Preparation and application of amphiphilic glucan derivative carrier targeting tumor-associated fibroblasts and its pharmaceutical composition

A technology related to fibroblasts and tumors, which is applied in the field of preparation and application of amphiphilic dextran derivative carriers and their pharmaceutical compositions, and can solve problems such as lack of responsiveness, slow drug release speed, and hindrance to drug efficacy , to achieve the effects of improving solubility, promoting penetration, good biocompatibility and stability

Active Publication Date: 2022-03-18
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the lack of responsiveness, the multi-core structure formed by amphiphilic dextran and the high compatibility of the hydrophobic region with poorly soluble drugs, the nanoparticles are highly stable, resulting in slow drug release and hindering the drug effect.

Method used

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  • Preparation and application of amphiphilic glucan derivative carrier targeting tumor-associated fibroblasts and its pharmaceutical composition
  • Preparation and application of amphiphilic glucan derivative carrier targeting tumor-associated fibroblasts and its pharmaceutical composition
  • Preparation and application of amphiphilic glucan derivative carrier targeting tumor-associated fibroblasts and its pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Carboxylated dextran-FAPα-responsive peptide-octadecylamine (Dex-peptide-C 18 ) is prepared as follows:

[0045] (1) Dissolve 2000 mg of dextran in dimethyl sulfoxide to obtain a dextran solution; add 380 mg of glutaric anhydride and 10 mg of DMAP into the dextran solution, and react at room temperature for 24 hours. The reaction solution was added dropwise to excess ice ethanol to form a precipitate. The collected precipitate was washed three times with ice ethanol, redissolved in water, dialyzed (MWCO=7000) for 72 hours, and freeze-dried to obtain the carboxylated dextran intermediate (Dex- COOH);

[0046] (2) Take 132 mg of Boc-Ser-Gly-Pro, a peptide linker protected by Boc, and dissolve it in 10 mL of DMF; add 108 mg of octadecylamine, 55 mg of HOBT and 77 mg of EDC successively, react for 24 hours, add an appropriate amount of water to mix with the reaction solution, and extract the product with ethyl acetate , washed three times with dilute hydrochloric acid, so...

Embodiment 2

[0049] The preparation method of carboxylated dextran-FAPα response peptide-deoxycholic acid (Dex-peptide-DOCA) is as follows:

[0050] (1) Dissolve 2000 mg of dextran in dimethyl sulfoxide to obtain a dextran solution; add 334 mg of succinic anhydride and 10 mg of DMAP into the dextran solution, and react at room temperature for 24 hours. The reaction solution was added dropwise to excess ice ethanol to form a precipitate. The collected precipitate was washed three times with ice ethanol, redissolved in water, dialyzed (MWCO=7000) for 72 hours, and freeze-dried to obtain the carboxylated dextran intermediate (Dex- COOH);

[0051] (2) Dissolve 1000 mg of deoxycholic acid (DOCA) in 20 mL of tetrahydrofuran, add 381 mg of NHS and 628 mg of DCC respectively, react for 12 hours, remove the white precipitate by suction filtration, add excess cyclohexane to produce a precipitate, and collect the white precipitate by suction filtration to obtain deoxygenation Cholic acid-activated e...

Embodiment 3

[0055] Carboxylated dextran-FAPα-responsive peptide-laurylamine (Dex-peptide-C 12 ) is prepared as follows:

[0056] (1) Dissolve 2000 mg of dextran in dimethyl sulfoxide to obtain a dextran solution; add 427 mg of adipic anhydride and 10 mg of DMAP into the dextran solution, and react at room temperature for 24 hours. The reaction solution was added dropwise to excess ice ethanol to form a precipitate. The collected precipitate was washed three times with ice ethanol, redissolved in water, dialyzed (MWCO=7000) for 72 hours, and freeze-dried to obtain the carboxylated dextran intermediate (Dex- COOH);

[0057] (2) Take 167 mg of Boc-Ile-Gly-Pro-Ala, a peptide linker protected by Boc, and dissolve it in 10 mL of DMF; add 74 mg of laurylamine, 55 mg of HOBT and 77 mg of EDC successively, react for 24 hours, add an appropriate amount of water to mix with the reaction solution, and extract with ethyl acetate The product was washed three times with dilute hydrochloric acid, sodiu...

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Abstract

The invention provides an amphiphilic dextran derivative carrier targeting tumor-associated fibroblasts and the preparation and application of a pharmaceutical composition thereof, including a derivative backbone modified by a carboxyl group of a hydrophilic dextran, and a FAP-α-responsive Peptide Tether and Hydrophobic Molecules. The amphiphilic derivative self-assembles in an aqueous solution to form nanoparticles, and can be physically loaded with pharmacologically active molecules for tumor therapy. Its main features are: 1) After the nanoparticles reach the lesion site, the specific peptide linker can be cleaved by FAP-α, which is specifically and highly expressed on the surface of tumor-associated fibroblasts, so that the nanoparticles are rapidly degraded; 2) through Physically loaded pharmacologically active molecules are quickly released from the disintegrated nanoparticles, which can effectively kill or inhibit the function of tumor-associated fibroblasts, thereby weakening the physical barrier of the tumor matrix, and in combination with other anti-tumor agents, it helps to promote anti-tumor agents Penetration, thereby effectively improving the therapeutic effect of anti-tumor agents.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to the preparation and application of an amphiphilic dextran derivative carrier targeting tumor-associated fibroblasts and a pharmaceutical composition thereof. Background technique [0002] The occurrence and development of tumors is a dynamic process of the interaction between tumor cells and their microenvironment. Cancer-associated fibroblasts (CAFs) are the main components of the tumor microenvironment, which can promote many common cancers by secreting cytokines, including pancreatic cancer, ovarian cancer, colorectal cancer and breast cancer Wait. In addition, tumor-associated fibroblasts are major producers of extracellular matrix (fibronectin, collagen, and α-smooth muscle actin), constituting a dense physical barrier around tumor cells that severely impedes the penetration of clinical chemotherapeutic drugs , resulting in chemotherapy resistance. Therefore, the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08B37/02A61K9/51A61K47/36A61K47/18A61K47/28A61K45/00A61K31/357A61K31/352A61K31/05A61P35/00
CPCC08B37/0009A61K9/5161A61K9/5169A61K9/5123A61K45/00A61K31/357A61K31/352A61K31/05A61P35/00
Inventor 霍美蓉殷婷婕周新源张盼
Owner CHINA PHARM UNIV
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