WO2021175275A1 - Albumine modifiée de manière hydrophobe, son procédé de préparation et son application - Google Patents

Albumine modifiée de manière hydrophobe, son procédé de préparation et son application Download PDF

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WO2021175275A1
WO2021175275A1 PCT/CN2021/078980 CN2021078980W WO2021175275A1 WO 2021175275 A1 WO2021175275 A1 WO 2021175275A1 CN 2021078980 W CN2021078980 W CN 2021078980W WO 2021175275 A1 WO2021175275 A1 WO 2021175275A1
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alkyl
optionally substituted
albumin
alkenyl
group
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PCT/CN2021/078980
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English (en)
Chinese (zh)
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柯天一
檀琳
劳芳
孙楚楚
于海勇
欧阳芳幸
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昆山新蕴达生物科技有限公司
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Priority to CN202180018719.6A priority Critical patent/CN115397846A/zh
Publication of WO2021175275A1 publication Critical patent/WO2021175275A1/fr

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    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/62—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 non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This application relates to hydrophobically modified albumin, in particular to the modified albumin obtained by introducing a hydrophobic group at the free sulfhydryl group of albumin, its preparation method and use, and the preparation of the hydrophobically modified albumin Protein compounds.
  • the biggest obstacle to the administration (especially injection administration) of poorly water-soluble drugs is low solubility. It is difficult to prepare suitable preparations and often requires various methods to increase solubility, such as The drug is prepared into a salt, the drug is modified, a latent solvent is added, a cosolvent is added, and a surfactant is added for solubilization. These methods have various drawbacks. Since salt formation often requires strong acid or base conditions, it is often not suitable for many drugs. There are few physiologically safe latent solvents, and the dosage is limited. The safety of the cosolvent that increases the solubility of the drug by forming a complex with the drug is not easy to ensure.
  • Solubilization by surfactant micelles has the following problems: micelles are easily dissociated during clinical dilution, leading to drug precipitation; the application of surfactants can easily cause a variety of toxic side effects, such as drug-induced rash, shortness of breath, bronchospasm, Hypotension, nephrotoxicity, neurotoxicity, cardiotoxicity, etc.
  • HSA Human serum albumin
  • Mature HSA is a single polypeptide chain containing 585 amino acid residues, with a large number of free amino and carboxyl groups, but only one free sulfhydryl group in the 34th cysteine residue.
  • An important application of HSA in the field of pharmacy is as a carrier of pharmaceutical active ingredients. There have been many strategies to modify albumin by using its free amino group, carboxyl group or sulfhydryl group to use it as a carrier.
  • One strategy is to modify the hydrophobic groups such as fatty acids on the active ingredients of the drug (such as anti-tumor drugs) so that the drug can bind to albumin in the body to extend the half-life of the drug, such as CN101384623B, CN108187063A and CN105440112A; or, when albumin is free
  • the sulfhydryl group is modified with PEG and other groups to increase the water solubility of albumin, such as CN102378576A, CN101709085B and so on.
  • Another strategy is to hydrophobically modify the free amino and carboxyl groups of albumin. Due to its amphiphilic nature, the modified albumin self-assembles into nanoparticles in an aqueous medium.
  • nanoparticles can encapsulate poorly water-soluble compounds to improve their properties.
  • Solubility such as CN101220093A and CN102172404A.
  • the free amino group, carboxyl group or sulfhydryl group of albumin can also be hydrophilically modified, such as CN101543630A.
  • albumin has a large number of free amino groups and carboxyl groups
  • the modified albumin obtained by this strategy carries a large number of hydrophobic modification groups, and the average particle size of the nanoparticles formed is greater than 100 nanometers.
  • the outer shell of the albumin nanoparticles has a considerable number of hydrophobic groups, as shown in Figure 1A.
  • the above-mentioned modification method is a multi-point modification of multiple groups on the surface of albumin, and the degree of modification and the specific site of the modification are uncontrollable, which is not conducive to quality control and preparation of medicines.
  • This application only selects the site-specific hydrophobic modification at the free sulfhydryl group of albumin, introduces hydrophobic groups, and obtains a new hydrophobically modified albumin. Since an albumin molecule has only one free sulfhydryl group, the hydrophobic modification performed in this application has high controllability, and the obtained product has a small particle size and uniformity, which is beneficial for quality control and preparation of medicines.
  • the resulting hydrophobically modified albumin will spontaneously assemble in an aqueous medium (such as aqueous solution, blood, etc.) to form hydrophobic groups facing inward (hydrophobic interface), and natural albumin groups facing outward (hydrophilic interface)
  • the structure is shown in Figure 1B. It can be expected that this structure reduces the risk that the modified hydrophobic group may trigger an immune response, that is, it reduces the immunogenicity of the modified albumin molecule and improves the safety.
  • the present application provides a modified albumin, which is composed of albumin and a hydrophobic enhancement moiety connected to the S atom in the free sulfhydryl group of the albumin, and the modified albumin may be of the general formula ( I) means:
  • Q is the S atom in the free sulfhydryl group of the albumin
  • C is the hydrophobicity enhancing part, and is represented by the general formula (II):
  • L is the connection unit connected to Q
  • Z is the spacer base
  • n 1 or 0
  • M is a hydrophobic group.
  • this application provides a compound of general formula (X):
  • R is a part containing a reactive group that can connect the compound of formula (X) with S in the free sulfhydryl group by reacting with the free sulfhydryl group of albumin and provide the above-mentioned
  • the hydrophobicity enhancing part of general formula (II) is a part containing a reactive group that can connect the compound of formula (X) with S in the free sulfhydryl group by reacting with the free sulfhydryl group of albumin and provide the above-mentioned
  • Z is the spacer as defined above
  • M is the hydrophobic group described above.
  • the present application provides a method for preparing the modified albumin of the present application, the method comprising combining the albumin with the compound of the general formula (X) described above in allowing the free sulfhydryl group of the albumin The step of the reaction under the conditions of the reaction with R.
  • the application provides a composition comprising the modified albumin of the application and optionally unmodified albumin.
  • this application provides a pharmaceutical or cosmetic composition, which comprises:
  • a carrier encapsulating a poorly water-soluble compound with pharmaceutical or cosmetic activity the carrier being the modified albumin of the application or the composition according to the fourth aspect above;
  • the present application provides a method for improving the solubility of a poorly water-soluble compound with pharmaceutical or cosmetic activity in an aqueous medium, and the method includes the following steps:
  • step (3) Mixing the two solutions described in step (1) and step (2);
  • the present application provides the use of the modified albumin of the present application or the composition according to the fourth aspect above as a carrier for poorly water-soluble compounds with pharmaceutical or cosmetic activity.
  • the present application provides the use of the modified albumin of the present application or the composition according to the fourth aspect above as a carrier in the preparation of a pharmaceutical or cosmetic composition containing a poorly water-soluble compound with pharmaceutical or cosmetic activity .
  • the present application provides a kit, which at least contains: i) a poorly water-soluble compound with pharmaceutical or cosmetic activity, ii) unmodified albumin, and iii) the formula (X) described above Compound.
  • Figure 1 The schematic diagram of Figure 1A shows the nanoparticles formed in aqueous medium of modified albumin obtained by hydrophobically modifying the free amino and carboxyl groups of HSA according to the prior art, with the exception of some of the nanoparticles facing inward (hydrophobic interface) In addition to the hydrophobic modification groups, there are a large number of hydrophobic modification groups facing outwards (hydrophilic surfaces), which are exposed to the human environment.
  • Figure 1B is a schematic diagram showing the hydrophobically modified albumin nanoparticle formed in an aqueous medium according to the present invention, in which the hydrophobic modification group faces inward (hydrophobic interface) and the natural albumin group faces outward (hydrophilic interface) .
  • FIG. 1 LC-MS spectrum of rHA (rHA-CA) modified with SYN-LPD19002 prepared in Example 7.
  • Figure 3 Deconvolution of the LC-MS spectrum of Figure 2.
  • Figure 4 HPLC profile of rHA (rHA-PEG 2 -PA) modified with SYN-LPD19005 prepared in Example 8.
  • Figure 5 LC-MS spectrum of rHA (rHA-PEG 2 -PA) modified with SYN-LPD19005 prepared in Example 8.
  • Figure 6 Deconvolution of the LC-MS spectrum of Figure 5.
  • Figure 7 HPLC profile of rHA (rHA-PA) modified with SYN-LPD19001 prepared in Example 9.
  • Figure 8 LC-MS spectrum of rHA (rHA-PA) modified with SYN-LPD19001 prepared in Example 9.
  • hydrophobic modified albumin and “modified albumin” are used interchangeably, and mean a modified albumin obtained by introducing a hydrophobic group at a free sulfhydryl group of albumin.
  • the free sulfhydryl group of the albumin is the sulfhydryl group of the cysteine residue of the albumin corresponding to the 34th position of SEQ ID NO:1.
  • the correspondence of amino acid residues between different amino acid sequences can be determined by sequence alignment methods known in the art.
  • modifier or “conjugation modifier” includes compounds of general formula (X), (XII) and (XIII) as defined herein, and can be used interchangeably.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 30 (ie, C 1-30 alkyl), such as C 1-12 alkyl, C 1-10 alkyl, C 1-6 alkyl, C 1-4 Alkyl, C 4-8 alkyl, C 5-25 alkyl, C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13-17 alkyl, C 7-15 alkyl base.
  • Examples that may be mentioned include but are not limited to: ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl , N-hexyl, heptene, octyl, C 11 alkyl or C 15 alkyl.
  • the alkyl group may be optionally substituted.
  • alkenyl means a linear or branched hydrocarbon group, which may contain 2 to 30 carbon atoms (ie, C 2-30 alkenyl), such as C 2-12 alkenyl, C 2-10 alkenyl, C 2-6 alkenyl, C 2-4 alkenyl, C 4-8 alkenyl, C 5-25 alkenyl, C 7-23 alkenyl, C 9-21 alkenyl, C 11 -19 alkenyl, C 13-17 alkenyl, C 7-15 alkenyl, and may contain 1 or more double bonds, such as 1-8, or 1, 2, 3, 4, 5, or 6 double bonds.
  • C 2-30 alkenyl such as C 2-12 alkenyl, C 2-10 alkenyl, C 2-6 alkenyl, C 2-4 alkenyl, C 4-8 alkenyl, C 5-25 alkenyl, C 7-23 alkenyl, C 9-21 alkenyl, C 11 -19 alkenyl, C 13-17 alkenyl, C 7-15 alkeny
  • Examples that may be mentioned include but are not limited to: vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentene Base, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, heptenyl , Octenyl, C 11 alkenyl, C 15 alkenyl, C 17 alkenyl, C 19 alkenyl or C 21 alkenyl, such as heptadec-8-alkenyl, nonadec-4,7,10, 13,16-pentaenyl, nonadecan-4,7,10,13-tetraenyl, docosa-3,6,9,12,15,18-hexaenyl.
  • the alkenyl group may be optionally substituted.
  • alkynyl means a linear or branched hydrocarbon group, which may contain 2 to 30 carbon atoms (ie, C 2-30 alkynyl), such as C 2-12 alkynyl, C 2-10 alkynyl, C 2-6 alkynyl, C 2-4 alkynyl, C 4-8 alkynyl, C 5-25 alkynyl, C 7-23 alkynyl, C 9-21 alkynyl, C 11 -19 alkynyl, C 13-17 alkynyl, C 7-15 alkynyl, and may contain 1 or more triple bonds, such as 1-8, or 1, 2, 3, 4, 5, or 6 triple bonds.
  • C 2-30 alkynyl such as C 2-12 alkynyl, C 2-10 alkynyl, C 2-6 alkynyl, C 2-4 alkynyl, C 4-8 alkynyl, C 5-25 alkynyl, C 7-23 alkynyl, C 9-21 alkynyl, C
  • Examples that may be mentioned include but are not limited to: ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4- Pentynyl, 2-hexynyl, 3-hexynyl, octenyl, C 11 alkynyl, C 15 alkynyl, C 17 alkynyl, C 19 alkynyl, C 21 alkynyl, and the like.
  • the alkynyl group may be optionally substituted.
  • alkoxy means an alkyl group (as defined above) attached to the rest of the molecule through an oxygen atom, which has the structure of "-O-alkyl".
  • the alkoxy group is preferably a C 1-8 alkoxy group, a C 1-6 alkoxy group, a C 1-4 alkoxy group or a C 1-3 alkoxy group.
  • Representative examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy Group, tert-butoxy, pentoxy, hexyloxy, etc.
  • the alkoxy group may be optionally substituted.
  • alkylthio means an alkyl group (as defined above) attached to the rest of the molecule through a sulfur atom, which has the structure of "-O-alkyl".
  • the alkylthio group is preferably a C 1-8 alkylthio group, a C 1-6 alkylthio group, a C 1-4 alkylthio group or a C 1-3 alkylthio group, for example, a methylthio group or an ethylthio group.
  • the alkylthio group may be optionally substituted.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring.
  • the cycloalkyl group has 3 to 15, for example 3 to 10 carbon atoms, 3 to 7 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, 5 to 7 carbon atoms, 4 to 6 Carbon atoms or 5 to 6 carbon atoms, etc.
  • C 3 -C 10 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 10 ring-forming carbon atoms.
  • Examples that may be mentioned include, but are not limited to: monocyclic cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl; and bicyclic cycloalkyls, Including spirocyclic, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl and the like.
  • the cycloalkyl group may be optionally substituted.
  • aryl or “aromatic ring” refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6 - 10 aryl means an aryl group having 6 to 10 carbon atoms, preferably phenyl or naphthyl. The aryl group may be optionally substituted.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5-14 ring atoms, especially having 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14 ring atoms, especially 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and it contains at least one heteroatom (such as oxygen) which may be the same or different , Nitrogen or sulfur), and, in addition, may be benzo-fused in each case.
  • heteroatom such as oxygen
  • nitrogen or sulfur nitrogen
  • heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, Oxadiazolyl, thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., or azaindole, and their benzo derivatives such as indole, benzo Imidazole, quinoline, isoquinoline, etc.
  • the heteroaryl group may be optionally substituted.
  • halo or halogen group is defined to include F, Cl, Br, or I.
  • amino acid includes natural amino acids and unnatural amino acids.
  • amino acid has the following structure:
  • R 3' is selected from: H; C 1-6 alkyl; is selected from SH, SCH 3 , NH 2 , OH, COOH, -CONH 2 , -NHCOCH 3 , -NHCHO, -NHCONH 2 , guanidyl, Optionally substituted C 6-10 aryl (preferably phenyl, 4-OH-phenyl, biphenyl, naphthyl) and optionally substituted 5 to 10-membered heteroaryl (preferably imidazole, indole) 1 C 1-6 alkyl substituted by one or more substituents; C 3-10 cycloalkyl (preferably cyclohexyl); C 6-10 aryl (preferably phenyl);
  • peptide refers to a compound formed by peptide bonds of two or more amino acids as described above.
  • the amino acids may be the same or different.
  • the peptide is formed from 2 to 20 identical or different amino acids, for example 2 to 15, 2 to 10, 2 to 5 or 3 to 4.
  • substitution means that one or more (for example, 1, 2, 3, or 4) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is The normal valence in the current situation and the substitution forms a stable compound. Combinations of substituents and/or variables are only permissible when such combinations form stable compounds.
  • the group can be (1) unsubstituted or (2) substituted. Unless otherwise specified, in the case of substitution, the group is substituted by one or more substituents independently selected from the following groups: hydroxy, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, cyano, nitro, -C (O) C 1 -C 6 alkyl, -C (O) OH, -C(O)OC 1 -C 6 alkyl, -C(O)NH 2 , -C(O)NH(C 1 -C 6 alkyl), -C(O)N(C 1 -C 6 alkane ⁇ ) 2 , NH 2 -C 1 -C 6 alkyl-, NH (C 1 -C 6 alkyl), -NH 2 , -NH (C 1 -C 6 alkyl), -NH 2 ,
  • each substituent is selected independently of the other. Therefore, each substituent may be the same or different from another (other) substituent.
  • variable or substituent can be selected from different variants, and the variable or substituent appears more than once, then the variants can be the same or different.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5, or 10 under reasonable conditions.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • poorly water-soluble compound refers to a compound having a water solubility of less than 0.01 g at 20°C.
  • poorly water-soluble compounds include, but are not limited to, curcumin, paclitaxel, docetaxel, cisplatin, and the like.
  • pharmaceutically or cosmetically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other components constituting the pharmaceutical or cosmetic composition and/or the mammal to be treated with it.
  • the numerical ranges described herein should be understood to encompass any and all sub-ranges contained therein.
  • the range “1 to 10” should be understood to include not only the explicitly stated value of 1 to 10, but also any single value within the range of 1 to 10 (e.g., 2, 3, 4, 5, 6, 7, 8 and 9) and sub-ranges (e.g. 1 to 2, 1.5 to 2.5, 1 to 3, 1.5 to 3.5, 2.5 to 4, 3 to 4.5, etc.).
  • This principle also applies to a range where only one value is used as the minimum or maximum value.
  • the present application provides a modified albumin, which is composed of albumin and free sulfhydryl groups with the albumin (for example, the cysteine residue at position 34 corresponding to SEQ ID NO:1).
  • the hydrophobic enhancing part connected by the S atom in the sulfhydryl group, and the modified albumin is represented by the general formula (I):
  • Q is the S atom in the free sulfhydryl group of the albumin (for example, the sulfhydryl group corresponding to the cysteine residue at position 34 of SEQ ID NO:1);
  • C is the hydrophobicity enhancing part, and is represented by the general formula (II):
  • L is the linker connected to Q
  • Z is the spacer base
  • n 1 or 0
  • M is a hydrophobic group.
  • Human serum albumin is a natural water-soluble macromolecule, and one of its important applications in the field of pharmacy is as a carrier of pharmaceutical active ingredients.
  • Mature HSA is a single polypeptide chain containing 585 amino acid residues (amino acid sequence is shown in SEQ ID NO: 1), with a large number of free amino and carboxyl groups on the chain, but only the cysteine residue at position 34 1 free sulfhydryl group in.
  • Additional exemplary amino acid sequences of human serum albumin can be obtained through GenBank accession numbers such as AAN17825.1, CAA23754.1, or AAX63425.1.
  • the albumin may be serum albumin isolated and purified from the host.
  • the serum albumin may be mammalian serum albumin known to those skilled in the art, including but not limited to mouse, rat, rabbit, guinea pig, dog, cat, sheep, cow, sheep, horse or human albumin.
  • the albumin is human serum albumin.
  • Appropriate human-isolated serum albumin is commercially available, for example, from Shenzhen Zhuoyue Biotechnology Co., Ltd. under article number 70024-90-7, or from ProSpec under article number PRO-354, or article number EY-XQ0489 Since Haixingbanghe.
  • any recombinant albumin known to those skilled in the art can be used to form the modified albumin of the present application.
  • the recombinant albumin may be mammalian albumin well known to those skilled in the art, including but not limited to recombinant mouse, rat, rabbit, guinea pig, dog, cat, sheep, cow, sheep, horse or human albumin.
  • the recombinant albumin is recombinant human albumin (rHA).
  • Suitable recombinant albumin is commercially available, for example, from Huabei Pharmaceutical under the article number 201801D2002, or from Sigma-Aldrich under the article number A9731, or from Heyuan Biotechnology under the article number HYC002M01.
  • the Albumedix company provides Series products can also be used in this application.
  • the recombinant albumin is produced in a host cell.
  • Any host cell capable of producing foreign recombinant protein can be used to produce recombinant albumin.
  • the host cell is a yeast, bacteria, plant, insect, animal, or human cell that can be transformed to produce recombinant albumin.
  • the host is cultured in a liquid medium.
  • the host may be a bacterial strain, such as Escherichia coli and Bacillus subtilis.
  • the host may be a yeast strain, such as Saccharomyces cerevisiae, Pichia pastoris, Kluyveromyces lactis, Arxula adeninivorans, and Hansen polymorpha. Yeast (Hansenula polymorpha).
  • the host is Pichia pastoris.
  • the host may be a plant, such as Oryza Sativa or rice seed culture.
  • albumin useful in the present application includes molecular variants of albumin.
  • Variants of albumin include natural variants produced by human albumin polymorphisms. Through electrophoresis analysis under different conditions, more than 30 distinct genetic variants of human serum albumin have been identified. See, Weitkamp, Ann. Hum. Genet, 36(4): 381-92 (1973); Weitkamp, Isr. J. Med. Sci., 9(9): 1238-48 (1973); Fine et al., Biomedicine, 25(8): 291-4 (1976); Fine et al., Rev. Fr. Trans/us. Immunohematol, 25(2): 149-63. (1982); Rochu et al., Rev. Fr. Transfus.
  • albumin derivatives that are substantially homologous to albumin can also be used in this application.
  • the albumin derivative has at least 75%, at least 80%, at least 85%, more preferably at least 90%, and most preferably at least 95% amino acid sequence identity with albumin.
  • the albumin or a variant or homologue thereof has a free sulfhydryl group. In some embodiments, the albumin or a variant or homologue thereof includes a single free sulfhydryl group. In some embodiments, the single free sulfhydryl group of the albumin or a variant or homologue thereof is the sulfhydryl group corresponding to the cysteine residue at position 34 of SEQ ID NO:1.
  • the albumin is selected from albumin having a cysteine residue corresponding to the 34th position of SEQ ID NO:1; preferably selected from human serum albumin (HSA), recombinant human Albumin (rHA), bovine serum albumin and porcine serum albumin.
  • HSA human serum albumin
  • rHA recombinant human Albumin
  • bovine serum albumin bovine serum albumin
  • porcine serum albumin the albumin includes the amino acid sequence shown in SEQ ID NO:1.
  • the modified albumin of the present application can be combined with the compound of the general formula (X) described above to allow the free sulfhydryl group of the albumin (for example, when the free sulfhydryl group corresponding to SEQ ID NO:1
  • the sulfhydryl group of the cysteine residue at position 34 reacts with R under the reaction conditions.
  • the reaction can be selected from: Michael addition reaction, sulfhydryl-disulfide bond exchange reaction, substitution reaction and click chemistry.
  • the linker L in the modified albumin of the present application can be derived from R in the general formula (X) through the reaction.
  • the application provides the modified albumin described above, wherein L is represented by the general formula (III):
  • the bond identified by a is bonded to Q, and the bond identified by b is bonded to (Z) m -M;
  • R 1 is S, or is selected from the following optionally substituted groups:
  • the bond identified by f is bonded to Q, and the bond identified by k is bonded to R 2 ;
  • R 11 is each independently selected from: H, optionally substituted C 1-12 alkyl, -COOH, -COOC 1-6 alkyl, -CH(R 15 )NH-CO-C 1-6 alkyl, C 6-10 aryl groups and 5 to 10-membered heteroaryl groups;
  • R 12 is selected from H, optionally substituted C 1-12 alkyl and optionally substituted C 2-12 alkenyl;
  • R 13 is selected from: optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl and
  • R 13' is selected from: optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl,
  • u 0, 1, 2 or 3;
  • R 14 and R 15 are each independently H or C 1-6 alkyl
  • R 16 is selected from H and optionally substituted C 1-12 alkyl (preferably C 1-6 alkyl, more preferably C 1-4 alkyl);
  • p 0, 1 or 2;
  • Each R a is independently selected from hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio and halogen;
  • R 2 is selected from: direct bond, O, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1 -6 alkyl) -,-(optionally substituted C 1-6 alkyl) -C 3-6 cycloalkyl -, -O- (optionally substituted C 1-6 alkyl) -, -NH- (Optionally substituted C 1-6 alkyl) -, -O- (optionally substituted C 2-6 alkenyl) -, -NH- (optionally substituted C 2-6 alkenyl) -, optional It is (R b) q-substituted phenyl, optionally substituted with (R b) q-substituted pyridyl, - (optionally substituted (R b) q -phenyl) - (optionally substituted C 1-6 alkoxy Group) -,-(
  • j is an integer of 1-10, such as 2;
  • q 0, 1, 2 or 3;
  • R b is each independently selected from H, hydroxy, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio and halogen;
  • R 1 and R 2 together are optionally substituted C 1-6 alkyl
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH;
  • R" is selected from H, optionally substituted C 1-6 alkyl and optionally substituted C 2-6 alkenyl, preferably H.
  • each R 11 is independently selected from: H; optionally substituted C 1-6 alkyl, preferably optionally substituted C 1-4 alkyl; -COOH; -COOC 1-4 alkyl Group; -CH(R 15 )NH-CO-C 1-4 alkyl; phenyl; and 5- to 7-membered heteroaryl.
  • u is 1 or 2.
  • R 14 and R 15 are each independently H or C 1-4 alkyl, preferably H, methyl or ethyl; more preferably H or methyl.
  • R 13 is selected from: optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl,
  • R 13' is selected from: optionally substituted C 1-4 alkyl; optionally substituted C 2-4 alkenyl; More preferably Wherein R 15 is C 1-4 alkyl, preferably methyl; or
  • R 16 is selected from H and optionally substituted C 1-6 alkyl, more preferably optionally substituted C 1-4 alkyl.
  • R b is each independently selected from H, hydroxy, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio and halogen, preferably H Or nitro.
  • R 1 and R 2 together are optionally substituted C 1-4 alkyl.
  • R" is selected from H, optionally substituted C 1-4 alkyl, and optionally substituted C 2-4 alkenyl, preferably H.
  • the application provides the modified albumin described above, wherein:
  • R 2 is selected from: optionally substituted C 1-6 alkyl and optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j -(optionally substituted C 1-6 alkyl)- ,-(Optionally substituted C 1-6 alkyl) -C 3-6 cycloalkyl -, -O- (optionally substituted C 1-6 alkyl) -, -NH- (optionally substituted C 1-6 alkyl)-, -O-(optionally substituted C 2-6 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; and
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH.
  • R 2 is selected from: optionally substituted C 2-5 alkyl, optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-4 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -),-(optionally substituted C 1-4 alkyl)-C 3-6 cycloalkyl-(preferably- CH 2 -cyclohexane-), -O- (optionally substituted C 1-4 alkyl) -, -NH- (optionally substituted C 1-4 alkyl) -, -O- (optionally substituted C 2-4 alkenyl)-, -NH-(optionally substituted C 2-4 alkenyl)-;
  • the C 1-4 alkyl group is preferably -CH 2 -CH 2 -.
  • R 2 is selected from C 2-5 alkyl groups, more preferably -CH 2 -CH 2 -or -(CH 2 ) 5 -.
  • X 1 is CO or NH.
  • the application provides the modified albumin described above, wherein
  • R 1 is selected from the following optionally substituted groups:
  • R 11 is each independently selected from: H, optionally substituted C 1-6 alkyl, -COOH, -COOC 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;
  • R 2 is selected from: optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, -O- (optionally substituted C 1-6 alkyl)-and -NH- (optionally Substituted C 1-6 alkyl)-;
  • X 1 is selected from: CO, S(O) 2 , P(O)(OR”) and NH.
  • each of R 11 is independently selected from: H, optionally substituted C 1-4 alkyl, -COOH, -COOC 1-4 alkyl, phenyl, and 5- to 7-membered heteroaryl .
  • X 1 is CO or NH.
  • the application provides the modified albumin described above, wherein
  • R 1 is the following optionally substituted group:
  • R 12 is an optionally substituted C 1-12 alkyl group or an optionally substituted C 2-12 alkenyl group
  • R 2 is selected from optionally substituted C 1-6 alkyl and optionally substituted C 2-6 alkenyl
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH, preferably CO.
  • X 1 is CO.
  • the application provides the modified albumin described above, wherein
  • R 1 is selected from the following optionally substituted groups:
  • R 2 is selected from optionally substituted C 1-6 alkyl and optionally substituted C 2-6 alkenyl
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH.
  • X 1 is CO.
  • the application provides the modified albumin described above, wherein
  • R 1 is selected from the following optionally substituted groups:
  • R 13 is selected from:
  • R 13' is selected from:
  • R 2 is selected from: optionally substituted C 1-6 alkyl and optionally substituted C 2-6 alkenyl;
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH;
  • u and R 15 are each as defined above.
  • R 13 is
  • R 13' is
  • R 2 is selected from: optionally substituted C 1-4 alkyl and optionally substituted C 2-4 alkenyl.
  • X 1 is CO.
  • the application provides the modified albumin described above, wherein
  • R 1 is S
  • R 2 is selected from: an optionally substituted (R b) q phenyl, optionally substituted (R b) q pyridyl, - (optionally substituted (R b) q phenyl) - (optionally Substituted C 1-6 alkyl) -,-(optionally substituted by (R b ) q pyridyl)-(optionally substituted C 1-6 alkyl) -,-(optionally (R b ) q substituted phenyl)-(optionally substituted C 2-6 alkenyl)-and-(optionally substituted by (R b ) q pyridyl)-(optionally substituted C 2-6 alkenyl)- ;
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR") and NH, preferably CO or NH;
  • Each of q and R b is as defined above.
  • the application provides the modified albumin described above, wherein:
  • R 1 and R 2 together are optionally substituted C 1-4 alkyl, preferably methyl;
  • X 1 is selected from: CO, S(O) 2 and P(O)(OR"), preferably CO.
  • Albumin is a natural water-soluble macromolecule with a large number of free amino groups and carboxyl groups that can be used for hydrophobic modification. In this application, only free sulfhydryl groups of albumin are selected as modification sites to introduce hydrophobic groups.
  • the so-modified albumin can self-assemble into nanoparticles in an aqueous medium, has an increased affinity for poorly water-soluble compounds, and has a good encapsulation effect.
  • the hydrophobic group M in the modified albumin of the present application can be derived from aliphatic hydrocarbons (e.g., octyl, dodecyl, hexadecyl, octadecyl), aliphatic alcohols (e.g., stearyl Alcohol, sphingosine), aliphatic aldehydes (e.g. palm aldehyde, hexadecenal), fatty acids (e.g.
  • caprylic acid stearic acid, dodecanoic acid, palmitic acid, oleic acid, eicosapentaene) Acid, docosahexaenoic acid, arachidonic acid
  • fatty acid esters e.g. fatty acid glycerides
  • ceramides e.g. 1,2-heptadecanoyl-sn-glycerol-3 -Phospho-L-serine (sodium salt), 1,2-diphytanyl-sn-glycerol-3-phosphate-(1'-rac-glycerol) (sodium salt) and phosphatidylinositols), sterol Classes (e.g.
  • cholic acid compounds e.g. cholic acid, deoxycholic acid, Hyotcholic acid and lithocholic acid
  • the application provides the modified albumin described above, wherein M is selected from:
  • N-terminal is connected to L-(Z) m , and the -OH of the C-terminal carboxyl group is replaced by -NH-R 3 or -OR 3 ;
  • X 4 is selected from: direct bond, O, CO, S(O) 2 , P(O)(OR"') and NH;
  • R"' is selected from: H and R 41 ;
  • R 3 and R 4 are each independently selected from:
  • R 41 and a R 41 '-O-, R 41' -C (O) O- or R 41 '-C (O) NH- substituted with R 41;
  • R 41 , R 41' , R 42 and R 43 are each independently selected from:
  • R 41 , R 41 ′ , R 42 and R 43 are each independently selected from:
  • C 5-25 alkyl preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13-17 alkyl or C 7-15 alkyl, such as C 5 alkyl, C 7 alkyl group, C 11 alkyl group or C 15 alkyl group;
  • C 5-25 alkenyl preferably C 7-23 alkenyl, C 9-21 alkenyl, C 11-19 alkenyl, C 13-17 alkenyl, C 7-15 alkenyl, such as C 5 alkenyl, C 7 alkenyl, C 11 alkenyl, C 15 alkenyl, C 17 alkenyl, C 19 alkenyl or C 21 alkenyl; and
  • C 5-25 alkynyl preferably C 7-23 alkynyl, C 9-21 alkynyl, C 11-19 alkynyl, C 13-17 alkynyl or C 7-15 alkynyl, such as C 5 alkynyl, C 7 alkynyl, C 11 alkynyl, C 15 alkynyl, C 17 alkynyl, C 19 alkynyl, or C 21 alkynyl.
  • the optionally substituted groups derived from sterols and bile acids are:
  • each R 3 is independently selected from: C 7 alkyl, C 15 alkyl, C 17 alkenyl, C 19 alkenyl, C 21 alkenyl, and C 23 alkenyl;
  • n-octyl n-pentadecyl
  • X 4 is CO, S(O) 2 or P(O)(OR"'), preferably CO;
  • R 4 is selected from: R 41 is and R 41 '-C (O) O- and R 41' -C (O) NH- substituted with R 41;
  • R 41 and R 41' are each independently selected from: C 7 alkyl, C 15 alkyl, C 17 alkenyl, C 19 alkenyl, C 21 alkenyl, and C 23 alkenyl;
  • n-octyl n-pentadecyl
  • X 4 is O or NH
  • R 42 and R 43 are each independently selected from:
  • n-octyl n-pentadecyl
  • X 4 is CO, S(O) 2 or P(O)(OR"'), preferably CO;
  • R 4 is optionally substituted Preferably
  • X 4 is O
  • R 4 is optionally substituted Preferably
  • the application provides the modified albumin described above, wherein M is selected from:
  • R 3 is as defined above;
  • R 3' is selected from: H; optionally substituted C 1-6 alkyl; is selected from SH, SCH 3 , NH 2 , OH, COOH, -CONH 2 , -NHCOCH 3 , -NHCHO, -NHCONH 2 , guanidine C 1-6 alkyl substituted with one or more substituents of an optionally substituted C 6-10 aryl group and an optionally substituted 5- to 10-membered heteroaryl group; C 3-10 cycloalkyl; and C 6-10 aryl.
  • the C 6-10 aryl group is selected from phenyl, 4-OH-phenyl, biphenyl and naphthyl; the 5- to 10-membered heteroaryl group is selected from imidazole, indole.
  • the modified albumin of the present application optionally includes a divalent spacer Z connecting the linker L and the hydrophobic group M.
  • the present application provides the modified albumin described above, wherein Z can be represented by the general formula (V):
  • X 2 is selected from: direct bond, O, CO, S(O) 2 , P(O)(OR") and NH;
  • X 3 is selected from: direct bond, O, CO, S(O) 2 , P(O)(OR"') and NH;
  • X 5 is selected from: CO and S(O) 2 ;
  • g is 1, 2, 3, 4, 5 or 6;
  • h is 0 or 1;
  • r is 0, 1, 2, 3, 4, 5 or 6;
  • t 0, 1, 2, 3, 4, 5 or 6;
  • s is an integer from 0 to 100;
  • R" and R"' are each as defined above.
  • g is 1, 2 or 3, more preferably 2; preferably, h is 0, or h is preferably 1; preferably, r is 1, 2 or 3, more preferably 2; preferably, t It is 0, 1, 2, or 3, more preferably 0; preferably, s is an integer from 0 to 10, preferably 0, 1, 2, 3, 4, 5, or 6, more preferably 0, 1, or 2.
  • the present application provides the modified albumin described above, wherein Z can be represented by the general formula (V-i):
  • X 2 is preferably selected from: O, CO, S(O) 2 , P(O)(OR") and NH, preferably CO or NH; and r is 1, 2 or 3, more preferably 2.
  • X 1 is CO, S(O) 2 or P(O)(OR"), and X 2 is O or NH; or X 1 is O Or NH, and X 2 is CO, S(O) 2 or P(O)(OR").
  • X 2 is preferably a direct bond; and r is zero.
  • X 1 is CO, S(O) 2 or P(O)(OR").
  • X 3 is preferably selected from: O, CO, S(O) 2 , P(O)(OR"') and NH, preferably CO or NH.
  • X 3 is O or NH
  • X 4 is CO, S(O) 2 or P(O)(OR"'); or X 3 is CO, S(O) 2 or P(O) (OR"'), and X 4 is a direct bond, O or NH.
  • -[X 2 -(CH 2 ) r -(OCH 2 CH 2 ) s -(CH 2 ) t -X 3 ]- is preferably selected from: -O-CH 2 CH 2 -CO-, -O-(CH 2 CH 2 ) 2 -CO-, -CO-CH 2 CH 2 -O-, -O-CH 2 CH 2 -O-, -CO-CH 2 CH 2- CO-, -NH-CH 2 CH 2 -NH-, -CO-CH 2 CH 2 -NH-, -NH-CH 2 CH 2 -CO-, -O-CH 2 CH 2 -S(O) 2- , -S(O) 2 -CH 2 CH 2 -O-, -NH-CH 2 CH 2 -O-, -O-CH 2 CH 2 -NH-, -NH-CH 2 CH 2 -(OCH 2 CH 2 ) 2 -NH-, -NH-CH 2 CH
  • the application provides the modified albumin described above, wherein the modified albumin has a structure represented by the following general formula (VI):
  • the present application provides the modified albumin described above, wherein the modified albumin has a structure represented by the following general formula (VII):
  • the application provides the modified albumin described above, wherein
  • R 2 is selected from: optionally substituted C 1-6 alkyl (such as C 2-5 alkyl) and optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-6 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-6 alkyl)-C 3-6 cycloalkyl-(preferably -CH 2 -Cyclohexane-), -O- (optionally substituted C 1-6 alkyl) -, -NH- (optionally substituted C 1-6 alkyl) -, -O- (optional Substituted C 2-6 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-6 alkyl or optionally substituted C 2-6 alkenyl Group; more preferably a C 2-5 alkyl group, more preferably -CH 2 -CH 2
  • X 1 is O, CO, S(O) 2 , P(O)(OR”) or NH;
  • n 0;
  • X 2 is CO, S(O) 2 , P(O)(OR") or NH, preferably CO or NH, and
  • X 3 is CO, S(O) 2 , P(O)(OR"') or NH, preferably CO or NH;
  • R 4 is selected from:
  • R 41 and a R 41 '-O-, R 41' -C (O) O- or R 41 '-C (O) NH- substituted with R 41;
  • R 41 , R 41 ' , R 42 and R 43 are each independently selected from: C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13 -17 alkyl, C 7-15 alkyl; and C 5-25 alkenyl, preferably C 7-23 alkenyl, C 9-21 alkenyl, C 11-19 alkenyl, C 13-17 alkenyl, C 7-15 alkenyl; and
  • R 2 is preferably selected from: optionally substituted C 2-5 alkyl and optionally substituted C 2-4 alkenyl, -(CH 2 CH 2 O) j- (Optionally substituted C 1-4 alkyl) -(preferably -(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-4 alkyl) -C 3-6 cycloalkane Group-(preferably -CH 2 -cyclohexane-), -O- (optionally substituted C 1-4 alkyl) -, -NH- (optionally substituted C 1-4 alkyl) -, -O -(Optionally substituted C 2-4 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-4 alkyl or optionally substituted C 2-4 alkenyl;
  • the C 1-4 alkyl group is preferably -CH 2 -CH 2 -.
  • R 2 is selected from C 2-5 alkyl groups, more preferably -CH 2 -CH 2 -or -(CH 2 ) 5 -.
  • R 41 , R 41 ′ , R 42 and R 43 are preferably each independently selected from C 7 alkyl, C 15 alkyl, C 17 alkenyl, C 19 alkenyl, C 21 alkenyl and C 23 alkenyl, preferably: n-octyl, n-pentadecyl,
  • m is 1, X 2 is CO or NH, and X 3 is CO or NH.
  • R 41 , R 41 ′ , R 42 and R 43 are preferably each independently selected from: C 7-23 alkyl, preferably C 9-21 alkyl, C 11-19 Alkyl, C 13-17 alkyl or C 7-15 alkyl; and C 7-23 alkenyl, preferably C 9-21 alkenyl, C 11-19 alkenyl, C 13-17 alkenyl or C 7- 15 alkenyl.
  • R 4 is preferably optionally substituted
  • the application provides the modified albumin described above, wherein m is 1.
  • r is 2; s is 2; and t is 0; or r is 2; s is 0; and t is 0.
  • X 4 is a direct bond, O, CO or NH.
  • the present application provides the modified albumin described above, wherein Z is represented by the general formula (V-ii):
  • X 2 is preferably selected from: O, CO, S(O) 2 , P(O)(OR") and NH, preferably NH; and r is 1, 2 or 3, More preferably, it is 2. In these embodiments, more preferably, X 1 is CO, S(O) 2 or P(O)(OR"), and X 2 is NH.
  • s is preferably 1, 2, 3, 4, 5 or 6, more preferably 2.
  • X 3 is preferably selected from: CO, S(O) 2 , P(O)(OR"') and NH, preferably CO. In these embodiments, it is more preferred Ground, X 3 is CO, and X 4 is O or NH, preferably O.
  • X 5 is preferably CO.
  • -[X 2 -(CH 2 ) r -(OCH 2 CH 2 ) s -NH-X 5 -(CH 2 ) g -X 3 ]- is preferably selected from:
  • the present application provides the modified albumin described above, wherein the modified albumin has a structure represented by the following general formula (VI'):
  • the present application provides the modified albumin described above, wherein the modified albumin has a structure represented by the following general formula (VII'):
  • m is 1.
  • the application provides the modified albumin described above, wherein
  • R 2 is selected from: optionally substituted C 1-6 alkyl (such as C 2-5 alkyl) and optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-6 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-6 alkyl)-C 3-6 cycloalkyl-(preferably -CH 2 -Cyclohexane-), -O- (optionally substituted C 1-6 alkyl) -, -NH- (optionally substituted C 1-6 alkyl) -, -O- (optional Substituted C 2-6 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-6 alkyl or optionally substituted C 2-6 alkenyl Group; more preferably a C 2-5 alkyl group, more preferably -CH 2 -CH 2
  • X 1 is CO, S(O) 2 or P(O)(OR"), preferably CO;
  • X 2 is NH
  • X 3 is CO, S(O) 2 or P(O)(OR"'), preferably CO;
  • X 4 is O or NH
  • R 4 is selected from:
  • R 41 and a R 41 '-O-, R 41' -C (O) O- or R 41 '-C (O) NH- substituted with R 41;
  • R 41 , R 41 ' , R 42 and R 43 are each independently selected from: C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13 -17 alkyl or C 7-15 alkyl; and C 5-25 alkenyl, preferably C 7-23 alkenyl, C 9-21 alkenyl, C 11-19 alkenyl, C 13-17 alkenyl or C 7-15 alkenyl; and
  • R 2 is selected from: optionally substituted C 2-5 alkyl and optionally substituted C 2-4 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-4 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -),-(optionally substituted C 1-4 alkyl)-C 3-6 cycloalkyl-(preferably- CH 2 -cyclohexane-), -O- (optionally substituted C 1-4 alkyl) -, -NH- (optionally substituted C 1-4 alkyl) -, -O- (optionally substituted C 2-4 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-4 alkyl or optionally substituted C 2-4 alkenyl ;
  • the C 1-4 alkyl group is preferably -CH 2 -CH 2 -.
  • R 2 is selected from C 2-5 alkyl groups, more preferably -CH 2 -CH 2 -or -(CH 2 ) 5 -.
  • R 41 , R 41 ' , R 42 and R 43 are each independently selected from C 7 alkyl, C 15 alkyl, C 17 alkenyl, C 19 alkenyl, C 21 alkenyl and C 23 alkenyl, preferably: n-octyl, n-pentadecyl,
  • the application provides the modified albumin described above, wherein
  • R 2 is an optionally substituted C 1-6 alkyl group, preferably a C 2-5 alkyl group, more preferably -CH 2 -CH 2 -;
  • X 1 is CO
  • X 2 is NH
  • X 3 is CO
  • X 4 is O
  • X 5 is CO
  • R 4 is and
  • R 42 and R 43 are each independently selected from: C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13-17 alkyl or C 7- 15 alkyl.
  • ADC linkers used in antibody-drug conjugates can be used as spacers in the present application.
  • the ADC linker that can be used as the spacer in the present application can be selected from:
  • the peptides described in items (1) and (2) above are formed from 2 to 20 (for example, 2 to 15, 2 to 10, 2 to 5 or 3 to 4) identical or different amino acids;
  • the peptide is a dipeptide represented by the general formula (IX):
  • the part additionally contains oligosaccharides, -(CH 2 ) n -and/or -(CH 2 CH 2 O) n -;
  • the part may be selected from:
  • Each R Z1 is independently selected from: H, optionally substituted C 1-12 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl, such as methyl);
  • Each R Z2 is independently selected from: H; C 1-6 alkyl (preferably C 1-4 alkyl); is selected from SH, SCH 3 , NH 2 , OH, COOH, CONH 2 , guanidino, optionally One or more substitutions of substituted C 6-10 aryl (preferably phenyl, 4-OH-phenyl, biphenyl) and optionally substituted 5- to 10-membered heteroaryl (preferably imidazole, indole) Group substituted C 1-6 alkyl; C 3-10 cycloalkyl (preferably cyclohexyl); and C 6-10 aryl (preferably phenyl);
  • n is an integer selected from 1-10, such as 1, 2, 3, 4, 5, 6, or 7.
  • Z can be selected from:
  • the application provides a modified albumin, wherein Z is as described above.
  • m is 1 and X 4 is a direct bond, O or NH.
  • the application provides modified albumin, wherein
  • R 2 is selected from: optionally substituted C 1-6 alkyl (such as C 2-5 alkyl) and optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-6 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-6 alkyl)-C 3-6 cycloalkyl-(preferably -CH 2 -Cyclohexane-), -O- (optionally substituted C 1-6 alkyl) -, -NH- (optionally substituted C 1-6 alkyl) -, -O- (optional Substituted C 2-6 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-6 alkyl or optionally substituted C 2-6 alkenyl Group; more preferably a C 2-5 alkyl group, more preferably -CH 2 -CH 2
  • X 1 is O, NH, CO, S(O) 2 or P(O)(OR");
  • R 4 is selected from:
  • R 41 and a R 41 '-O-, R 41' -C (O) O- or R 41 '-C (O) NH- substituted with R 41;
  • R 41 , R 41 ' , R 42 and R 43 are each independently selected from: C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13 -17 alkyl, C 7-15 alkyl; and C 5-25 alkenyl, preferably C 7-23 alkenyl, C 9-21 alkenyl, C 11-19 alkenyl, C 13-17 alkenyl, C 7-15 alkenyl; and
  • R 2 is selected from: optionally substituted C 2-5 alkyl and optionally substituted C 2-4 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-4 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-4 alkyl)-C 3-6 cycloalkyl-(preferably -CH 2 -Cyclohexane-), -O- (optionally substituted C 1-4 alkyl) -, -NH- (optionally substituted C 1-4 alkyl) -, -O- (optional Substituted C 2-4 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-4 alkyl or optionally substituted C 2-4 alkenyl base;
  • the C 1-4 alkyl group is preferably -CH 2 -CH 2 -.
  • R 2 is selected from C 2-5 alkyl groups, more preferably -CH 2 -CH 2 -or -(CH 2 ) 5 -.
  • R 41 , R 41 ' , R 42 and R 43 are each independently selected from C 7 alkyl, C 15 alkyl, C 17 alkenyl, C 19 alkenyl, C 21 alkenyl and C 23 alkenyl, preferably: n-octyl, n-pentadecyl,
  • the present application provides the modified albumin described above, wherein m is zero.
  • X 1 is CO, S(O) 2 or P(O)(OR"), preferably CO, and X 4 is O or NH; or
  • X 1 is O or NH, preferably NH, and X 4 is CO, S(O) 2 or P(O)(OR"'), preferably CO.
  • R 4 is selected from: R 41 , and is substituted by R 41' -O-, R 41' -C(O)O- and R 41' -C(O)NH- The R 41 .
  • X 1 is O or NH, preferably NH;
  • X 4 is CO, S(O) 2 or P(O)(OR"'), preferably CO;
  • R 4 is selected from optionally substituted groups selected from the following:
  • X 1 is CO, S(O) 2 or P(O)(OR"), preferably CO;
  • X 4 is O
  • R 4 is selected from the following optionally substituted groups:
  • the application provides modified albumin, which is represented by the general formula (I):
  • Q is the S atom in the free sulfhydryl group of HSA or recombinant human albumin (rHA) (for example, the sulfhydryl group corresponding to the cysteine residue at position 34 of SEQ ID NO:1);
  • the present application provides a compound of general formula (X) for use as a modifier for preparing the modified albumin described above:
  • R is a part containing a reactive group that can react with the free sulfhydryl group of albumin (for example, the sulfhydryl group corresponding to the cysteine residue at position 34 of SEQ ID NO:1)
  • the compound of general formula (X) is connected to the S in the free sulfhydryl group and provides the hydrophobic enhancing part of general formula (II) as described above;
  • Z is a spacer, as defined above;
  • n is as defined above;
  • M is a hydrophobic group, as defined above.
  • linker L in the hydrophobic enhancing portion of the general formula (II) is derived from the free sulfhydryl group of the albumin and the reactive group-containing portion of the conjugation modifier of the general formula (X) R's reaction.
  • the reaction between the reactive group and the free sulfhydryl group is selected from: Michael addition reaction, sulfhydryl-disulfide bond exchange reaction, substitution reaction, and click chemistry.
  • the reactive group is selected from the group consisting of Michael reactive acceptors and disulfide bond-containing groups.
  • R is represented by the general formula (XI):
  • R 1' is a reactive group, which is selected from the following optionally substituted groups:
  • X is CH or N
  • R 1 ' is halogen, e.g. F, Cl, Br or I;
  • R 11, R 12, R 13 , R 13 ', R 14, R 16, R a, R b, R 2, X 1, p and q are each as defined above.
  • R 1' is
  • R 11 is each independently selected from: H, optionally substituted C 1-6 alkyl, -COOH, -COOC 1-6 alkyl, C 6-10 aryl (such as phenyl), and 5 to 10 membered heteroaryl base;
  • X 1 is selected from: CO, S(O) 2 , P(O)(OR") and NH, preferably CO or NH.
  • R 1' is And R 12 , R 2 and X 1 are each as defined above.
  • R 1' is selected from:
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH, preferably CO.
  • R 1' is And R 13 , R 13 , R 2 and X 1 are each as defined above.
  • R 1' is
  • R 2 is selected from: an optionally substituted (R b) q phenyl, optionally substituted (R b) q pyridyl, - (optionally substituted (R b) q phenyl) - (optionally Substituted C 1-6 alkyl) -,-(optionally substituted by (R b ) q pyridyl)-(optionally substituted C 1-6 alkyl) -,-(optionally (R b ) q substituted phenyl)-(optionally substituted C 2-6 alkenyl)-and-(optionally substituted by (R b ) q pyridyl)-(optionally substituted C 2-6 alkenyl)- ;
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH, preferably CO or NH.
  • R 1 ' is halogen, e.g. F, Cl, Br or I
  • R 2 is an optionally substituted C 1-6 alkyl group, preferably an optionally substituted C 1-4 alkyl, more preferably methyl
  • X 1 is selected from CO, S(O) 2 and P(O)(OR"), preferably CO.
  • R 1' is
  • R 2 is selected from: optionally substituted C 1-6 alkyl (such as C 2-5 alkyl) and optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-6 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-6 alkyl)-C 3-6 cycloalkyl-(preferably -CH 2 -Cyclohexane-), -O- (optionally substituted C 1-6 alkyl) -, -NH- (optionally substituted C 1-6 alkyl) -, -O- (optional Substituted C 2-6 alkenyl) -, -NH- (optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-6 alkyl (for example, C 2-5 alkyl) and any Optional substituted C 2-6 alkenyl; more preferably C 2-5 alkyl, more preferably
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR") and NH, preferably CO or NH.
  • the application provides the modifier described above, wherein the modifier is represented by the general formula (XII):
  • R 1′ , R 2 , X 1 , X 2 , X 3 , r, s, t, M, and m are each as defined above.
  • the modifier is represented by the general formula (XIII):
  • R 1′ , R 2 , X 1 , X 2 , X 3 , r, s, t, X 4 , R 4 and m are each as defined above.
  • R 2 , X 1 , X 2 , X 3 , R 4 and m are each as defined above.
  • m is 1.
  • r is 2; s is 2; and t is 0; or r is 2; s is 0; and t is 0.
  • X 4 is a direct bond, O, CO, or NH.
  • the application provides the modifier described above, wherein the modifier is represented by the general formula (XIV):
  • R 1′ , R 2 , X 1 , X 2 , X 3 , X 5 , g, r, s, M, and m are each as defined above.
  • the modifier is represented by the general formula (XV):
  • R 1′ , R 2 , R 4 , X 1 , X 2 , X 3 , X 4 , X 5 , g, r, s, and m are each as defined above.
  • m is preferably 1.
  • R 2 is selected from: optionally substituted C 1-6 alkyl (such as C 2-5 alkyl) and optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-6 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-6 alkyl)-C 3-6 cycloalkyl-(preferably -CH 2 -Cyclohexane-), -O- (optionally substituted C 1-6 alkyl) -, -NH- (optionally substituted C 1-6 alkyl) -, -O- (optional Substituted C 2-6 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-6 alkyl or optionally substituted C 2-6 alkenyl Group; more preferably a C 2-5 alkyl group, more preferably -CH 2 -CH 2
  • X 1 is CO, S(O) 2 or P(O)(OR"), preferably CO;
  • X 2 is NH
  • X 3 is CO, S(O) 2 or P(O)(OR"'), preferably CO;
  • X 4 is O or NH
  • R 4 is selected from:
  • R 41 and a R 41 '-O-, R 41' -C (O) O- or R 41 '-C (O) NH- substituted with R 41;
  • R 41 , R 41 ' , R 42 and R 43 are each independently selected from: C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13 -17 alkyl or C 7-15 alkyl; and C 5-25 alkenyl, preferably C 7-23 alkenyl, C 9-21 alkenyl, C 11-19 alkenyl, C 13-17 alkenyl or C 7-15 alkenyl; and
  • R 2 is an optionally substituted C 1-6 alkyl group, preferably a C 2-5 alkyl group, more preferably -CH 2 -CH 2 -;
  • X 1 is CO
  • X 2 is NH
  • X 3 is CO
  • X 4 is O
  • X 5 is CO
  • R 4 is and
  • R 42 and R 43 are each independently selected from: C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13-17 alkyl or C 7- 15 alkyl.
  • the application provides the modifier described above, wherein:
  • Z is an ADC linker as defined above that can be used as a spacer in the present application.
  • R 2 , X 1 , X 4 , and R 4 are each as defined above;
  • n is as defined above, and is preferably 1.
  • the application provides the modifier described above, wherein m is zero.
  • X 1 is CO, S(O) 2 or P(O)(OR"), preferably CO, and X 4 is O or NH; or
  • X 1 is O or NH, preferably NH, and X 4 is CO, S(O) 2 or P(O)(OR"'), preferably CO.
  • R 4 is selected from: R 41 , and is substituted by R 41' -O-, R 41'- C(O)O- and R 41'- C(O)NH- The R 41 .
  • X 1 is O or NH, preferably NH;
  • X 4 is CO, S(O) 2 or P(O)(OR"'), preferably CO;
  • R 4 is selected from optionally substituted groups selected from the following:
  • X 1 is CO, S(O) 2 or P(O)(OR"), preferably CO;
  • X 4 is O
  • R 4 is selected from the following optionally substituted groups:
  • the application provides the modifiers described above, which are selected from the following table:
  • the present application provides a method for preparing the above-mentioned modified albumin, the method comprising allowing the albumin and the above-mentioned modifier to allow free sulfhydryl groups of the albumin (for example, in Corresponding to the step of reacting the sulfhydryl group of the cysteine residue at position 34 of SEQ ID NO:1 with R or R 1'.
  • the reaction is selected from Michael addition reaction, sulfhydryl-disulfide bond exchange reaction and substitution reaction.
  • the method includes combining the free sulfhydryl group of the albumin (e.g., the sulfhydryl group corresponding to the cysteine residue at position 34 of SEQ ID NO:1) with
  • R is represented by the general formula (XI):
  • M, R 2 , X 1 , X 2 , X 3 , X 4 , R 4 , X, R b , m, r, s, t and q are as defined above;
  • R 1 ' is halogen, e.g. F, Cl, Br or I
  • R 2 is an optionally substituted C 1-6 alkyl group, preferably an optionally substituted C 1-4 alkyl, more Preferably methyl
  • X 1 is selected from CO, S(O) 2 and P(O)(OR"), preferably CO;
  • Z, M, R 2 , X 1 , X 2 , X 3 , X 4 , R 4 , m, r, s and t are as defined above.
  • the method of the present application may include the following steps:
  • a suitable concentration for example, about 31.25 mg/mL
  • the modifier can be dissolved in a suitable solvent (such as ethanol, or a mixed solvent of ethanol and ethyl acetate) to prepare a solution with a suitable concentration (such as about 2.01 mg/mL) and used as the ethanol phase for the reaction.
  • a suitable solvent such as ethanol, or a mixed solvent of ethanol and ethyl acetate
  • step (3) The solution of the modifier described in step (2) is added to the solution of albumin described in step (1) to prepare the modified albumin.
  • the solution of modifier is added dropwise to the solution of albumin.
  • This application also provides methods for preparing compounds of general formula (X) used as modifiers.
  • the compound of general formula (X) can be prepared by the following method:
  • R is R 1 '-R 2 -X 1 - ;
  • M is -X 4 -R 4 ;
  • n 0 or 1
  • R 1 ' is as defined above, preferably
  • R a and p are as defined above, preferably, p is 0;
  • R 2 is as defined above, preferably a C 1-6 alkyl group, more preferably a C 2-5 alkyl group, for example -CH 2 -CH 2 -;
  • X 1 is NH
  • X 2 is CO
  • X 3 is as defined above, preferably CO;
  • r is as defined above, preferably 2;
  • t is as defined above, preferably 0;
  • s is as defined above, preferably 0;
  • R 4 is as defined above, preferably:
  • X 4 is CO, O or NH
  • X 4 is CO and R 4 is:
  • X 3 is CO and X 4 is O or NH:
  • the compound of formula In-2 is selected from:
  • the method includes a step of subjecting an amine of formula In-1 to an acid of formula In-2 to undergo a condensation reaction to provide a compound of general formula (X).
  • the condensation reaction may be carried out in a suitable organic solvent, and the organic solvent may be selected from: DMF, DMSO, acetonitrile, THF, NMP, and a mixture of two or more of them.
  • the condensation reaction can be carried out in the presence of a suitable mixture, and the condensation agent can be selected from: HBTU, HOBT/EDCI, DCC and CDI.
  • the condensation reaction may be carried out in the presence of a suitable organic base, and the organic base may be selected from: pyridine, triethylamine, diisopropylethylamine and the like.
  • the condensation reaction can be carried out at a temperature of 20 to 40° C. for a suitable time, for example, 4 h or longer.
  • the resulting product can optionally be purified, for example by column chromatography or high performance liquid chromatography.
  • the compound of general formula (X) can be prepared by the following method:
  • R is R 1 '-R 2 -X 1 - ;
  • M is -X 4 -R 4 ;
  • n 0;
  • R 1 ' is as defined above, preferably
  • R a and p are as defined above, preferably, p is 0;
  • R 2 is as defined above, preferably a C 1-6 alkyl group, more preferably a C 2-5 alkyl group, for example -CH 2 -CH 2 -;
  • X 1 is CO
  • R 4 is as defined above, preferably More preferably
  • X 4 is O
  • the method includes the following steps:
  • Step 1 Reacting an acid of formula In-3 with an oxalyl chloride of formula In-4 to provide an acid chloride of formula In-5.
  • the reaction can be carried out in a suitable organic solvent, and the organic solvent can be selected from dichloromethane, chloroform, 1,2-dichloroethane, THF, acetonitrile, or a mixture of two or more of them.
  • the reaction can be carried out at a temperature of 0-30° C. for a suitable time, for example, 4 h or longer.
  • oxalyl chloride can be replaced with thionyl chloride.
  • Step 2 The acid chloride of formula In-5 and the alcohol of formula In-6 undergo an esterification reaction to provide a conjugate of general formula (X).
  • the esterification reaction can be carried out in a suitable organic solvent, and the organic solvent can be selected from DMF, dichloromethane, chloroform, 1,2-dichloroethane, THF, DMSO, dioxane, NMP and their A mixture of two or more of them.
  • the condensation reaction may be carried out at a temperature of 20-40° C. for a suitable time, for example, the reaction may take 4 hours or longer.
  • the resulting product can optionally be purified, for example by column chromatography or high performance liquid chromatography.
  • the compound of general formula (X) can be prepared by the following method:
  • R is R 1 '-R 2 -X 1 - ;
  • M is -X 4 -R 4 ;
  • Z is -[X 2 -(CH 2 ) r -(OCH 2 CH 2 ) s -(CH 2 ) t -X 3 ]-
  • n 1;
  • R 1 ' is as defined above, preferably
  • R a and p are as defined above, preferably, p is 0;
  • R 2 is as defined above, preferably a C 1-6 alkyl group, more preferably a C 2-5 alkyl group, for example -CH 2 -CH 2 -;
  • X 1 is CO
  • X 2 is NH
  • X 3 is as defined above, preferably CO or NH;
  • r is as defined above, preferably 2;
  • t is as defined above, preferably 0;
  • s is as defined above, preferably 2;
  • R 4 is as defined above, preferably:
  • X 4 is as defined above, preferably CO, NH or O;
  • the compound of formula In-8 is selected from:
  • the method includes the step of reacting an ester of formula In-7 with an amine of formula In-8 to provide a compound of general formula (X).
  • the reaction can be carried out in a suitable organic solvent, the organic solvent can be selected from dichloromethane, chloroform, 1,2-dichloroethane, THF, DMF, DMSO, dioxane, NMP and their A mixture of two or more.
  • the reaction can be carried out at a temperature of 20-40° C. for a suitable time, for example, 4 h or longer.
  • the resulting product can optionally be purified, for example by column chromatography or high performance liquid chromatography.
  • the compound of general formula (X) can be prepared by the following method:
  • R is R 1 '-R 2 -X 1 - ;
  • M is -X 4 -R 4 ;
  • Z is -[X 2 -(CH 2 ) r -(OCH 2 CH 2 ) s -NH-X 5 -(CH 2 ) g -X 3 ]-;
  • n 1;
  • R 1 ' is as defined above, preferably
  • R a and p are as defined above, preferably, p is 0;
  • R 2 is as defined above, preferably a C 1-6 alkyl group, more preferably a C 2-5 alkyl group, for example -CH 2 -CH 2 -;
  • X 1 is as defined above, preferably CO;
  • X 2 is as defined above, preferably NH;
  • X 3 is as defined above, preferably CO;
  • g is as defined above, preferably 2;
  • r is as defined above, preferably 2;
  • s is as defined above, preferably 2;
  • R 4 is as defined above, preferably:
  • X 4 is as defined above, preferably O or NH, more preferably O;
  • X 5 is as defined above, preferably CO;
  • the compound of formula In-9 can also be provided in the form of a salt, such as hydrochloride;
  • the compound of formula In-9 is:
  • the compound of formula In-10 is:
  • the method includes the step of subjecting the amine of formula In-9 or its salt to the acid of formula In-10 to undergo a condensation reaction to provide a compound of formula (X).
  • the condensation reaction may be carried out in a suitable organic solvent, and the organic solvent may be selected from: DMF, DMSO, acetonitrile, THF, NMP, and a mixture of two or more of them.
  • the condensation reaction can be carried out in the presence of a suitable mixture, and the condensation agent can be selected from: HBTU, HOBT/EDCI, DCC and CDI.
  • the condensation reaction may be carried out in the presence of a suitable organic base, and the organic base may be selected from: pyridine, triethylamine, diisopropylethylamine and the like.
  • the condensation reaction can be carried out at a temperature of 20 to 40° C. for a suitable time, for example, 4 h or longer.
  • the resulting product can optionally be purified, for example by column chromatography or high performance liquid chromatography.
  • composition and pharmaceutical or cosmetic composition containing the same
  • the present application provides a composition comprising the modified albumin described above and optionally unmodified albumin.
  • the composition can be used as a carrier, preferably as a carrier for poorly water-soluble compounds, especially poorly water-soluble compounds with pharmaceutical or cosmetic activity.
  • the composition can be considered a carrier composition.
  • the carrier composition includes the modified albumin and unmodified albumin.
  • the modified albumin accounts for about 1% to about 99%, such as about 5% to about 70%, based on the total weight of the unmodified albumin and modified albumin. It is preferably about 5% to about 20%.
  • the carrier composition is in solid (e.g., lyophilized powder) or liquid form (e.g., aqueous solution).
  • this application provides a pharmaceutical or cosmetic composition, which comprises:
  • a carrier encapsulating a poorly water-soluble compound with pharmaceutical or cosmetic activity the carrier being the modified albumin described above or the carrier composition according to the fourth aspect above;
  • the term "medicine” or “pharmaceutical composition” includes an agent for preventing or treating a disease or condition and a diagnostic agent for diagnosing a disease or condition.
  • a pharmaceutically or cosmetically acceptable carrier depends on the dosage form of the pharmaceutical or cosmetic composition, and firstly on the route of administration of the dosage form (for example, a dosage form for oral, nasal, intradermal, subcutaneous, topical, intramuscular or intravenous administration) , And secondly depends on the formulation of the dosage form.
  • the pharmaceutically or cosmetically acceptable carrier may include water (such as water for injection), buffers, isotonic salt solutions such as PBS (phosphate buffered saline), glucose, mannitol, dextrose, lactose, starch, hard Magnesium fatty acid, cellulose, magnesium carbonate, 0.3% glycerin, hyaluronic acid, ascorbic acid, lactic acid, ethanol, polyalkylene glycols such as polyethylene glycol (e.g., polyethylene glycol 4000) or polypropylene glycol, triglycerides Wait.
  • water such as water for injection
  • buffers isotonic salt solutions such as PBS (phosphate buffered saline), glucose, mannitol, dextrose, lactose, starch, hard Magnesium fatty acid, cellulose, magnesium carbonate, 0.3% glycerin, hyaluronic acid, ascorbic acid, lactic acid, ethanol, polyalkylene glycols
  • the pharmaceutical or cosmetic composition of the present application may also contain various additives, such as wetting agents, emulsifiers, or buffering agents, as required.
  • the pharmaceutical or cosmetic composition is in a solid, semi-solid or liquid form, preferably in the form of a solution, suspension, emulsion or lyophilized powder, and more preferably injectable.
  • the present application provides a method for improving the solubility of a poorly water-soluble compound with pharmaceutical or cosmetic activity in an aqueous medium, and the method includes the following steps:
  • step (3) Mixing the two solutions described in step (1) and step (2);
  • the present application provides the use of the modified albumin described above or the carrier composition according to the fourth aspect described above as a carrier for poorly water-soluble compounds with pharmaceutical or cosmetic activity.
  • the present application provides the modified albumin described above or the carrier composition according to the fourth aspect described above as a carrier for preparing pharmaceutical or cosmetic compositions containing poorly water-soluble compounds with pharmaceutical or cosmetic activity.
  • the pharmaceutical or cosmetic composition is in a solid, semi-solid or liquid form, preferably a solution, suspension, emulsion or lyophilized powder, and more preferably injectable.
  • the present application provides a kit, which at least contains: i) a poorly water-soluble compound with pharmaceutical or cosmetic activity, ii) unmodified albumin, and iii) the modifier described above.
  • the kit can be used to prepare the pharmaceutical or cosmetic composition described herein according to the methods described in the third and sixth aspects above when the poorly water-soluble compound with pharmaceutical or cosmetic activity is administered close to Apply.
  • the poorly water-soluble compounds with pharmaceutical or cosmetic activity include (but are not limited to): antioxidants, such as but not limited to flavonoids and polyphenol compounds; anti-tumor agents, such as but not limited to docetaxel, taxanes Compounds, platinum, camptothecins, vinblastines, anthraquinones, nucleosides, podophyllotoxins, DNA topoisomerase inhibitors; immunomodulators, such as cyclosporines; steroids or non- Steroid anti-inflammatory agents; cardiovascular agents; antibiotics; antifungal agents; and antiviral agents.
  • antioxidants such as but not limited to flavonoids and polyphenol compounds
  • anti-tumor agents such as but not limited to docetaxel, taxanes Compounds, platinum, camptothecins, vinblastines, anthraquinones, nucleosides, podophyllotoxins, DNA topoisomerase inhibitors
  • immunomodulators such as cyclosporines; steroids or non- Steroid anti-inflammatory agents
  • Examples that may be mentioned include, but are not limited to: curcumin, paclitaxel, docetaxel, cisplatin, hydroxycamptothecin, camptothecin, vinblastamide, teniposide, etoposide, methotrexate, cyclosporin A, Rapamycin, Nimodipine, Adriamycin, Breviscapine, Ginkgolide, Silymarin, Daunorubicin, Mitomycin, Indomethacin, Ibuprofen, Ketoprofen, Naproxen, Nitraconazole, fenofibrate, itraconazole, amphotericin B, bifendate, progesterone, dihydrotestosterone, haloperidol, and risperidone.
  • a modified albumin which is composed of albumin and a hydrophobic enhancement moiety connected to the S atom in the free sulfhydryl group of the albumin, and the modified albumin is represented by the general formula (I):
  • Q is the S atom in the free sulfhydryl group of the albumin
  • C is the hydrophobicity enhancing part, and is represented by the general formula (II):
  • L is the linker connected to Q
  • Z is the spacer base
  • n 1 or 0
  • M is a hydrophobic group.
  • the bond identified by a is bonded to Q, and the bond identified by b is bonded to (Z) m -M;
  • R 1 is S, or is selected from the following optionally substituted groups:
  • the bond identified by f is bonded to Q, and the bond identified by k is bonded to R 2 ;
  • R 11 is each independently selected from: H, optionally substituted C 1-12 alkyl (preferably C 1-6 alkyl, more preferably C 1-4 alkyl), -COOH, -COOC 1-6 alkyl, -CH(R 15 )NH-CO-C 1-6 alkyl, C 6-10 aryl (such as phenyl) and 5 to 10 membered heteroaryl;
  • R 13 is selected from: optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl and (Preferred );
  • R 13' is selected from: optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, (Preferred ),
  • u 0, 1, 2 or 3, preferably 1 or 2;
  • R 14 and R 15 are each independently H or C 1-6 alkyl, preferably H or C 1-4 alkyl, more preferably H, methyl or ethyl; more preferably H or methyl;
  • R 13 is And wherein R 15 is preferably C 1-4 alkyl, more preferably methyl;
  • R 16 is selected from H and optionally substituted C 1-12 alkyl (preferably C 1-6 alkyl, more preferably C 1-4 alkyl);
  • p 0, 1 or 2;
  • Each R a is independently selected from hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio and halogen;
  • j is an integer of 1-10, such as 2;
  • q 0, 1, 2 or 3;
  • R b is each independently selected from H, hydroxy, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio and halogen;
  • R 1 and R 2 together are optionally substituted C 1-6 alkyl (e.g. C 1-4 alkyl); and
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH;
  • R" is selected from H, optionally substituted C 1-6 alkyl and optionally substituted C 2-6 alkenyl, preferably H.
  • R 2 is selected from: optionally substituted C 1-6 alkyl (such as C 2-5 alkyl) and optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-6 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-6 alkyl)-C 3-6 cycloalkyl-(preferably -CH 2 -Cyclohexane-), -O- (optionally substituted C 1-6 alkyl) -, -NH- (optionally substituted C 1-6 alkyl) -, -O- (optional Substituted C 2-6 alkenyl) -, -NH- (optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-6 alkyl (for example, C 2-5 alkyl) and any Optional substituted C 2-6 alkenyl; more preferably C 2-5 alkyl, more preferably
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR") and NH, preferably CO or NH.
  • R 1 is selected from the following optionally substituted groups:
  • R 11 is each independently selected from: H, optionally substituted C 1-6 alkyl, -COOH, -COOC 1-6 alkyl, C 6-10 aryl (such as phenyl), and 5 to 10 membered heteroaryl base;
  • X 1 is selected from: CO, S(O) 2 , P(O)(OR") and NH, preferably CO or NH.
  • R 1 is the following optionally substituted group:
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH, preferably CO.
  • R 1 is selected from the following optionally substituted groups:
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH, preferably CO.
  • R 1 is selected from the following optionally substituted groups:
  • R 13 is selected from: Preferably
  • R 13' is selected from: Preferably
  • R 2 is selected from: optionally substituted C 1-6 alkyl and optionally substituted C 2-6 alkenyl;
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR”) and NH, preferably CO;
  • u and R 15 are each as defined in any one of embodiments 2 to 4.
  • R 1 is S
  • R 2 is selected from: an optionally substituted (R b) q phenyl, optionally substituted (R b) q pyridyl, - (optionally substituted (R b) q phenyl) - (optionally Substituted C 1-6 alkyl) -,-(optionally substituted by (R b ) q pyridyl)-(optionally substituted C 1-6 alkyl) -,-(optionally (R b ) q substituted phenyl)-(optionally substituted C 2-6 alkenyl)-and-(optionally substituted by (R b ) q pyridyl)-(optionally substituted C 2-6 alkenyl)- ;
  • X 1 is selected from: O, CO, S(O) 2 , P(O)(OR") and NH, preferably CO or NH;
  • Each of q and R b is as defined in any one of Embodiments 2 to 4.
  • R 1 and R 2 together are optionally substituted C 1-4 alkyl, preferably methyl;
  • X 1 is selected from: CO, S(O) 2 and P(O)(OR"), preferably CO.
  • the C-terminus is connected to L-(Z) m , and the N-terminus is substituted by -CO-R 3 or -S(O) 2 -R 3 ;
  • N-terminal is connected to L-(Z) m , and the -OH of the C-terminal carboxyl group is replaced by -NH-R 3 or -OR 3 ;
  • X 4 is selected from: direct bond, O, CO, S(O) 2 , P(O)(OR"') and NH;
  • R"' is selected from: H and R 41 ;
  • R 3 and R 4 are each independently selected from:
  • R 41 and a R 41 '-O-, R 41' -C (O) O- or R 41 '-C (O) NH- substituted with R 41;
  • R 41 , R 41' , R 42 and R 43 are each independently selected from:
  • C 1-30 alkyl preferably C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13-17 alkyl or C 7-15 alkyl , Such as C 5 alkyl, C 7 alkyl, C 11 alkyl or C 15 alkyl;
  • C 2-30 alkenyl preferably C 5-25 alkenyl, preferably C 7-23 alkenyl, C 9-21 alkenyl, C 11-19 alkenyl, C 13-17 alkenyl or C 7-15 alkenyl , Such as C 5 alkenyl, C 7 alkenyl, C 11 alkenyl, C 15 alkenyl, C 17 alkenyl, C 19 alkenyl or C 21 alkenyl; and
  • C 2-30 alkynyl preferably C 5-25 alkynyl, preferably C 7-23 alkynyl, C 9-21 alkynyl, C 11-19 alkynyl, C 13-17 alkynyl or C 7-15 alkynyl , Such as C 5 alkynyl, C 7 alkynyl, C 11 alkynyl, C 15 alkynyl, C 17 alkynyl, C 19 alkynyl or C 21 alkynyl; and
  • R 3 is each independently selected from: C 7 alkyl, C 15 alkyl, C 17 alkenyl, C 19 alkenyl, C 21 alkenyl, and C 23 alkenyl Group, preferably: n-octyl, n-pentadecyl,
  • X 4 is CO, S(O) 2 or P(O)(OR"'), preferably CO;
  • R 4 is selected from: R 41 is and R 41 '-C (O) O- and R 41' -C (O) NH- substituted with R 41;
  • R 41 and R 41' are each independently selected from: C 7 alkyl, C 15 alkyl, C 17 alkenyl, C 19 alkenyl, C 21 alkenyl and C 23 alkenyl, preferably: n-octyl, n Pentadecyl,
  • X 4 is O or NH
  • R 4 is Preferred
  • X 4 is CO, S(O) 2 or P(O)(OR"'), preferably CO;
  • R 4 is optionally substituted More preferably
  • X 4 is O
  • R 4 is optionally substituted Preferably
  • R 3 is as defined in Embodiment 12;
  • R 3' is selected from: H; C 1-6 alkyl; is selected from SH, SCH 3 , NH 2 , OH, COOH, -CONH 2 , -NHCOCH 3 , -NHCHO, -NHCONH 2 , guanidino, optionally One or one of substituted C 6-10 aryl (preferably phenyl, 4-OH-phenyl, biphenyl, naphthyl) and optionally substituted 5- to 10-membered heteroaryl (preferably imidazole, indole) C 1-6 alkyl substituted with multiple substituents; C 3-10 cycloalkyl (preferably cyclohexyl); and C 6-10 aryl (preferably phenyl);
  • X 2 is selected from: direct bond, O, CO, S(O) 2 , P(O)(OR") and NH;
  • X 3 is selected from: direct bond, O, CO, S(O) 2 , P(O)(OR"') and NH;
  • X 5 is selected from: CO and S(O) 2 ;
  • g is 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably 2;
  • h is 0 or 1;
  • r is 0, 1, 2, 3, 4, 5 or 6, preferably 1, 2 or 3, more preferably 2;
  • t is 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2 or 3, more preferably 0;
  • s is an integer from 0 to 100, preferably an integer from 0 to 10, preferably 0, 1, 2, 3, 4, 5 or 6, more preferably 0, 1 or 2;
  • R" is as defined in Embodiment 2.
  • R"' is as defined in Embodiment 12.
  • X 2 is selected from: O, CO, S(O) 2 , P(O)(OR") and NH, preferably CO or NH;
  • r is 1, 2 or 3, more preferably 2.
  • X 1 is CO, S(O) 2 or P(O)(OR"), and X 2 is O or NH; or
  • X 1 is O or NH
  • X 2 is CO, S(O) 2 or P(O)(OR").
  • X 2 is a direct bond
  • X 1 is CO, S(O) 2 or P(O)(OR").
  • t 0, 1, 2 or 3, more preferably 0.
  • s is 0, 1, 2, 3, 4, 5, or 6, more preferably 0, 1, or 2.
  • X 3 is selected from: O, CO, S(O) 2 , P(O)(OR"') and NH, preferably CO or NH.
  • X 3 is O or NH, and X 4 is CO, S(O) 2 or P(O)(OR"'); or
  • X 3 is CO, S(O) 2 or P(O)(OR"'), and X 4 is a direct bond, O or NH.
  • R 1 , R 2 and X 1 are each as defined in any one of embodiments 2 to 30;
  • X 2 , X 3 , r, s, and t are each as defined in any one of embodiments 20 to 30.
  • Q and m are each as defined in any one of Embodiments 1 to 30;
  • R 1 , R 2 and X 1 are each as defined in any one of embodiments 2 to 30;
  • X 2 , X 3 , r, s, and t are each as defined in any one of embodiments 20 to 30;
  • R 4 and X 4 are each as defined in any one of embodiments 12 to 30.
  • R 2 is selected from: optionally substituted C 1-6 alkyl (such as C 2-5 alkyl) and optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-6 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-6 alkyl)-C 3-6 cycloalkyl-(preferably -CH 2 -Cyclohexane-), -O- (optionally substituted C 1-6 alkyl) -, -NH- (optionally substituted C 1-6 alkyl) -, -O- (optional Substituted C 2-6 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-6 alkyl or optionally substituted C 2-6 alkenyl Group; more preferably a C 2-5 alkyl group, more preferably -CH 2 -CH 2
  • X 1 is O, CO, S(O) 2 , P(O)(OR”) or NH;
  • n 0;
  • X 2 is CO, S(O) 2 , P(O)(OR") or NH, preferably CO or NH, and
  • X 3 is CO, S(O) 2 , P(O)(OR"') or NH, preferably CO or NH;
  • R 4 is selected from:
  • R 41 and a R 41 '-O-, R 41' -C (O) O- or R 41 '-C (O) NH- substituted with R 41;
  • R 41 , R 41 ' , R 42 and R 43 are each independently selected from: C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13 -17 alkyl or C 7-15 alkyl; and C 5-25 alkenyl, preferably C 7-23 alkenyl, C 9-21 alkenyl, C 11-19 alkenyl, C 13-17 alkenyl or C 7-15 alkenyl; and
  • X 2 is selected from: O, CO, S(O) 2 , P(O)(OR") and NH, preferably NH;
  • r is 1, 2 or 3, more preferably 2.
  • X 1 is CO, S(O) 2 or P(O)(OR"), and X 2 is NH.
  • s is 1, 2, 3, 4, 5, or 6, more preferably 2.
  • X 3 is selected from: CO, S(O) 2 , P(O)(OR"') and NH, preferably CO.
  • X 3 is CO, and X 4 is O or NH, preferably O.
  • X 5 is CO.
  • R 1 , R 2 and X 1 are each as defined in any one of embodiments 2 to 20 and 37 to 44;
  • X 2 , X 3 , X 5 , g, r, and s are each as defined in any one of embodiments 20 and 37 to 44.
  • modified albumin of any one of embodiments 1 to 20 and 37 to 44, wherein the modified albumin has a structure represented by the following general formula (VII'):
  • Q and m are each as defined in any one of Embodiments 1 to 20 and 37 to 44;
  • R 1 , R 2 and X 1 are each as defined in any one of embodiments 2 to 20 and 37 to 44;
  • X 2 , X 3 , X 5 , g, r, and s are each as defined in any one of embodiments 20 and 37 to 44;
  • R 4 and X 4 are each as defined in any one of Embodiments 12 to 20 and 37 to 44.
  • R 2 is selected from: optionally substituted C 1-6 alkyl (such as C 2-5 alkyl) and optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-6 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-6 alkyl)-C 3-6 cycloalkyl-(preferably -CH 2 -Cyclohexane-), -O- (optionally substituted C 1-6 alkyl) -, -NH- (optionally substituted C 1-6 alkyl) -, -O- (optional Substituted C 2-6 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-6 alkyl or optionally substituted C 2-6 alkenyl Group; more preferably a C 2-5 alkyl group, more preferably -CH 2 -CH 2
  • X 1 is CO, S(O) 2 or P(O)(OR"), preferably CO;
  • X 2 is NH
  • X 3 is CO, S(O) 2 or P(O)(OR"'), preferably CO;
  • X 4 is O or NH
  • R 4 is selected from:
  • R 41 and a R 41 '-O-, R 41' -C (O) O- or R 41 '-C (O) NH- substituted with R 41;
  • R 41 , R 41 ' , R 42 and R 43 are each independently selected from: C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13 -17 alkyl or C 7-15 alkyl; and C 5-25 alkenyl, preferably C 7-23 alkenyl, C 9-21 alkenyl, C 11-19 alkenyl, C 13-17 alkenyl or C 7-15 alkenyl; and
  • R 2 is an optionally substituted C 1-6 alkyl group, preferably a C 2-5 alkyl group, more preferably -CH 2 -CH 2 -;
  • X 1 is CO
  • X 2 is NH
  • X 3 is CO
  • X 4 is O
  • X 5 is CO
  • R 4 is and
  • R 42 and R 43 are each independently selected from: C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13-17 alkyl or C 7- 15 alkyl.
  • a peptide wherein when m is 1, the N-terminus of the peptide is connected to L in the general formula (II) or X 1 in the general formula (III), and the C-terminus of the peptide is connected to the general formula ( The M in II) or the X 4 in the general formula (IV) are connected;
  • the peptides described in items (1) and (2) above are formed from 2 to 20 identical or different amino acids;
  • the peptide is a dipeptide represented by the general formula (IX):
  • the part additionally contains oligosaccharides, -(CH 2 ) n -and/or -(CH 2 CH 2 O) n -;
  • the part may be selected from:
  • Each R Z1 is independently selected from: H, optionally substituted C 1-12 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl, such as methyl);
  • Each R Z2 is independently selected from: H; C 1-6 alkyl (preferably C 1-4 alkyl); is selected from SH, SCH 3 , NH 2 , OH, COOH, CONH 2 , guanidino, optionally One or more substitutions of substituted C 6-10 aryl (preferably phenyl, 4-OH-phenyl, biphenyl) and optionally substituted 5- to 10-membered heteroaryl (preferably imidazole, indole) Group substituted C 1-6 alkyl; C 3-10 cycloalkyl (preferably cyclohexyl); and C 6-10 aryl (preferably phenyl);
  • n is an integer selected from 1-10, such as 1, 2, 3, 4, 5, 6 or 7;
  • Z is selected from:
  • n 1 and X 4 is a direct bond, O or NH.
  • R 2 is selected from: optionally substituted C 1-6 alkyl (such as C 2-5 alkyl) and optionally substituted C 2-6 alkenyl, -(CH 2 CH 2 O) j- (optionally substituted C 1-6 alkyl)-(preferably-(CH 2 CH 2 O) 2 -CH 2 -), -(optionally substituted C 1-6 alkyl)-C 3-6 cycloalkyl-(preferably -CH 2 -Cyclohexane-), -O- (optionally substituted C 1-6 alkyl) -, -NH- (optionally substituted C 1-6 alkyl) -, -O- (optional Substituted C 2-6 alkenyl)-, -NH-(optionally substituted C 2-6 alkenyl)-; preferably optionally substituted C 1-6 alkyl or optionally substituted C 2-6 alkenyl Group; more preferably a C 2-5 alkyl group, more preferably -CH 2 -CH 2
  • X 1 is O, NH, CO, S(O) 2 or P(O)(OR");
  • R 4 is selected from:
  • R 41 and a R 41 '-O-, R 41' -C (O) O- or R 41 '-C (O) NH- substituted with R 41;
  • R 41 , R 41 ' , R 42 and R 43 are each independently selected from: C 5-25 alkyl, preferably C 7-23 alkyl, C 9-21 alkyl, C 11-19 alkyl, C 13 -17 alkyl or C 7-15 alkyl; and C 5-25 alkenyl, preferably C 7-23 alkenyl, C 9-21 alkenyl, C 11-19 alkenyl, C 13-17 alkenyl or C 7-15 alkenyl; and
  • X 1 is CO, S(O) 2 or P(O)(OR"), preferably CO, and X 4 is O or NH; or
  • X 1 is O or NH, preferably NH, and X 4 is CO, S(O) 2 or P(O)(OR"'), preferably CO.
  • R 4 is selected from: R 41, and a R 41 '-O-, R 41' -C (O) O- and R 41 '-C (O) NH- substituted with R 41.
  • X 1 is O or NH, preferably NH
  • X 4 is CO, S(O) 2 or P(O)(OR"'), preferably CO;
  • R 4 is selected from optionally substituted groups selected from the following:
  • X 1 is CO, S(O) 2 or P(O)(OR"), preferably CO;
  • X 4 is O
  • R 4 is selected from the following optionally substituted groups:
  • R 41 , R 41 ' , R 42 and R 43 are each independently selected from C 7 alkyl, C 15 alkyl, C 17 alkene Group, C 19 alkenyl, C 21 alkenyl and C 23 alkenyl, preferably: n-octyl, n-pentadecyl,
  • albumin is selected from the group consisting of human serum albumin (HSA), recombinant human albumin (rHA), bovine serum albumin, and porcine serum albumin.
  • HSA human serum albumin
  • rHA recombinant human albumin
  • bovine serum albumin bovine serum albumin
  • porcine serum albumin Protein; for example, the albumin includes the amino acid sequence shown in SEQ ID NO:1.
  • Q is the S atom of HSA or rHA in the sulfhydryl group corresponding to the cysteine residue at position 34 of SEQ ID NO:1;

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Abstract

L'invention concerne une albumine modifiée hydrophobiquement, son procédé de préparation, et une application de celle-ci. L'albumine modifiée hydrophobiquement est obtenue par introduction d'un groupe hydrophobe sur le site d'un groupe sulfhydryle radical de l'albumine. L'albumine modifiée hydrophobiquement peut être utilisée en guise de véhicule pour encapsuler des médicaments faiblement solubles dans l'eau ou des substances actives cosmétiques. L'invention concerne également une composition de véhicule comprenant l'albumine modifiée hydrophobiquement, un médicament ou une composition cosmétique comprenant l'albumine modifiée hydrophobiquement ou la composition de véhicule, et un modificateur pour préparer l'albumine modifiée hydrophobiquement.
PCT/CN2021/078980 2020-03-06 2021-03-04 Albumine modifiée de manière hydrophobe, son procédé de préparation et son application WO2021175275A1 (fr)

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WO2007071068A1 (fr) * 2005-12-22 2007-06-28 Conjuchem Biotechnologies Inc. Procede de production de conjugues d'albumine preformes et agent therapeutique
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CN102172404A (zh) * 2011-02-28 2011-09-07 中国药科大学 烷基化重组人血清白蛋白及其药学组合物的制备和应用
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US20110218156A1 (en) * 2010-02-04 2011-09-08 Alexander Chucholowski Molecular entities for binding, stabilization and cellular delivery of negatively charged molecules
CN102266288B (zh) * 2011-07-14 2012-11-21 四川大学 一种基于胆固醇修饰的还原敏感性肿瘤靶向脂质体
CN108309938B (zh) * 2018-02-14 2021-06-01 沈阳药科大学 主动定制白蛋白冕的药物传递载体及其在药学中的应用

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WO2005103087A1 (fr) * 2004-04-23 2005-11-03 Conjuchem Biotechnologies Inc. Procede de purification de conjugues d'albumine
WO2007071068A1 (fr) * 2005-12-22 2007-06-28 Conjuchem Biotechnologies Inc. Procede de production de conjugues d'albumine preformes et agent therapeutique
CN101543630A (zh) * 2009-04-20 2009-09-30 中国药科大学 白蛋白两亲性衍生物及其药学组合物的制备和应用
CN102172404A (zh) * 2011-02-28 2011-09-07 中国药科大学 烷基化重组人血清白蛋白及其药学组合物的制备和应用
CN103360609A (zh) * 2013-07-16 2013-10-23 天津大学 一种新型的双亲性的蛋白质-高分子键合体及其制备方法

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CN114591386A (zh) * 2022-05-10 2022-06-07 深圳厚存纳米药业有限公司 一种含尿苷衍生物的纳米粒、核酸纳米复合物及其制备方法和用途

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