WO2007037273A1 - Introduction d’une substance dans une cellule au moyen d’une nanoparticule présentant un peptide rendant une membrane cellulaire perméable - Google Patents

Introduction d’une substance dans une cellule au moyen d’une nanoparticule présentant un peptide rendant une membrane cellulaire perméable Download PDF

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Publication number
WO2007037273A1
WO2007037273A1 PCT/JP2006/319176 JP2006319176W WO2007037273A1 WO 2007037273 A1 WO2007037273 A1 WO 2007037273A1 JP 2006319176 W JP2006319176 W JP 2006319176W WO 2007037273 A1 WO2007037273 A1 WO 2007037273A1
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cell
nanoparticle
virus
protein
cells
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PCT/JP2006/319176
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English (en)
Japanese (ja)
Inventor
Akihiko Kondo
Masaru Muraoka
Ichiro Yamada
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National University Corporation Kobe University
Beacle Inc.
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Publication of WO2007037273A1 publication Critical patent/WO2007037273A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to nanoparticles presenting cell membrane-penetrating peptides.
  • the inventors of the present invention have heretofore introduced a biorecognition molecule into a particle (HBsAg particle) composed of hepatitis B virus surface antigen protein, which makes the introduced substance specific to the target site. It has been found to be effective as a DDS transporter for transporting and introducing the product safely and safely (Patent Documents 1 to 3).
  • Ribosomes are widely known as other means for introducing substances into cells.
  • Patent Document 1 WO01 / 64930
  • the present inventor introduced a specific cell-introducing peptide into nanoparticles such as virus nanoparticles and ribosomes and presented them on the particle surface, thereby producing cells or yarns and weaves. It has been found that it is possible to significantly increase the efficiency of substance introduction into the plant.
  • nanoparticle according to item 1 wherein the nanoparticle is a virus particle containing a viral protein or a liposome containing a phospholipid.
  • a variant of hepatitis B virus surface antigen protein that lacks part or all of the hepatocyte binding region and has a cell-penetrating peptide.
  • macromolecules such as proteins and genes that can greatly increase the efficiency of introduction of substances into cells and yarns and can only reduce the dose of nanoparticles for substance introduction. It can be easily introduced into cell Z tissue.
  • the virus particle is not particularly limited as long as it is nano-sized and can contain the introduced substance, and examples thereof include nanoparticles containing virus proteins such as hepatitis B virus and Sendai virus. Nanoparticles containing hepatitis B virus protein are particularly preferred. Examples of hepatitis B virus proteins include surface antigen protein (HBsA g) and core protein, and HBsAg is preferably exemplified. HBsAg may use natural protein (SEQ ID NO: 5; serotype y type)) N-terminal preSl region (108 amino acids), part of preS2 region (55 amino acids) deleted You may do it.
  • a region spanning the preSl and preS2 regions for example 21-153, preferably 33-153, at least one amino acid (eg 33-153, 50-153) is deleted be able to.
  • the average particle size of the virus particles is about 50 to 600 nm, preferably about 100 to 500 nm, and more preferably about 100 to 400 nm.
  • SEQ ID NO: 5 shows the entire amino acid sequence of HBsAg from which 11 amino acids on the N-terminal side of the adr type are deleted, and corresponds to the HBsAg of ayw type.
  • amino acid number of HBs Ag corresponding to ayw type
  • each corresponding amino acid The position corresponds, and the position can be easily recognized by those skilled in the art.
  • the ribosome has an average particle diameter of about 50 to 500 nm, preferably about 80 to 400 nm, more preferably about 100 to 200 nm.
  • Ribosomes can be produced by sonication, reverse phase evaporation, freeze-thaw, lipid lysis, spray drying, and the like. Examples of ribosome components include phospholipids, cholesterols, and fatty acids.
  • nanoparticles having an organic polymer as a constituent element include the nanocarriers described above.
  • nanocarriers include polyethylene glycol and amino acid such as lysine, aspartic acid, and glutamic acid, and block copolymers of polymers such as lactic acid, glycolic acid, and ⁇ -strength prolatatone.
  • polyethylene glycol and poly L Block copolymer of lysine ⁇ PEG—PLL ⁇ , alpha—acetato poly— (ethylene glycol) — block—poly (D, L—lactide) ⁇ P EG-PLA ⁇ block copolymer of polyethylene glycol and poly—L glutamate
  • examples thereof include a polymer, a block copolymer of polyethylene glycol and poly L-aspartic acid, and the like.
  • a cell-penetrating peptide may be linked to the inside of the protein or the N-terminus or C-terminus.
  • the cell-penetrating peptide can be linked to the side chain of an amino acid that can bind preferably to the main chain.
  • the cell-permeable peptide needs to be presented on the surface of the nanoparticles, it is connected to the outer surface of the nanoparticle and presented to the surface rather than the inner surface of the particle or the inner surface of the hollow nanoparticle. It is preferable to do so.
  • HBsAg there is an a-antigenic determinant site (a epitope) in the middle of Pre-S1 (108 amino acid residues), Pre-S2 (55 amino acid residues) and S region (226 amino acid residues). It is possible to insert a cell-penetrating peptide into a region exposed outside the particle and present it outside the nanoparticle.
  • the site exposed outside the S region include the amino acid residues 105 to 155 of the S region. Therefore, if necessary, at least one amino acid at the exposed site (105-155) may be deleted, substituted or inserted, and a cell-penetrating peptide may be inserted at the exposed site.
  • Pre-S1 108 amino acid residues
  • Pre-S2 55 amino acid residues
  • at least one amino acid of 21-153 is deleted, substituted or inserted as necessary
  • Pre—Sl, Pre—S2 A cell-penetrating peptide may be inserted into any region of these, preferably at the N-terminal, a site corresponding to 21-153.
  • the nanoparticles are composed of lipids (particularly phospholipids), for example, phospholipids such as phosphatidylserine and phosphatidylethanolamine may be linked to other cell-permeable peptides such as cholesterol.
  • a cell-penetrating peptide can be linked to lipid to present the cell-penetrating peptide on the ribosome surface.
  • the cell-permeable peptide is an amino acid (lysine, dartamic acid, aspartic acid, etc.) present in the organic polymer.
  • it is linked to functional groups such as COOH, NH, and OH derived from hydroxycarboxylic acids (lactic acid, glycolic acid, etc.) via amide bonds or ester bonds.
  • the cell penetrating peptide is not particularly limited as long as it is presented on the surface without destroying the structure of the nanoparticles, and examples thereof include the following:
  • TLM Cell penetrating peptides
  • AAVALLPAVLLALLAP AAVLLPVLLAAP (Kaposi FGF signal sequences);
  • VTVLALuALAGVuVu Human beta3 integrin signal sequence
  • GALFLGWLGAAGSTMGA gp41 fosion sequence
  • MGLGLHLLVLAAALQGA Caiman crocodylus Ig (v) light chain
  • LGTYTQDFNKFHTFPQTAIGVGAP (hCT derived peptide).
  • KLALKLALKALKAALKLA Amphiphilic model peptide
  • virus hollow nanoparticles containing hepatitis B virus protein or a variant thereof As virus hollow nanoparticles containing hepatitis B virus protein or a variant thereof,
  • HBsAg protein particles may be combined with hepatitis B virus internal core antigen protein to form particles.
  • the virus nanoparticle for encapsulating the introduced substance in the present invention includes a hepatitis B virus protein or a variant thereof as a main component, and the protein may have a sugar chain.
  • the nanoparticles may contain a lipid component.
  • the virus nanoparticles also constitute 75 to 85 parts by weight of hepatitis B virus protein variant, 5 to 15 parts by weight lipid, and 5 to 15 parts by weight sugar chain strength. Is done.
  • lipids of virus nanoparticles include phospholipids derived from the endoplasmic reticulum membrane of eukaryotic cells, and may contain a small amount of cholesterol.
  • the virus hollow nanoparticles used in the examples of the present application are 80 parts by weight of hepatitis B virus protein variant.
  • the variant of the present invention may be further introduced with various mutations as long as it has the ability to form virus nanoparticles in addition to the deletion of the preS region and the introduction of a cell-penetrating peptide.
  • one or several or a plurality of hepatitis B virus proteins for example 1 to 50, preferably 1 to 20, more preferably 1 to 10, more preferably 1 to 5, particularly 1 to 3.
  • Amino acids may be substituted, added, deleted or inserted.
  • DNA encoding the protein may be used as a method for introducing mutations such as substitution, attachment, deletion, and insertion.
  • genes such as Cytospecific 'mutagenegenes (Methods in Enzymology, 154, 350, 367-382 (1987); 100, 468 (1983); Nucleic Acids Res., 12, 9441 (1984))
  • Chemical methods such as engineering methods, phosphate triester method and phosphate amidite method (for example, using a DNA synthesizer) (J. Am. Chem. Soc, 89, 4801 (1967); 91, 335) 0 (1969); Science, 150, 178 (1968); Tetrahedron Lett., 22, 1859 (1981)). Codon selection can be determined by taking into account the codon usage of the host.
  • Encapsulation of the substance in the virus hollow particle may be carried out by an electoporation method.
  • the introduced substance is encapsulated in the ribosome, and the ribosome and hepatitis B virus nanoparticles are fused to form the nanoparticle.
  • the introduced substance may be included in the particles. Fusion of virus nanoparticles and ribosome can be easily carried out by mixing ribosome and virus particles in water or an aqueous medium and stirring or shaking as necessary.
  • HBsAg variants including a cell-penetrating peptide as described in SEQ ID NO: 4 and part or all of the preSl site involved in hepatocyte specificity were lost as nanoparticles of the present invention.
  • the virus particle mainly composed of (modified) is mainly explained as an example, but other virus particles, ribosomes or nanocarriers can be similarly applied.
  • substances specific to target cells or target tissues can also be introduced.
  • a molecule that recognizes a specific cell include a cell function regulatory molecule such as a growth factor and cytodynamic force, a cell surface antigen, a tissue-specific antigen, a molecule for identifying a cell and tissue such as a receptor, Molecules derived from viruses and microorganisms, antibodies, sugar chains, lipids and the like are preferably used.
  • a protein capable of binding an antibody Fc domain eg, ZZ tag; VDNKFNKEQQNAFYEILHLPNLNEEQRNAFIQSLKDDPSQSA
  • a cell recognition molecule can be introduced into a component of a nanoparticle such as an HBsAg variant according to a known method.
  • the DNA encoding the hepatitis B virus protein or a variant thereof and the DNA encoding the ZZ tag are optionally passed through the DNA encoding the spacer peptide.
  • the desired hollow bionanoparticles can be obtained by linking them in-frame, incorporating them into vectors, expressing them in eukaryotic cells, and mixing the resulting hollow bionanoparticles with antibodies capable of recognizing target cells. Obtainable.
  • the cell recognition site is a sugar chain
  • a method of adding piotin to the hollow nanoparticle by chemical modification and presenting a piotin-labeled sugar chain or the like via streptavidin or the like can be mentioned.
  • Variants of HBsAg protein include variants with altered antigenicity (variants in which parts involved in antigenicity such as epitopes are deleted and Z-substituted), particle structure stability, cell selectivity, etc. There may be.
  • the variant is further introduced into a site where the cell-penetrating peptide can be presented on the surface.
  • Preferable nanoparticles include those obtained by expressing HBsAg protein in eukaryotic cells.
  • the method for producing virus hollow particles is described in Patent Documents 1 to 3, etc., and the method for preparing HBsAg is described in Vaccine. 2001 Apr 30; 19 (23-24): 3154-63.
  • Physicoc hemical and immunological characterization of hepatitis B virus envelope particles ex exclusively consisting of the entire L (pre- SI + pre- S2 + S) protein.Yamada T, Iwabuk i H, Kanno T, Tanaka H, Kawai T, Fukuda H, Kondo A, Seno M, Tanizawa K , Kuro da S ..
  • the protein is preferably expressed and accumulated as a membrane protein on the endoplasmic reticulum membrane, and released as nanoparticles.
  • eukaryotic cells that can be used include mammalian cells such as mammals, yeast, and the like. Such particles are extremely safe for the human body because they do not contain any HBV genome.
  • the cell selectivity of the nanoparticles of the present invention over hepatocytes or other cells can be enhanced by introducing a cell recognition molecule into at least a part of the protein constituting the particles as necessary.
  • the nanoparticle of the present invention encapsulating the introduced substance expresses a function in the cell Z tissue, but it is It can be preferably used to introduce a substance that is difficult to move into the cell z tissue.
  • the nanoparticles of the present invention are administered into the body by intravenous injection or the like, the particles circulate in the body and can efficiently introduce substances into various cells.
  • even a substance with a short half-life in vivo can act effectively because the substance is protected in the nanoparticles of the present invention until it is introduced into the cell z tissue.
  • the nanoparticles of the present invention can also be preferably used as a cell introduction reagent by mixing with target cells in vitro.
  • the substance to be introduced is not particularly limited.
  • various drugs that are introduced into cells to cause physiological effects for example, physiologically active proteins such as hormones, lymphokines, and enzymes; antigenic proteins that act as vaccines; intracellular And genes such as plasmids, or genes involved in specific gene expression that induces or induces expression; various genes and antisense introduced for gene therapy.
  • “Gene” introduced includes not only DNA but also RNA.
  • the introduced substance is preferably a high molecular weight physiologically active substance such as a protein or gene, but preferable results can be obtained even when applied to various low molecular weight drugs.
  • the gene, protein, etc. may be a natural gene or a synthesized gene, or a modified gene or protein.
  • HBsAg represents hepatitis B virus surface antigen.
  • HBsAg When expressed in eukaryotic cells, HBsAg is expressed and accumulated as a membrane protein on the endoplasmic reticulum membrane. After that, aggregation occurs between molecules, and it is released as HBsAg particles to the lumen side in a budding manner with the force of taking up the endoplasmic reticulum membrane.
  • HBsAg particles are expressed using eukaryotic cells such as yeast cells, mammalian cells (CHO cells, HEK293 cells, COS cells, etc.), insect cells (S19, Sf21, HighFive strains, etc.) It was obtained after purifying (patent documents 1 to 3).
  • eukaryotic cells such as yeast cells, mammalian cells (CHO cells, HEK293 cells, COS cells, etc.), insect cells (S19, Sf21, HighFive strains, etc.) It was obtained after purifying (patent documents 1 to 3).
  • TLM was added to three types of deletion mutation-introduced proteins (21-153, ⁇ 33-153, ⁇ 50-153) constructed by genetic engineering techniques based on the hepatitis B virus L protein (SEQ ID NO: 5).
  • a plasmid was constructed to express the inserted protein.
  • the constructed gene was transformed into the yeast Saccharomyces cerevisiae AH22R-strain by the spheroplast method, and high-producing strains were screened.
  • the obtained high-producing strain was cultured in large quantities on an industrial medium, and the cells were collected.
  • the yeast was crushed with glass beads, the cell extract was collected, and the particles were purified by performing cesium chloride density gradient ultracentrifugation twice and sucrose density gradient ultracentrifugation once.
  • Fig. 2 Three types of protein expression plasmids were constructed in which TLM was inserted into a deletion mutant in which hepatitis B virus L protein was genetically modified (Fig. 2).
  • a 50-TLM transformant was selected to obtain a high-producing strain.
  • transformants were cultured in 3 ml of industrial medium in a test tube, and microbial cells in 1 ml were collected, dissolved in 250 ml of Buffer A, disrupted with glass beads, and the yeast extract was washed with PBS. The sample was diluted 100 times and the amount of particles was measured with an enzyme immunoassay apparatus IMx. In addition, we performed stamp stamp lot analysis for high-producing strains. As a result, the A 50-TLM produced the most power and was used in the subsequent experiments.
  • the plurality of bands confirmed by silver staining are degradation products of sugar chains and proteases.
  • FIG. 1 schematically shows the structure of a nanoparticle of the present invention composed of HBsAg.
  • TLM membrane permeation domain
  • FIG. 2 shows the structure of the plasmid used in the examples.
  • FIG.3 Silver dyeing of purified particles.
  • the primary antibody is an anti-HBsAg mouse antibody
  • the secondary antibody is an anti-mouse IgG antibody.
  • FIG. 4 shows the result of sugar chain treatment (PNGase F treatment).
  • PNGase F treatment sugar chain treatment
  • FIG. 5 shows the result of trypsin treatment. Trypsin cleaves the C-terminal side of Lys and Arg. Lane 1: Trypsin treatment Ohr; Lane 2: Trypsin treatment lhr; Lane 3: Trypsin treatment 2hr; Lane 4: Trypsin treatment 3hr; Lane 5: Trypsin treatment 4hr; Lane 6: Trypsin treatment 5hr; Lane 7: Trypsin treatment 6hr Lane 8: Trypsin treatment 7 hr; Lane 9: Trypsin treatment 8 hr; TLM: Transmembrane domain; S: S domain.
  • FIG. 6 shows a comparison of fluorescence intensity between ⁇ 50-153 and ⁇ 50-153 + TLM.
  • FIG. 7 shows the results (fluorescence intensity) of an introduction experiment into NuE cells (human hepatocytes).
  • FIG. 8 shows the results (fluorescence intensity) of an introduction experiment into NA cells (human squamous cell carcinoma cells).
  • FIG. 9 shows the results (fluorescence intensity) of an introduction experiment into Cos7 cells (monkey kidney cells).
  • FIG. 10 shows the results (fluorescence intensity) of an introduction experiment into PC12 cells (rat adrenal pheochromocytoma).
  • FIG. 11 shows the results of an introduction experiment into H69 cells (human lung cancer cells).
  • the left side of the figure and graph shows that there is no eletroporation (without EP), and the right side shows that there is electoral position (with EP).
  • FIG. 12 shows the results (fluorescence intensity) of an introduction experiment into MOLT4 cells (human lymphoblast cells).
  • MOLT4 cells human lymphoblast cells.
  • the left side of the figure and graph shows that there is no electrification (no EP), and the right side shows that there is electrification (with EP).

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Abstract

L’invention concerne une nanoparticule capable d’encapsuler une substance à délivrer, comprenant au moins un élément constituant choisi parmi un groupe comportant une protéine, un lipide et un polymère organique. Dans la nanoparticule, un peptide rendant une cellule perméable est en liaison covalente avec ledit au moins un élément constituant pour présenter le peptide à la surface de la nanoparticule.
PCT/JP2006/319176 2005-09-28 2006-09-27 Introduction d’une substance dans une cellule au moyen d’une nanoparticule présentant un peptide rendant une membrane cellulaire perméable WO2007037273A1 (fr)

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JP2005281443A JP2007089440A (ja) 2005-09-28 2005-09-28 細胞膜透過ペプチドを提示したナノ粒子による細胞への物質導入
JP2005-281443 2005-09-28

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US10842755B2 (en) 2018-03-23 2020-11-24 University Of South Carolina Nanoparticles for brain targeted drug delivery

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JP2009120532A (ja) * 2007-11-14 2009-06-04 Osaka Univ 糖及び糖鎖認識機構を利用する物質送達用及びバイオイメージング用バイオナノカプセル
KR102332124B1 (ko) * 2017-03-23 2021-11-26 부경대학교 산학협력단 결빙 제어용 펩타이드 표면 개질된 나노입자

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10842755B2 (en) 2018-03-23 2020-11-24 University Of South Carolina Nanoparticles for brain targeted drug delivery

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