man, Manα1,6 (Manα1,3) Manα1,6 (Manα1,2Manα1, 2Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc, Manα1,6 (Manα1,3) Manα1,6 (Manα1,2Manα1,3) Manβ , 4GlcNAcβ1,4GlcNAc, Manα1,6 (Manα1,3) Manα1,6 (Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc and Manα1,6 (Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc and combinations of two or more thereof 259. A sugar chain-modified liposome according to item 258, wherein the sugar chain selected from the group is contained at a modified bond density of at least 0.0075 mg sugar chain / mg lipid. (Item 261) The sugar chain according to item 258, wherein a sugar chain selected from the group consisting of Manα1,2Man, Manα1,4Man and Manα1,3Man is contained at a modified bond density of about 0.0075 mg sugar chain / mg lipid. Modified liposomes. (Item 262) The sugar chain-modified liposome according to item 258, wherein Manα1,6 (Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc is contained at a modified binding density of about 0.0205 mg sugar chain / mg lipid. (Item 263) Fucα1,2Gal, Fucα1,2Galβ1,3GlcNAcβ1,3Galβ1,4Glc, GalNAcα1,3 (Fucα1,2) Gal, Galβ1,3GalNAc, Galβ1,3 (Fucα1,4) GlcNAcβ1,3Galβ1,4Glc, Fucα1,2) Gal, Galβ1,4Glc, Galβ1,4GlcNAc, Galβ1,4 (Fucα1,3) GlcNAc, Fucα1,2Galβ1,4 (Fucα1,3) GlcNAc, Neu5Acα2,6GalNAcα1-Ol-G4 259. Item 258, wherein a sugar chain selected from the group consisting of Galβ1,3 (Fucα1,4) GlcNAc is included at a modified binding density of about 0.025 mg sugar chain / mg lipid. The sugar chain-modified liposome. (Item 264) The sugar according to item 258, wherein Manα1,6 (Manα1,3) Manα1,6 (Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc is contained at a modified binding density of about 0.0275 mg sugar chain / mg lipid. Chain-modified liposomes. (Item 265) Item 258, wherein Manα1,6 (Manα1,3) Manα1,6 (Manα1,2Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc is included at a modified binding density of about 0.031 mg sugar chain / mg lipid. The sugar chain-modified liposome. (Item 266) Manα1,6 (Manα1,3) Manα1,6 (Manα1,2Manα1,2Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc is included at a modified binding density of about 0.035 mg sugar chain / mg lipid, Item 258 The sugar chain-modified liposome according to 1. (Item 267) Manα1,2Manα1,6 (Manα1,3) Manα1,6 (Manα1,2Manα1,2Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc is included at a modified binding density of about 0.0385 mg sugar chain / mg lipid, 258. The sugar chain-modified liposome according to item 258. (Item 268) Manα1,2Manα1,6 (Manα1,2Manα1,3) Manα1,6 (Manα1,2Manα1,2Manα1,3) Manβ1,4GlcNAcβ1,4GlcNAc is included at a modified binding density of about 0.042 mg sugar chain / mg lipid. 259. The sugar chain-modified liposome according to item 258. (Item 269) Fucα1,2Galβ1,4 (Fucα1,3) Glc, Neu5Acα2,3Galβ1,4Glc, Galβ1,3GalNAc, Galβ1,3GlcNAcβ1,3Galβ1,4Glc, Galβ1,4 (Fucα1,3) Glc, FcG1, Gc 3 (Fucα1,2) Gal, GalNAcα1-OL-Ser, Galβ1,6GlcNAc, Galα1,3Gal, 3 ′-(O—SO₃H) A sugar chain selected from the group consisting of Galβ1,3 (Fucα1,4) GlcNAc, Neu5Acα2,3Galβ1,4 (Fucα1,3) GlcNAc and Neu5Acα2,3Galβ1,3 (Fucα1,4) GlcNAc is about 0.5 mg. 259. The sugar chain-modified liposome of item 258, which is contained at a modified binding density of sugar chain / mg lipid. (Item 270) Galβ1,3GalNAcβ1,4Galβ1,4Glcβ1,1Cer + Neu5Acα2,3Galβ1,3GalNAcβ1,4 (Neu5Acα2,3) Galβ1,4Glcβ1,1Cer is included at a modified binding density of about 0.75 mg sugar chain / mg lipid 58 The sugar chain-modified liposome according to 1. (Item 271) A sugar chain selected from the group consisting of Fucα1,2Gal, GalNAcα1,3 (Fucα1,2) Gal, Galβ1,3GalNAc, Galβ1,4Glc and Galβ1,4 (Fucα1,3) Glc is about 0.025. 259. Sugar chain modified liposome according to item 258, which is included at a modified bond density of about 0.5 mg sugar chain / mg lipid. (Item 272) The sugar chain-modified liposome according to any one of items 1 to 271, wherein the sugar chain is bound to the membrane of the liposome via a linker. (Item 273) The sugar chain-modified liposome according to item 272, wherein the linker is a biological protein. (Item 274) The sugar chain-modified liposome according to item 273, wherein the linker is a human-derived protein. (Item 275) The sugar chain-modified liposome according to item 274, wherein the linker is a human-derived serum protein. (Item 276) The sugar chain-modified liposome according to item 272, wherein the linker is human serum albumin or bovine serum albumin. (Item 277) The sugar chain-modified liposome according to any one of items 1 to 276, wherein the sugar chain-modified liposome is rendered hydrophilic by binding a hydrophilic compound to at least one of a liposome membrane or a linker. . (Item 278) The sugar chain-modified liposome according to any one of items 1 to 271, wherein the liposome and the sugar chain are bound by a peptide bond. (Item 279) Item 2 wherein the ganglioside on the membrane of the liposome and the linker are covalently bonded, and the end of the linker is bonded by a peptide bond.
72. The sugar chain-modified liposome according to 72. (Item 280) The sugar chain-modified liposome according to item 277, wherein the hydrophilic compound is tris (hydroxyalkyl) aminoalkane. (Item 281) Liposome No. 27, 29, 40, 45, 50, 53, 56, 67, 68, 69, 70, 71, 87, 105, 117, 120, 125, 139, 142, 150, 152, 153, 154, 175, 184, 186, 197, 204, 224, 225, 230, 237, 240, 273, 285, 288, 290 or 301, a sugar chain-modified liposome. (Item 282) A drug delivery vehicle for intravenous administration and oral administration, comprising the sugar chain-modified liposome according to any one of items 1 to 281. (Item 283) A composition for intravenous administration and oral administration comprising the sugar chain-modified liposome according to any one of items 1 to 281 and a substance desired to be administered. (Item 284) The composition for intravenous and oral administration according to item 283, wherein the desired substance is a substance selected from diagnostic agents, research reagents and functional foods. (Item 285)
The diagnostic agent is a DNA probe diagnostic agent, X-ray contrast agent, radioactive reagent, radioactive contrast agent, radioactive diagnostic agent, fluorescent reagent, fluorescent contrast agent, fluorescent diagnostic agent, CT contrast agent, PET contrast agent, SPECT contrast agent Agent, MRI contrast agent, AIDS diagnostic reagent, hematology test reagent, functional test reagent, microbial test reagent, molecular imaging, in vivo imaging, fluorescence imaging, luminescence imaging, cell sorter, PET and SPECT 284. The composition for intravenous administration and oral administration according to item 284, which is a diagnostic agent.
(Item 286) The composition for intravenous administration and oral administration according to item 284, wherein the research reagent is a reagent used in recombinant DNA technology, immunoassay, hybridization method, enzyme assay. (Item 287) The composition for intravenous administration and oral administration according to item 284, wherein the functional food is a food containing vitamins, minerals, amino acids, and carbohydrates. (Item 288) A pharmaceutical composition for intravenous administration and oral administration, further comprising the sugar chain-modified liposome according to any one of items 1 to 281 and a pharmaceutically active ingredient. (Item 289) The pharmaceutical composition for intravenous and oral administration according to item 288, wherein the sugar chain-modified liposome encapsulates or binds a drug or gene. (Item 290)
The drug is a biopharmaceutical or biotherapeutic substance (for example, siRNA, shRNA, siRNA derivative, shRNA derivative, RNA, RNA derivative, DNA, DNA derivative, monoclonal antibody, vaccine, interferon, hormone, prostaglandin, transcription factor, Recombinant protein, antibody drug, nucleic acid>
Pharmaceuticals, gene therapy agents), alkylated anticancer agents, antimetabolites, plant-derived anticancer agents, anticancer antibiotics, biological response modifiers (BRM) / cytokines, platinum complex anticancer agents, immunotherapy Drugs, hormone anticancer drugs, tumor drugs such as monoclonal antibodies, central nervous system drugs, peripheral nervous system / sensory organ drugs, respiratory disease drugs, cardiovascular drugs, gastrointestinal drugs, hormone drugs, urology / Reproductive organ drugs, vitamins, nourishing tonics, metabolic drugs, antibiotics / chemotherapeutic drugs, testing drugs, anti-inflammatory drugs, eye disease drugs, central nervous system drugs, autoimmune drugs, cardiovascular drugs, diabetes, Lifestyle-related diseases such as hyperlipidemia, corticosteroids, immunosuppressants, antibacterial agents, antiviral agents, angiogenesis inhibitors, cytokines , Chemokines, anti-cytokine antibodies, anti-chemokine antibodies, anti-cytokine / chemokine receptor antibodies, siRNA, shRNA, miRNA, smRNA, antisense RNA or gene therapy-related nucleic acid preparations such as ODN or DNA, neuroprotective factors, antibody drugs 299. A pharmaceutical composition for intravenous and oral administration according to item 289, selected from the group consisting of a molecular target drug, an osteoporosis / bone metabolism improving drug, a neuropeptide, and a bioactive peptide / protein.
(Item 291) The composition for intravenous administration and oral administration is for delivering the biological factor into a tumor to a subject in need of the biological factor, and the substance is the biological 290. A pharmaceutical composition for intravenous and oral administration according to item 290, comprising a genetic factor. (Item 292) A drug delivery vehicle for intravenous administration and oral administration for treating a mammal having a disorder of respiratory system, circulatory system, digestive system, urinary / genital system, central nervous system or peripheral nervous system The drug delivery vehicle for intravenous administration and oral administration comprises the sugar chain-modified liposome according to item 1 and a pharmaceutically acceptable carrier, and the sugar chain-modified liposome is effective for treating the disorder. A pharmaceutical composition for intravenous and oral administration, comprising an amount of the drug. (Item 293) Use of the sugar chain-modified liposome according to item 1 for the production of a composition for intravenous administration and oral administration. (Item 294) The composition for intravenous administration and oral administration contains a medicament for treating disorders of the respiratory system, circulatory system, digestive system, urinary / genital system, central nervous system or peripheral nervous system. , Use according to Item 293. (Item 295) A method for treating a subject having a disorder of respiratory system, circulatory system, digestive system, urinary / genital system, central nervous system or peripheral nervous system, Administering a pharmaceutical composition for intravenous and oral administration for treating a disorder, the pharmaceutical composition for intravenous and oral administration comprising a sugar chain-modified liposome and a pharmaceutically acceptable carrier. A method wherein the glycosylated liposome contains an effective amount of an agent to treat the disorder. (Item 296) A method for delivering a biological agent to a target site in a subject in need of the biological agent, the method administering the sugar chain-modified liposome according to item 1. A method wherein the sugar chain-modified liposome contains an effective amount of the biological agent. (Item 297) A method for producing a sugar chain-modified liposome, which comprises the following steps: (a) a step of providing a liposome; (b) a step of hydrophilizing the liposome as necessary; c) if necessary, a step of binding a linker to the hydrophilized liposome to form a linker-bound liposome; and (d) a sugar chain bound to the liposome to generate a sugar chain-modified liposome. A method comprising the steps of: (Item 298) A method for producing a sugar chain-modified liposome according to item 297, wherein the step of hydrophilizing the liposome in step (b) is performed directly or indirectly on the lipid membrane of the liposome or on the linker. Wherein the linker used in step (c) is a human-derived protein, and in step (d), a saccharide is directly or indirectly attached to the liposome. A method comprising a step of binding a sugar chain to produce a sugar chain-modified liposome under conditions for binding the chain. (Item 299) A method for producing the sugar chain-modified liposome according to item 297, wherein in the step (d), the sugar chain and the liposome are bound under conditions suitable for oral administration. (Item 300) A method for producing a sugar chain-modified liposome according to item 297, wherein the sugar chain is the sugar chain according to any one of items 1 to 257. (Item 301) A method for producing a sugar chain-modified liposome for delivering a drug to a target delivery site, the method comprising the following: (a) having various sugar chain densities to the target delivery site Providing a sugar chain-modified liposome that achieves delivery; (b) determining, for the sugar chain density on the sugar chain-modified liposome, a density that achieves optimal delivery to the delivery site; and (c) the A method comprising incorporating a drug into the determined optimal sugar chain-modified liposome to produce a drug-containing liposome.

As mentioned above, although this invention has been illustrated using preferable embodiment of this invention, this invention should not be limited and limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. It is understood that those skilled in the art can implement an equivalent range from the description of specific preferred embodiments of the present invention based on the description of the present invention and common general technical knowledge. Patents, patent applications, and documents cited herein should be incorporated by reference in their entirety, as if the contents themselves were specifically described herein. Understood.

Hereinafter, although an example explains the composition of the present invention in detail, the present invention is not limited to this. The reagents used in the following were commercially available unless otherwise specified.

(Example 1. Preparation of liposome) Liposomes were prepared according to a previously reported method (Yamazaki, N., Kodama, M. and Gabis, H.-J. (1994) Methods Enzymol. 242, 56-65). Prepared using dialysis method. That is, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, ganglioside, and dipalmitoyl phosphatidylethanolamine were mixed in a molar ratio of 35: 40: 5: 15: 5 to give a total lipid amount of 45.6 mg, respectively. 46.9 mg of sodium acid was added and dissolved in 3 ml of chloroform / methanol solution. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane. The obtained lipid membrane was suspended in 3 ml of TAPS buffer (pH 8.4) and sonicated to obtain a transparent micelle suspension. Further, the micelle suspension was mixed with a PM10 membrane (Amicon Co., USA) and a phosphate buffer solution with a pH of 7.2 (Phosphate Buffered Saline (PBS): Na ₂ HPO ₄ (25.55 g) / KH ₂ PO ₄ (2 .72 g) / NaN ₃ (0.8 g) / NaCl (35.4 g)) to prepare 10 ml of uniform liposomes (average particle size 100 nm).

Example 2 Hydrophilization Treatment on Liposome Lipid Membrane Surface 10 ml of liposome solution prepared in Example 1 was subjected to ultrafiltration using XM300 membrane (Amicon Co., USA) and CBS buffer (pH 8.5). The pH of the solution was brought to 8.5 by filtration. Next, 10 ml of a crosslinking reagent bis (sulfocuccinimidyl) suberate (BS3; Pierce Co., USA) was added and stirred at 25 ° C. for 2 hours. Thereafter, the mixture was further stirred overnight at 7 ° C. to complete the chemical binding reaction between the lipid dipalmitoylphosphatidylethanolamine and BS3 on the liposome membrane. Then, this liposome solution was subjected to ultrafiltration with an XM300 membrane and a CBS buffer (pH 8.5). Next, 40 mg of tris (hydroxymethyl) aminomethane dissolved in 1 ml of CBS buffer (pH 8.5) was added to 10 ml of the liposome solution, stirred at 25 ° C. for 2 hours, and then stirred at 7 ° C. overnight to form a liposome membrane. The chemical binding reaction between BS3 bound to the above lipid and tris (hydroxymethyl) aminomethane was completed. As a result, the hydroxyl group of tris (hydroxymethyl) aminomethane was coordinated on the lipid dipalmitoylphosphatidylethanolamine of the liposome membrane to make it hydrated and hydrophilic.

(Example 3. Binding of human serum albumin (HSA) to the liposome membrane surface) Human serum albumin (HSA) binding to the liposome membrane surface was reported by a previously reported method (Yamazaki, N., Kodama, M. and. Gabius, H.-J. (1994) Methods Enzymol. 242, 56-65) using the coupling reaction method. That is, this reaction is carried out by a two-step chemical reaction. First, 1 ml of TAPS (N-Tris (hydroxymethyl) methyl-3-aminopropanesulfuric acid) buffer is used to convert the ganglioside present on the surface of 10 ml of the liposome membrane obtained in Example 2. After adding 43 mg of sodium metaperiodate dissolved in solution (pH 8.4) and stirring for 2 hours at room temperature to oxidize periodate, ultrafilter with XM300 membrane and PBS buffer (pH 8.0) This gave 10 ml of oxidized liposomes. To this liposome solution, 20 mg of human serum albumin (HSA) was added and stirred at 25 ° C. for 2 hours, and then 100 μl of 2M NaBH ₃ CN was added to PBS (pH 8.0) and stirred overnight at 10 ° C. HSA was bound by a coupling reaction between ganglioside on liposome and HSA. And after ultrafiltration with XM300 membrane and CBS buffer (pH 8.5), 10 ml of HSA binding liposome solution was obtained.

(Example 4. Preparation of sugar chain) The sugar chains shown in Table 2 below were used.

The mass of each sugar chain was measured and pretreated for use in Example 5 below. When using a combination of two or more sugar chains, each sugar chain was mixed.

(Example 5. Binding of sugar chain onto liposome membrane surface-bound human serum albumin (HSA)) 0.5 ml aqueous solution in which 50 μg of each sugar chain prepared in Example 4 was dissolved in 0.25 g of NH ₄ HCO _3. In addition, the mixture was stirred at 37 ° C. for 3 days, and then filtered through a 0.45 μm filter to complete the amination reaction at the reducing end of the sugar chain to obtain 50 μg of a glycosylamine compound of each sugar chain. Next, 1 mg of a crosslinking reagent 3,3′-dithiobis (sulfosuccinimidylpropionate) (DTSSP; Pierce Co., USA) was added to 1 ml of a part of the liposome solution obtained in Example 3 at 25 ° C. The mixture was stirred for an hour and then at 7 ° C. overnight, and ultrafiltered with an XM300 membrane and a CBS buffer (pH 8.5) to obtain 1 ml of liposomes in which DTSSP was bound to HSA on the liposomes. Next, 50 μg of the above-mentioned glycosylamine compound was added to this liposome solution, and the mixture was stirred at 25 ° C. for 2 hours, then stirred at 7 ° C. overnight, and ultrafiltered with XM300 membrane and PBS buffer solution (pH 7.2). Then, the glycosylated amine compound was bound to DTSSP on liposome membrane-bound human serum albumin. As a result, 2 ml each of liposomes (total lipid amount 2 mg, total protein amount 200 μg, average particle size 100 nm) in which the sugar chains shown in Table 2 were combined with human serum albumin and liposomes were obtained.

Table 6 below shows the results of binding onto liposome membrane surface-bound human serum albumin (HSA) when each sugar chain is used. Unless otherwise specified, these sugar chains were bound to liposome membrane surface-bound human serum albumin by the same method and conditions as in Example 5. In Table 6, compound (1) represents a glucosylamine compound of each sugar chain.

(Preparation Example 1. Binding of Tris (hydroxymethyl) aminomethane onto Liposome Membrane-Bound Human Serum Albumin (HSA)) To prepare a liposome as a comparative sample, 1 ml of a part of the liposome liquid obtained in Example 3 1 mg of a crosslinking reagent 3,3′-dithiobis (sulfosuccinimidylpropionate (DTSSP; Pierce Co., USA) was added and stirred at 25 ° C. for 2 hours, followed by overnight at 7 ° C. Ultrafiltration with CBS buffer (pH 8.5) was performed to obtain 1 ml of liposome in which DTSSP was bound to HSA on the liposome, and then tris (hydroxymethyl) aminomethane (Wako Co., Japan) was added to the liposome solution. ) Add 13 mg, stir at 25 ° C. for 2 hours, then stir at 7 ° C. overnight, and add XM300 membrane and PBS buffer (p In 7.2), tris (hydroxymethyl) aminomethane was bound to DTSSP on liposomal membrane-bound human serum albumin by 13 mg of tris (hydroxymethyl) amino which was already in large excess in this step. Because of the presence of methane, the hydrophilic treatment on liposomal membrane-bound human serum albumin (HSA) was completed at the same time, and as a result, the hydrophilized tris (hydroxymethyl) aminomethane and human serum albumin as the final products 2 ml of liposome (abbreviation: TRIS) (total lipid amount 2 mg, total protein amount 200 μg, average particle size 100 nm) was obtained as a comparative sample in which liposome and liposome were bound.

(Example 6. Hydrophilization treatment on liposome membrane surface-bound human serum albumin (HSA)) For the liposomes to which the sugar chains prepared by the means of Example 5 were bound, HSA on the liposomes was separately treated by the following procedure. The protein surface was hydrophilized. Separately, 13 mg of tris (hydroxymethyl) aminomethane was separately added to 2 ml of the sugar chain-bound liposome, and stirred at 25 ° C. for 2 hours and then at 7 ° C. overnight, and then XM300 membrane and PBS buffer (pH 7.2). The unreacted product was removed by ultrafiltration at 2 to obtain 2 ml each of the glycosylated liposome complex subjected to hydrophilic treatment as a final product (total lipid amount 2 mg, total protein amount 200 μg, average particle size 100 nm). .

(Example 7. Measurement of lectin binding activity inhibition effect by various sugar chain-bound liposome complexes) In vitro lectin binding activity of each sugar chain-bound liposome complex prepared by the means of Preparation Example 1 and Example 6 is Measurement was performed in an inhibition experiment using a lectin-immobilized microplate according to a conventional method (Yamazaki, N. (1999) Drug Delivery System, 14, 498-505). That is, a lectin (E-selectin; R & D Systems Co., USA) was immobilized on a 96-well microplate. On this lectin-immobilized plate, 0.1 μg of biotinylated fucosylated fetuin as a comparative ligand and various sugar chain-bound liposome complexes having different concentrations (0.01 μg, 0.04 μg, 0.11 μg as protein mass, 0.33 μg, 1 μg) was added and incubated at 4 ° C. for 2 hours. After washing 3 times with PBS (pH 7.2), horseradish peroxidase (HRPO) -conjugated streptavidin was added. Furthermore, it incubated at 4 degreeC for 1 hour, and wash | cleaned 3 times by PBS (pH 7.2). Next, a peroxidase substrate was added and left at room temperature, and the absorbance at 405 nm was measured with a microplate reader (Molecular Devices Corp., USA). Biotinylation of fucosylated fetuin was purified by Centricon-30 (Amicon Co., USA) after treatment with sulfo-NHS-biotin reagent (Pierce Co., USA). HRPO-conjugated streptavidin was prepared by HRPO oxidation and streptavidin binding by reductive amination using NaBH ₃ CN. The results obtained by processing the measurement results as follows are shown in the following table.

Therefore, when the ratio of the average value of sample LY-1 is W, the calculation formula when the average value of sample LY-1 is X, hot is Y, and cold is Z is:
W = (X−Z) / (Y−Z) × 100
It can be expressed as.
FIG. 6 shows graph 1 of sample LY-1 and series IC 50 created based on Tables 7 and 8.
Graph 1 is based on Table 7. The X axis is a logarithmic memory. Each point on the line graph represents an average ratio of measured values at each concentration (horizontal axis) of sample LY-1. Since the control value differs depending on the sample, the vertical axis of the graph is represented by the ratio of the difference between hot and cold as 1, so that the comparison is easy. X-coordinate of the intersection point of the graph of the graph and sequence IC50 of Sample LY-1 is the value of _{IC 50.} The intersection is on a straight line including coordinates 1 (0.11, 0.562) and coordinates 2 (0.33, 0.414), and the equation is y = −0.673x +
0.636. The x coordinate of the intersection of two straight lines with y = 0.5 (series IC50 formula) is 0.202. Dividing this value by the molecular weight of the protein 69000 and dividing by the number of proteins 300 per liposome gives 9.76E-09.
These calculations can be automated using a computer program.

(Example 8. ¹²⁵ I labeling of various sugar chain-bound liposomes by chloramine T method) Chloramine T (Wako Pure Chemical Co., Japan) solution and sodium disulfite solution were used to be 3 mg / ml and 5 mg / ml, respectively. Prepared and used. 50 μl each of the sugar chain-bound liposome and tris (hydroxymethyl) aminomethane-bound liposome prepared according to Example 6 were separately placed in an Eppendorf tube, followed by 15 μl of ¹²⁵ I-NaI (NEN Life Science Product, Inc. USA), 10 μl of chloramine T solution was added and reacted. Every 5 minutes, 10 μl of chloramine T solution was added, and this operation was repeated twice. After 15 minutes, 100 μl of sodium disulfite was added as a reducing agent to stop the reaction. Next, it was placed on Sephadex G-50 (Pharmacia Biotech. Sweden) column chromatography, eluted with PBS, and the labeled product was purified. Finally, a non-labeled-liposome complex was added to adjust the specific activity (4 × 10 ⁶ Bq / mg protein) to obtain a ¹²⁵ I-labeled liposome solution.

(Example 9. Measurement of transfer amount of various sugar chain-bound liposome complexes from intestinal tract to blood in mice) Male ddY mice (7 weeks old) fasted except for water all day and night were labeled with ¹²⁵ I according to Example 8. 10 minutes after forcibly administering in an intestinal tract with an oral sonde for mice so that 0.2 ml of the conjugated sugar chain and tris (hydroxymethyl) aminomethane-conjugated liposome complex was 3 μg / one protein as the amount of protein. Later, 1 ml of blood was collected from the lower aorta under Nembutal anesthesia. Then, ¹²⁵ I radioactivity in blood was measured with a gamma counter (Alola ARC300). Furthermore, for the purpose of examining the in vivo stability of various liposome complexes, the serum of each blood was rechromatographed with Sephadex G-50, and all of the radioactivity was found in high molecular weight void fractions. The liposome complex was stable in vivo. The amount of radioactivity transferred from the intestinal tract into the blood was expressed as the ratio of radioactivity per ml of blood (% dose / ml blood) to the total radioactivity administered. Depending on the type of sugar chain used, sugar chain-modified liposomes may or may not migrate from the intestinal tract into the blood. The results are shown in the following table. In Table 7, the definition of target directivity evaluation (++, +) is as follows. Moreover, evaluation (-) represents a negative result and NA represents unmeasured. Based on this result, it is possible to determine the type and bond density of sugar chains that are optimal for oral administration.

(Example 10. In vivo kinetic study of sugar chain-modified liposomes) Experiments were performed on normal mice and tumor-bearing mice. The procedure is as follows. Measurement of the distribution amount of various sugar chain-modified liposomes and liposomes without sugar chain modification to each tissue was performed using normal mice and Ehrlich ascites tumor (EAT) cells (about 2 × 10 ⁷ cells) in male ddY mice. (7 weeks of age) Transplanted subcutaneously in the thigh, and cancer tissue grown to 0.3 to 0.6 g (after 6 to 8 days) was used in this experiment. These mice were orally administered with 0.2 ml of various ¹²⁵ I-labeled liposomes according to Example 8 at a rate of 3 μg / one protein, or injected into the tail vein for 10 minutes or 5 minutes. Later, tissues (blood, liver, heart, lung, pancreas, brain, cancer tissue, inflamed tissue around the cancer, small intestine, large intestine, lymph node, bone marrow, kidney, spleen, thymus, muscle) are removed, and the radioactivity of each tissue Was measured with a gamma counter (Aloka ARC 300). In addition, the amount of radioactivity distribution to each tissue was measured by the ratio of radioactivity per 1 g of each tissue to the total administered radioactivity (% dose / g tissue). In addition, sugar chain-modified liposomes, and liposomes to which tris (hydroxymethyl) aminomethane is bound instead of sugar chains as reference liposomes are administered orally or intravenously, and then delivered to the blood or each tissue. The magnification of the measured average value of the 4 animals and the measured average value of the 4 animals with the reference liposome was calculated. Based on this calculation result, the transferability into blood after oral administration and the target directivity to each organ were evaluated using a liposome combined with tris (hydroxymethyl) aminomethane as a reference liposome. The results are shown in the following table. Regarding delivery to organs when orally administered, the medium that has been transferred into the blood by oral administration shows the same tendency as intravenous injection. From the results shown in the following table, it was found that the sugar chain-modified liposome of the present invention accumulates at the tumor site and the inflammation site and has directivity to these sites. In Table 9, the definition of target directivity evaluation (++, +) is as follows. Moreover, evaluation (-) represents a negative result and NA represents unmeasured.

Tables 11 and 13 show the evaluation results showing the accumulation effect of the radioactive sugar chain liposomes on each tissue in mice by oral administration and intravenous administration of various radioactive sugar chain-modified liposomes. These results show that this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand to efficiently accumulate and deliver drugs, fluorescent substances, radiolabeled substances, etc. to diseased areas and various organs by active targeting. Is shown. Therefore, since the sugar chain-modified liposome of the present invention can visualize the accumulation in a target tissue such as a tumor, it also provides a delivery medium for use as a research reagent or a diagnostic agent as well as a therapeutic drug delivery medium. To do.

Example 11 Preparation of Anticancer Drug Doxorubicin Encapsulated Liposomes Liposomes were improved by a previously reported technique (Yamazaki, N., Kodama, M. and Gabis, H.-J. (1994) Methods Enzymol. 242, 56-65). Prepared using a modified cholate dialysis method. That is, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, ganglioside and dipalmitoyl phosphatidylethanolamine were mixed in a molar ratio of 35: 40: 5: 15: 5 to give a total lipid amount of 45.6 mg, respectively. 46.9 mg of sodium acid was added and dissolved in 3 ml of chloroform / methanol solution. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane. The obtained lipid membrane was suspended in 10 ml of TAPS buffered physiological saline (pH 8.4) and sonicated to obtain 10 ml of a transparent micelle suspension. To this micelle suspension, the anticancer drug doxorubicin completely dissolved to 3 mg / 1 ml with TAPS buffer (pH 8.4) was slowly added dropwise with stirring and mixed uniformly, and then the micelle suspension containing doxorubicin was added. Uniform anticancer drug doxorubicin-encapsulated liposome particle suspension 10 ml was prepared by ultrafiltration using PM10 membrane (Amicon Co., USA) and TAPS buffered saline (pH 8.4).

Results of measuring the particle size and zeta potential of the anticancer drug doxorubicin-encapsulated liposome particles in the obtained physiological saline suspension (37 ° C.) with a zeta potential / particle size / molecular weight measuring device (Model Nano ZS, Malvern Instruments Ltd, UK) The particle diameter was 50 to 350 nm, and the zeta potential was −30 to −10 mV.

(Example 12. Hydrophilization treatment on anticancer drug doxorubicin-encapsulated liposome lipid membrane surface) Anticancer drug doxorubicin-encapsulated liposome solution 10 ml prepared in Example 11 was treated with XM300 membrane (Amicon Co., USA) and CBS buffer (pH 8.5). The solution was adjusted to pH 8.5 by ultrafiltration using. Next, 10 ml of a cross-linking reagent bis (sulfosuccinimidyl) suberate (BS3; Pierce Co., USA) was added and stirred at 25 ° C. for 2 hours. Thereafter, the mixture was further stirred overnight at 7 ° C. to complete the chemical bonding reaction between the lipid dipalmitoylphosphatidylethanolamine and BS3 on the liposome membrane. Then, this liposome solution was subjected to ultrafiltration with an XM300 membrane and a CBS buffer (pH 8.5). Next, 40 mg of tris (hydroxymethyl) aminomethane dissolved in 1 ml of CBS buffer (pH 8.5) was added to 10 ml of the liposome solution, stirred at 25 ° C. for 2 hours, and then stirred overnight at 7 ° C. The chemical bonding reaction between BS3 bound to the lipids and tris (hydroxymethyl) aminomethane was completed. As a result, the hydroxyl group of tris (hydroxymethyl) aminomethane was coordinated on the lipid dipalmitoylphosphatidylethanolamine of the anticancer drug doxorubicin-encapsulated liposome membrane to make it hydrated and hydrophilic.

(Example 13. Binding of human serum albumin (HSA) to the surface of liposome membrane encapsulating anticancer drug doxorubicin) Binding of human serum albumin (HSA) to the surface of liposome membrane was performed by a previously reported method (Yamazaki, N., Kodama, M. and Gabis, H.-J. (1994) Methods Enzymol. 242, 56-65) using a coupling reaction method. That is, this reaction is a two-step chemical reaction. First, metaperiodic acid in which ganglioside present on the surface of 10 ml of liposome membrane obtained in Example 2 was dissolved in 1 ml of TAPS buffer (pH 8.4). After adding 43 mg of sodium and stirring at room temperature for 2 hours to oxidize periodate, 10 ml of oxidized liposome was obtained by ultrafiltration with XM300 membrane and PBS buffer (pH 8.0). To this liposome solution, 20 mg of human serum albumin (HSA) was added and stirred at 25 ° C. for 2 hours, and then 2M NaBH ₃ CN 100 μ1 was added to PBS (pH 8.0) and stirred overnight at 10 ° C. to prepare liposomes. HSA was bound by a coupling reaction between the above ganglioside and HSA. Then, after ultrafiltration with an XM300 membrane and a CBS buffer (pH 8.5), 10 ml of liposome solution encapsulating HSA-conjugated anticancer drug doxorubicin was obtained.

(Example 14. Preparation of sugar chain) A sugar chain was prepared by the same procedure as in Example 4.

(Example 15. Binding of sugar chain on anticancer drug doxorubicin-encapsulated liposome membrane surface-bound human serum albumin (HSA) and hydrophilic treatment of linker protein (HSA)) 50 μg of each sugar chain prepared in Example 14 After adding 25 g of NH ₄ HCO ₃ in 0.5 ml aqueous solution and stirring at 37 ° C. for 3 days, filtration through a 0.45 μm filter completes the amination reaction of the reducing end of the sugar chain, and each sugar chain As a result, 50 μg of a glycosylamine compound was obtained. Next, 1 mg of a cross-linking reagent 3,3′-dithiobis (sulfosuccinimidylpropionate) (DTSSP; Pierce Co., USA) was added to 1 ml of a part of the liposome solution encapsulating the anticancer drug doxorubicin obtained in Example 13 and 25. The mixture was stirred at 7 ° C. for 2 hours and then at 7 ° C. overnight, and ultrafiltered with an XM300 membrane and CBS buffer (pH 8.5) to obtain 1 ml of liposomes in which DTSSP was bound to HSA on the liposomes. Next, 50 μg of the above-mentioned glycosylamine compound having a sugar chain is added to the liposome solution, and the mixture is stirred at 25 ° C. for 2 hours, then stirred at 7 ° C. overnight, and limited with XM300 membrane and PBS buffer (pH 7.2). Each sugar chain was bound to DTSSP on liposome membrane surface-bound human serum albumin by external filtration. Next, 13 mg of tris (hydroxymethyl) aminomethane (Wako Co., Japan) was added to the liposome solution, and the mixture was stirred at 25 ° C. for 2 hours, and then stirred at 7 ° C. overnight, and the XM300 membrane and PBS buffer solution ( The glycosylated amine compound was bound to DTSSP on liposome membrane-bound human serum albumin by ultrafiltration at pH 7.2). As a result, a liposome obtained by hydrophilizing a linker protein (HSA) in which tris (hydroxymethyl) aminomethane, human serum albumin, and liposome were bound was obtained. As a result, 2 ml of anticancer drug doxorubicin-encapsulated liposomes (total lipid amount 2 mg, total protein amount 200 μg) obtained by hydrophilizing the linker protein (HSA) in which each sugar chain, human serum albumin and liposome were bound was obtained.

The particle diameter and zeta potential of the anticancer drug doxorubicin-encapsulated liposome particles in the obtained physiological saline suspension (37 ° C.) were measured with a zeta potential / particle diameter / molecular weight measuring apparatus (Model Nano ZS, Malvern Instruments Ltd, UK). As a result, the particle diameter was 50 to 350 nm, and the zeta potential was −30 to −10 mV.

(Preparation Example 2: Preparation of glycolipid liposome) Glycolipid liposomes (starting with FEE, EE, for example, liposome number 3, liposome number 37, liposome number 67, liposome number 218, etc.) were prepared as follows.

Liposomes were prepared using the cholic acid dialysis method. That is, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, ganglioside (containing 100% GM1 as a glycolipid sugar chain) and dipalmitoyl phosphatidylethanolamine in a molar ratio of 35: 40: 5: 15: 5, respectively. Was mixed so that the total lipid amount was 45.6 mg, 46.9 mg of sodium cholate was added, and dissolved in 3 ml of chloroform / methanol solution. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane. The obtained lipid membrane was suspended in 3 ml of TAPS buffer (pH 8.4) and sonicated to obtain 3 ml of a transparent micelle suspension. PBS buffer solution (pH 7.2) is added to the micelle suspension to make 10 ml, and then the micelle suspension is limited using PM10 membrane (Amicon Co., USA) and TAPS buffer solution (pH 8.4). 10 ml of a liposome particle suspension not subjected to uniform hydrophilic treatment by external filtration was prepared. Bolton Hunter reagent (BHR; Pierce Co., USA) 5 mg was added to this liposome solution and reacted at 25 ° C. for 2 hours and then at 7 ° C. for 4 hours to make dipalmitoylphosphatidylethanolamine BH, and then PBS buffer ( Ultrafiltration was carried out at pH 7.2). As a result, 10 ml of liposomes (abbreviation: EEGM1-BH) (total lipid amount 45.6 mg, average particle size 100 nm) as a comparative sample were obtained.

The particle diameter and zeta potential of the anticancer drug doxorubicin-encapsulated liposome particles in the obtained physiological saline suspension (37 ° C.) were measured by a zeta potential / particle diameter / molecular weight measuring apparatus (Model Nano ZS, Malvern Instruments Ltd., UK). As a result, the particle diameter was 50 to 350 nm, and the zeta potential was −30 to −10 mV.

(Example 16. Hydrophilization treatment on liposome membrane surface-bound human serum albumin (HSA)) With respect to the liposome to which the sugar chain prepared by the means of Example 15 was bound, the surface of the HSA protein on the liposome was treated by the following procedure. Hydrophilic treatment was performed. Separately, 13 mg of tris (hydroxymethyl) aminomethane was separately added to 2 ml of the sugar chain-bound liposome, and stirred at 25 ° C. for 2 hours and then at 7 ° C. overnight, and then XM300 membrane and PBS buffer (pH 7.2). The unreacted product was removed by ultrafiltration at 2 to obtain 2 ml each of the glycosylated liposome complex subjected to hydrophilic treatment as a final product (total lipid amount 2 mg, total protein amount 200 μg, average particle size 100 nm). .

(Example 17. Measurement of lectin binding activity inhibitory effect by various sugar chain-bound liposome complexes) In vitro lectin binding activity of each sugar chain-bound liposome complex prepared by the means of Example 16 was determined according to a conventional method (Yamazaki). N. (1999) Drug Delivery System, 14, 498-505), and measured in an inhibition experiment using a lectin-immobilized microplate. That is, a lectin (E-selectin; R & D Systems Co., USA) was immobilized on a 96-well microplate. To this lectin-immobilized plate, 0.1 μg of biotinylated fucosylated fetuin as a comparative ligand and various sugar chain-bound liposome complexes with different concentrations (as protein masses, 0.01 μg, 0.04 μg, 0.11 μg, 0.33 μg, 1 μg) was added and incubated at 4 ° C. for 2 hours. After washing 3 times with PBS (pH 7.2), horseradish peroxidase (HRPO) -conjugated streptavidin was added, further incubated at 4 ° C. for 1 hour, washed 3 times with PBS (pH 7.2), and peroxidase substrate Was added and allowed to stand at room temperature, and the absorbance at 405 nm was measured with a microplate reader (Molecular Devices Corp., USA). Biotinylation of fucosylated fetuin was purified by Centricon-30 (Amicon Co., USA) after treatment with sulfo-NHS-biotin reagent (Pierce Co., USA). HRPO-conjugated streptavidin was prepared by HRPO oxidation and streptavidin binding by reductive amination using NaBH ₃ CN. The results of measuring IC50 in the same manner as above are shown in the following table.

(Example 18. ¹²⁵ I labeling of various sugar chain-bound liposomes by chloramine T method) Chloramine T (Wako Pure Chemical Co., Japan) solution and sodium disulfite solution were used to be 3 mg / ml and 5 mg / ml, respectively. Prepared and used. 50 μl each of the sugar chain-bound liposome and tris (hydroxymethyl) aminomethane-bound liposome prepared according to Example 16 were separately placed in an Eppendorf tube, followed by 15 μl of ¹²⁵ I-NaI (NEN Life Science Product, Inc. USA), 10 μl of chloramine T solution was added and reacted. Every 5 minutes, 10 μl of chloramine T solution was added, and this operation was repeated twice. After 15 minutes, 100 μl of sodium disulfite was added as a reducing agent to stop the reaction. Next, it was placed on Sephadex G-50 (Pharmacia Biotech. Sweden) column chromatography, eluted with PBS, and the labeled product was purified. Finally, a non-labeled-liposome complex was added to adjust the specific activity (4 × 10 ⁶ Bq / mg protein) to obtain a ¹²⁵ I-labeled liposome solution.

(Example 19. Measurement of transfer amount of various sugar chain-bound liposome complexes from intestinal tract to blood in mice) Male ddY mice (7 weeks old) fasted except for water all day and night were labeled with ¹²⁵ I according to Example 17. 10 minutes after forcibly administering in an intestinal tract with an oral sonde for mice so that 0.2 ml of the glycan-linked and tris (hydroxymethyl) aminomethane-conjugated liposome complex was 3 μg / one protein as a protein amount. Later, 1 ml of blood was collected from the lower aorta under Nembutal anesthesia. Then, ¹²⁵ I radioactivity in blood was measured with a gamma counter (Alola ARC300). Furthermore, for the purpose of examining the in vivo stability of various liposome complexes, the serum of each blood was rechromatographed with Sephadex G-50, and all of the radioactivity was found in high molecular weight void fractions. The liposome complex was stable in vivo. The amount of radioactivity transferred from the intestinal tract into the blood was expressed as the ratio of radioactivity per ml of blood (% dose / ml blood) to the total radioactivity administered. Depending on the type of sugar chain used, there were those that migrated from the intestinal tract into the blood and those that did not migrate. The results are shown in the following table.

(Example 20. Treatment effect in mice having tumors by intravenous injection of various sugar chain-bound liposome complexes)

(1) Treatment effect of tail vein administration in tumor-bearing mice

Fibrosarcoma, muscle sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, lymphangiosarcoma, periosteum, mesothelioma, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, rectal cancer , Pancreatic cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, brain cancer, squamous cell carcinoma, sebaceous carcinoma, papillary carcinoma, cystadenocarcinoma, medullary cancer, bronchial progenitor Cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, cervical cancer, testicular cancer, small cell lung carcinoma, non-small cell lung cancer, bladder carcinoma, epithelium Cell carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblast A mouse model of a tumor selected from the group consisting of tumor, retinoblastoma, leukemia, lymphoma and Kaposi's sarcoma for about 10 days Education, to observe, used in the following experiment. These mice are divided into two groups: a sugar chain-modified liposome administration group encapsulating a drug that can be used for treatment of the target disease and a physiological saline administration group as a control. These mice are administered with a sugar chain-modified liposome encapsulating a drug or physiological saline 4 times a week for 2 weeks by tail vein administration. The disease site is observed twice a week for 4 weeks. As a result of comparing changes in the disease site of the drug-encapsulated sugar chain-modified liposome administration group and the physiological saline administration group, the drug-encapsulated sugar chain-modified liposome administration group had a good treatment effect from the start of administration despite the extremely small dose. On the other hand, no change is observed in the diseased site in the physiological saline administration group. Drug-encapsulated sugar chain-modified liposomes have a significant treatment effect by tail vein administration.

(2) Observation of drug transfer to tumor by tail vein injection using fluorescence microscope

Observation with a fluorescence microscope is performed as follows. The skin of the cancer site of a mouse having a tumor is excised, and the tumor site is exposed and fixed to a glass slide. A mouse is placed on the stage of a fluorescence microscope to search for blood vessels around the tumor site and determine a position where the blood vessel image can be clearly observed. The same drug-encapsulated sugar chain-modified liposome as in (1) above is administered into the 0.2 ml tail vein. Drug accumulation at the diseased site immediately after administration is observed with a fluorescence microscope. About the inhibition experiment by the modified sugar pre-administration, 0.2 mL of the modified sugar chain solution (60 mM) is administered 5 minutes before the administration of the drug-encapsulated sugar chain-modified liposome, and observation is performed by the same method as described above. Immediately after administration of the drug-encapsulated sugar chain-modified liposome, fluorescence of the drug is observed in the blood vessels around the disease site. At 5 minutes after administration, drug fluorescence is observed in the blood vessel wall. Thereafter, drug transfer to the diseased site is observed over time, and after 2 hours, fluorescence of the drug is seen inside the tissue around the blood vessel at the diseased site. Pre-administration of the modified sugar chain completely blocks the accumulation of the drug-encapsulated liposome at the disease site, and no fluorescence from the blood vessel wall is observed immediately after administration of the drug-encapsulated sugar chain-modified liposome. These results indicate that this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand and accumulates and delivers drugs to the disease site with high efficiency by active targeting.

(Example 21. Treatment effect in mice having tumors by oral administration of various sugar chain-bound liposome complexes)

(1) Treatment effect by oral administration in tumor-bearing mice

Fibrosarcoma, muscle sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, lymphangiosarcoma, periosteum, mesothelioma, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, rectal cancer , Pancreatic cancer, ovarian cancer, prostate cancer, uterine cancer, head and neck cancer, skin cancer, brain cancer, squamous cell carcinoma, sebaceous carcinoma, papillary carcinoma, cystadenocarcinoma, medullary cancer, bronchial progenitor Cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, cervical cancer, testicular cancer, small cell lung carcinoma, non-small cell lung cancer, bladder carcinoma, epithelium Cell carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblast A mouse model of a tumor selected from the group consisting of tumor, retinoblastoma, leukemia, lymphoma and Kaposi's sarcoma for about 10 days Education, to observe, used in the following experiment. These mice are divided into two groups: a sugar chain-modified liposome administration group encapsulating a drug that can be used for treatment of the target disease and a physiological saline administration group as a control. These mice are orally administered with a sugar chain-modified liposome encapsulating a drug or physiological saline 4 times a week for 2 weeks. The disease site is observed twice a week for 4 weeks. As a result of comparing changes in the disease site of the drug-encapsulated sugar chain-modified liposome administration group and the physiological saline administration group, the drug-encapsulated sugar chain-modified liposome administration group had a good treatment effect from the start of administration despite the extremely small dose. On the other hand, no change is observed in the diseased site in the physiological saline administration group. Drug-encapsulated sugar chain-modified liposomes have a significant therapeutic effect by oral administration.

(2) Observation of drug transfer to tumor site by oral administration using fluorescence microscope

Observation with a fluorescence microscope is performed as follows. The skin of the cancer site of a mouse having a tumor is excised, and the tumor site is exposed and fixed to a glass slide. A mouse is placed on the stage of a fluorescence microscope to search for blood vessels around the tumor site and determine a position where the blood vessel image can be clearly observed. 0.2 ml of the same drug-encapsulated sugar chain-modified liposome as in (1) above is orally administered. Drug accumulation at the diseased site immediately after administration is observed with a fluorescence microscope. About the inhibition experiment by the modified sugar pre-administration, 0.2 mL of the modified sugar chain solution (60 mM) is administered 5 minutes before the administration of the drug-encapsulated sugar chain-modified liposome, and observation is performed by the same method as described above. Immediately after administration of the drug-encapsulated sugar chain-modified liposome, fluorescence of the drug is observed in the blood vessels around the disease site. At 5 minutes after administration, drug fluorescence is observed in the blood vessel wall. Thereafter, drug transfer to the diseased site is observed over time, and after 2 hours, fluorescence of the drug is seen inside the tissue around the blood vessel at the diseased site. Pre-administration of the modified sugar chain completely blocks the accumulation of the drug-encapsulated liposome at the disease site, and no fluorescence from the blood vessel wall is observed immediately after administration of the drug-encapsulated sugar chain-modified liposome. These results indicate that this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand and accumulates and delivers drugs to the disease site with high efficiency by active targeting.

The target directivity of the sugar chain-modified liposome is controlled by the type of sugar chain. Furthermore, by considering the binding density of sugar chains, more appropriate tumor-directed sugar chain-modified liposomes can be selected. This targeting property is not changed whether or not the sugar chain-modified liposome contains a drug.

(Example 22. Preparation of vitamin A-encapsulated liposome, encapsulated drug quantification, and storage stability)

Liposomes were prepared using the cholic acid dialysis method. That is, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, ganglioside and dipalmitoyl phosphatidylethanolamine were mixed in a molar ratio of 35: 40: 5: 15: 5 to give a total lipid amount of 45.6 mg, respectively. 46.9 mg of sodium acid was added and dissolved in 3 ml of chloroform / methanol solution. The solution was evaporated and the precipitate was dried in vacuo to obtain a lipid membrane. The obtained lipid membrane was suspended in 3 ml of TAPS buffered physiological saline (pH 8.4) and sonicated to obtain 10 ml of a transparent micelle suspension. To this micelle suspension, vitamin A completely dissolved in TAPS buffer (pH 8.4) to 3 mg / 1 ml was slowly added dropwise with stirring and mixed uniformly. Was subjected to ultrafiltration using a PM10 membrane (Amicon Co., USA) and TAPS buffered saline (pH 8.4) to prepare 10 ml of a uniform suspension of liposome particles with vitamin A encapsulated therein. As a result of measuring the particle diameter and zeta potential of vitamin A-encapsulated liposome particles in the obtained physiological saline suspension (37 ° C.) with a zeta potential / particle diameter / molecular weight measuring apparatus (ModelNanoZS, Malvern Instruments Ltd, UK) The diameter was 50 to 350 nm, and the zeta potential was −30 to −10 mV. When the amount of the encapsulated drug in the liposome was measured at an absorbance of 260 nm, it was found that vitamin A was encapsulated at a concentration of about 280 μg / m1. This vitamin A-encapsulated liposome was stable without causing precipitation or aggregation even after storage in a refrigerator for 1 year.

(Example 23. Preparation of a sugar chain-modified liposome containing no ganglioside)

(1. Preparation of liposome)

Liposomes were prepared using the improved cholate dialysis method according to a previously reported method (Yamazaki, N., Kodama, M. and Gabis, H.-J. (1994) Methods Enzymol. 242, 56-65). That is, dipalmitoyl phosphatidylcholine, cholesterol, dicetyl phosphate, and dipalmitoyl phosphatidylethanolamine are mixed so that the total lipid amount is 45.6 mg, 46.9 mg of sodium cholate is added, and dissolved in 3 ml of chloroform / methanol solution. . The solution is evaporated and the precipitate is dried in vacuo to obtain a lipid membrane. The obtained lipid membrane is suspended in 3 ml of TAPS buffer (pH 8.4) and sonicated to obtain a transparent micelle suspension. Furthermore, the micelle suspension is subjected to ultrafiltration using a PM10 membrane (Amicon Co., USA) and a PBS buffer (pH 7.2) to prepare 10 ml of uniform liposomes (average particle size 100 nm).

(2. Hydrophilization treatment on the liposome lipid membrane surface)

Above 1. 10 ml of the liposome solution prepared in step 1 is subjected to ultrafiltration using an XM300 membrane (Amicon Co., USA) and a CBS buffer (pH 8.5) to bring the pH of the solution to 8.5. Next, 10 ml of a crosslinking reagent bis (sulfocuccinimidyl) suberate (BS3; Pierce Co., USA) is added and stirred at 25 ° C. for 2 hours. Thereafter, the mixture is further stirred overnight at 7 ° C. to complete the chemical binding reaction between the lipid dipalmitoylphosphatidylethanolamine and BS3 on the liposome membrane. Then, this liposome solution is subjected to ultrafiltration with an XM300 membrane and a CBS buffer (pH 8.5). Next, 40 mg of tris (hydroxymethyl) aminomethane dissolved in 1 ml of CBS buffer (pH 8.5) was added to 10 ml of the liposome solution, stirred at 25 ° C. for 2 hours, and then stirred at 7 ° C. overnight to form a liposome membrane. The chemical binding reaction between BS3 bound to the above lipid and tris (hydroxymethyl) aminomethane is completed. As a result, the hydroxyl group of tris (hydroxymethyl) aminomethane is coordinated on the lipid dipalmitoylphosphatidylethanolamine of the liposome membrane to render it hydrated and hydrophilic.

(3. Binding of human serum albumin (HSA) to the liposome membrane surface)

A treatment for binding human serum albumin (HSA) onto the liposome membrane surface is performed in the same manner as in Example 3. As a result, human serum albumin (HSA) does not bind on the liposome membrane surface.

(Example 24. Measurement of anticancer effect in tumor-bearing mice by intravenous injection of various sugar chain-bound liposome complexes)

(1) Antitumor effect of intravenous tail administration in cancer-bearing mice

The tumor-bearing mice were prepared by shaving the back hair of ddY 7-week-old mice (male, body weight 35 to 40 g) with an electric clipper and transplanting Ehrlich Ascites Tumor (about 5 × 10 ⁶ cells / mouse) subcutaneously. The animals were reared and observed for about 10 days, and cancer cells were engrafted and used for the experiment. The drug administration and the volume measurement of the cancer are divided into two groups: a doxorubicin-encapsulated liposome No. 155 administration group prepared at a concentration of 0.0625 mg / kg encapsulated doxorubicin as the administration drug and a physiological saline administration group as a control. Intravenous administration was administered 4 times a week for 2 weeks. From the 10th day after cancer cell transplantation, the major axis and minor axis of the cancer were measured with calipers at a frequency of twice a week for 4 weeks, and the growth volume of the cancer was calculated from the following formula. Cancer volume (mm ³ ) = (major axis + minor axis ² ) / 2 This result is shown in FIG. Comparison of changes in tumor growth volume between the doxorubicin-encapsulated liposome number 155 administration group and the physiological saline-administered group as a control group, but the growth of cancer in the doxorubicin-encapsulated liposome number 155 administration group despite the extremely small dose The suppressive effect was remarkable, and the growth of cancer was suppressed from the start of administration. Comparing the size (volume) of cancer tissue on the 34th day of transplantation, which was the final measurement day, the doxorubicin-encapsulated liposome No. 155 administration group showed a significant inhibitory effect compared to the physiological saline administration group. These results indicate that this anticancer drug-encapsulated / glycan-modified liposome has a strong anticancer effect at a very small dose of drug (FIG. 2).

FIG. 2 is a graph showing the antitumor effect in tumor-bearing mice after intravenous dosing of doxorubicin-encapsulated liposome No. 155.

(2) Observation of transfer of doxorubicin to cancer tissue by intravenous tail vein administration using a fluorescence microscope Observation with a fluorescence microscope is performed by excising the skin of a cancer site of a tumor-bearing mouse, exposing the cancer tissue, and then cancer on a slide glass. The site was fixed. A mouse was placed on the stage of a fluorescence microscope to search for blood vessels surrounding the cancer tissue, and a position where a blood vessel image could be clearly observed was determined. 0.2 ml of doxorubicin-encapsulated liposome No. 155 having a lipid concentration of 2 mg / mL and a doxorubicin concentration of 0.025 mg / mL was administered into the tail vein. Accumulation of doxorubicin in the cancer tissue immediately after administration was observed with a fluorescence microscope. About the inhibition experiment by the modified sugar pre-administration, 0.2 mL of the modified sugar chain (α1-6 mannobiose) solution (60 mM) was administered 5 minutes before administration of doxorubicin-encapsulated liposome No. 155, and observation was performed in the same manner as described above. The result is shown in Photo 1. Immediately after administration of doxorubicin-encapsulated liposome No. 155, fluorescence of doxorubicin was observed in blood vessels around the cancer tissue. Five minutes after administration, red fluorescence of doxorubicin was observed in the blood vessel wall. Thereafter, the transfer of doxorubicin to the tissue was observed over time, and after 2 hours, fluorescence of doxorubicin was observed inside the tumor tissue around the cancer blood vessel. Pre-administration of the modified sugar chain completely blocked accumulation of doxorubicin-encapsulated liposome # 155 in the tumor tissue, and no fluorescence from the blood vessel wall was observed immediately after administration of doxorubicin-encapsulated liposome # 155. These results show that this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand to efficiently accumulate and deliver drugs, fluorescent substances, radiolabeled substances, etc. to diseased areas and various organs by active targeting. (FIG. 3).

FIG. 3 is a fluorescence micrograph showing the accumulation effect of doxorubicin from tumor blood vessels to tumor tissues and cells in a tumor-bearing mouse by intravenous injection of doxorubicin-encapsulated liposome No. 155. The left and right images are green and red fluorescence micrographs of the same tumor tissue and cells, respectively. Green (left image) shows the natural fluorescence of blood vessels, tissues and cells, and red (right image). Shows fluorescence of doxorubicin, a fluorescent substance, in tumor tissues and cancer cells. These results show that this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand to efficiently accumulate and deliver drugs, fluorescent substances, radiolabeled substances, etc. to diseased areas and various organs by active targeting. Is shown. Therefore, since the sugar chain-modified liposome of the present invention can visualize the accumulation in a target tissue such as a tumor, it also provides a delivery medium for use as a research reagent or a diagnostic agent as well as a therapeutic drug delivery medium. To do.

(Example 25. Measurement of anticancer effects in cancer-bearing mice by oral administration of various sugar chain-bound liposome complexes)

(1) Anticancer effect by oral administration in cancer-bearing mice

The tumor-bearing mice were prepared by shaving the back hair of ddY 7-week-old mice (male, body weight 35 to 40 g) with an electric clipper and transplanting Ehrlich Ascites Tumor (about 5 × 10 ⁶ cells / mouse) subcutaneously. The animals were reared and observed for about 10 days, and cancer cells were engrafted and used for the experiment. The drug administration and the volume measurement of cancer are divided into two types: the doxorubicin-encapsulated liposome number 237 administration group prepared at a concentration of 0.375 mg / kg encapsulated doxorubicin as the administration drug and the physiological saline administration group as a control. The administration was administered 4 times a week for 2 weeks. From the 10th day after cancer cell transplantation, the major axis and minor axis of the cancer were measured with calipers at a frequency of twice a week for 4 weeks, and the growth volume of the cancer was calculated from the following formula. Cancer volume (mm ³ ) = (major axis + minor axis ² ) / 2 This result is shown in FIG. Comparison of changes in tumor growth volume between the doxorubicin-encapsulated liposome number 237 administration group and the physiological saline administration group as a control, but the growth of cancer in the doxorubicin-encapsulated liposome number 237 administration group despite the extremely small dose The suppressive effect was remarkable, and the growth of cancer was suppressed from the start of administration. When comparing the size (volume) of the cancer tissue on the 34th day of transplantation, which was the final measurement day, the doxorubicin-encapsulated liposome No. 237 administration group showed a significant inhibitory effect compared to the physiological saline administration group. These results indicate that this anticancer drug-encapsulated / glycan-modified liposome has a strong anticancer effect at an extremely small dose of drug (FIG. 4).

FIG. 4 is a diagram showing the anticancer effect in cancer-bearing mice by oral administration of doxorubicin-encapsulated liposome No. 237.

(2) Observation of transfer of doxorubicin to cancer tissue by oral administration using fluorescence microscope

For observation with a fluorescence microscope, the skin of the cancer site of the tumor-bearing mouse was excised, the cancer tissue was exposed, and the cancer site was fixed on a slide glass. A mouse was placed on the stage of a fluorescence microscope to search for blood vessels surrounding the cancer tissue, and a position where a blood vessel image could be clearly observed was determined. 0.3 ml of doxorubicin-encapsulated liposome No. 237 having a lipid concentration of 4 mg / mL and a doxorubicin concentration of 0.050 mg / mL was orally administered. Accumulation of doxorubicin in the cancer tissue immediately after administration was observed with a fluorescence microscope. About the inhibition experiment by the modified sugar pre-administration, 0.3 mL of the modified sugar chain (α1-3 mannobiose) solution (60 mM) was administered 5 minutes before the administration of doxorubicin-encapsulated liposome No. 237, and observation was performed in the same manner as described above. The result is shown in Photo 1. After administration of doxorubicin-encapsulated liposome No. 237, transfer of doxorubicin to the tissue was observed over time, and after 6 hours, fluorescence of doxorubicin was observed inside the tumor tissue around the cancer blood vessel. Pre-administration of the modified sugar chain completely blocked the accumulation of doxorubicin-encapsulated liposome number 237 in the tumor tissue, and no fluorescence was observed from the blood vessel wall immediately after administration of doxorubicin-encapsulated liposome number 237. These results show that this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand to efficiently accumulate and deliver drugs, fluorescent substances, radiolabeled substances, etc. to diseased areas and various organs by active targeting. (FIG. 5).

FIG. 5 is a fluorescence micrograph showing the effect of doxorubicin accumulation from tumor blood vessels to tumor tissues and cells in tumor-bearing mice after oral administration of doxorubicin-encapsulated liposome No. 237. The left and right images are green and red fluorescence micrographs of the same tumor tissue and cells, respectively. Green (left image) shows the natural fluorescence of blood vessels, tissues and cells, and red (right image). Shows fluorescence of doxorubicin, a fluorescent substance, in tumor tissues and cancer cells. These results show that this sugar chain-modified liposome utilizes the function of the sugar chain as a ligand to efficiently accumulate and deliver drugs, fluorescent substances, radiolabeled substances, etc. to diseased areas and various organs by active targeting. Is shown. Therefore, since the sugar chain-modified liposome of the present invention can visualize the accumulation in a target tissue such as a tumor, it also provides a delivery medium for use as a research reagent or a diagnostic agent as well as a therapeutic drug delivery medium. To do.

As mentioned above, although this invention has been illustrated using preferable embodiment of this invention, this invention should not be limited and limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. It is understood that those skilled in the art can implement an equivalent range based on the description of the present invention and the common general technical knowledge from the description of specific preferred embodiments of the present invention. Patents, patent applications, and references cited herein should be incorporated by reference in their entirety as if the contents themselves were specifically described herein. Understood.

The present invention has the utility that a diagnostic agent can be delivered to the intended delivery site. Thus, the present invention provides a tumor-directed drug delivery vehicle encapsulating a diagnostic agent in a sugar chain-modified liposome and related utility.

Claims (14)

A diagnostic drug delivery composition comprising a sugar chain-modified liposome to which at least one sugar chain selected from the following group is bound, and a diagnostic drug:
Neu5Aca2,3Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Fuca1,2Galb1,4 (Fuca1,3) Glc,
Neu5Aca2,3Galb1,4Glc,
Galb1,3GalNAcb1,4 (Neu5Aca2,8Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Galb1,4GlcNAc,
GalNAca1,3 (Fuca1,2) Gal,
3 '-(O-SO3H) Galb1,4 (Fuca1,3) GlcNAc,
Fuca1,2Gal,
Mana1,2Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Fuca1,2Galb1,3GlcNAcb1,3Galb1,4Glc,
Mana1,2Mana1,6 (Mana1,2Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Neu5Aca2,6Galb1,4GlcNAc,
Galb1,3GalNAcb1,4Galb1,4Glcb1,1Cer + Neu5Aca2,3Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Galb1,3 (Fuca1,4) GlcNAcb1,3Galb1,4Glc,
Galb1,3GlcNAcb1,3Galb1,4Glc,
Gala1,3 (Fuca1,2) Gal,
Galb1,3GalNAc,
Galb1,6GlcNAc,
Mana1,6 (Mana1,3) Man,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,2Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Galb1,3GlcNAc,
Mana1,2Man,
Galb1,4 (Fuca1,3) GlcNAc,
Gala1,3Gal,
Fuca1,2Galb1,4Glc,
Mana1,6 (Mana1,3) Mana1,6Manb1,4GlcNAcb1,4GlcNAc,
Galb1,4 (Fuca1,3) Glc,
GalNAca1-OL-serine,
Neu5Aca2,3Galb1,4 (Fuca1,3) GlcNAc,
Fuca1,2Galb1,4 (Fuca1,3) GlcNAc,
Galb1,4Glc,
Mana1,6Man,
Neu5Aca2,6GalNAca1-OL-serine,
Mana1,6 (Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Fuca1,2Galb1,3 (Fuca1,4) GlcNAc,
Mana1,4Man,
Neu5Ac2,6GalNAca1-OL-serine,
Neu5Aca2,6Galb1,4Glc,
Fuca1,2Galb1,3 (Fuca1,4) GlcNAcb1,3Galb1,4Glc,
Galb1,3GalNAcb1,4 (Neu5Aca2,3) Galb1,4Glcb1,1Cer,
Mana1,6 (Mana1,3) Mana1,6 (Mana1,3) Manb1,4GlcNAcb1,4GlcNAc,
Mana1,3Man,
Neu5Aca2,3Galb1,3 (Fuca1,4) GlcNAc,
3 '-(O-SO3H) Galb1,3 (Fuca1,4) GlcNAc,
Neu5Aca2,3Galb1,4GlcNAc,
Galb1,3 (Fuca1,4) GlcNAc. The diagnostic drug delivery composition according to claim 1, wherein the modified binding density of the sugar chain is 0.0075 to 0.75 mg sugar chain / mg lipid. The diagnostic drug delivery composition according to claim 1 or 2, wherein the sugar chain is bound to a membrane of the liposome via a linker. The diagnostic agent delivery composition according to claim 3, wherein the linker is a biological protein. The diagnostic agent delivery composition according to claim 4, wherein the linker is human serum albumin or bovine serum albumin. The diagnostic drug delivery composition according to any one of claims 1 to 5, wherein the sugar chain-modified liposome is rendered hydrophilic by binding a hydrophilic compound to at least one of a liposome membrane or a linker. . The diagnostic drug delivery composition according to any one of claims 1 to 6, wherein the liposome and the sugar chain are bound by a peptide bond. The diagnostic drug delivery composition according to claim 3, wherein the ganglioside on the membrane of the liposome and the linker are bonded by a covalent bond, and the terminal of the linker is bonded by a peptide bond. The hydrophilic compound is a low molecular weight hydrophilic compound, preferably a low molecular weight hydrophilic compound having at least one OH group, and more preferably a low molecular weight hydrophilic compound having at least two OH groups. The diagnostic agent delivery composition of claim 1 characterized by or being a tris (hydroxyalkyl) aminoalkane. The diagnostic agent delivery composition according to claim 1, wherein the diagnostic agent is a cancer diagnostic agent or an anti-inflammatory diagnostic agent. The diagnostic agent delivery composition according to claim 1, wherein the diagnostic agent is a radioactive diagnostic agent. The diagnostic agent delivery composition according to claim 1, wherein the diagnostic agent is a fluorescent diagnostic agent. The diagnostic agent delivery composition according to any one of claims 1 to 12, wherein the diagnostic agent delivery composition is orally administered. The diagnostic agent delivery composition according to any one of claims 1 to 12, wherein the diagnostic agent delivery composition is administered intravenously.