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Amphiphilic dextran derivative carrier targeting tumor-associated fibroblasts and preparation and application of pharmaceutical composition of amphiphilic dextran derivative carrier

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: 2021-06-01
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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  • Amphiphilic dextran derivative carrier targeting tumor-associated fibroblasts and preparation and application of pharmaceutical composition of amphiphilic dextran derivative carrier
  • Amphiphilic dextran derivative carrier targeting tumor-associated fibroblasts and preparation and application of pharmaceutical composition of amphiphilic dextran derivative carrier
  • Amphiphilic dextran derivative carrier targeting tumor-associated fibroblasts and preparation and application of pharmaceutical composition of amphiphilic dextran derivative carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]Carboxylated glucan-FAPα response peptide - octade amine (DEX-PEPTIDE-C18The preparation method is as follows:

[0045](1) 2000 mg of glucan was dissolved in dimethyl sulfoxide to obtain a dextran solution; 380 mg of glutanedhydride, 10 mgDMAP was added to the glucan solution, and at normal temperature reacted for 24 h. The reaction liquid was added dropwise to the excess of icy ethanol to form a precipitate, and the precipitate was collected three times using ice ethanol, and after reconstituted, dialysis (MWCO = 7000) 72h, lyophilized, ie, carboxylated glucan intermediate (DEX- COOH);

[0046](2) Take 132 mgboc protected peptide connection arms BOC-SER-GLY-PRO, dissolved in 10 mLDMF; 108 mg of octade amine, 55 mGhobt and 77 mgedc, reaction for 24 h, mixed with reaction mixture, mixed with reaction liquid, extract of ethyl acetate The three times were washed three times with dilute hydrochloric acid, sodium hydrogencarbonate solution and saturated brine. After filtration of anhydro...

Embodiment 2

[0049]The preparation method of carboxylated glucan-FAPα response peptide-peptide-doca is as follows:

[0050](1) 2000 mg of glucan was dissolved in dimethyl sulfoxide to obtain a dextran solution; 334 mg of butyleneic anhydride, 10 mgDMAP was added to the glucan solution, and the temperature reaction was at 24 h. The reaction liquid was added dropwise to the excess of icy ethanol to form a precipitate, and the precipitate was collected three times using ice ethanol, and after reconstituted, dialysis (MWCO = 7000) 72h, lyophilized, ie, carboxylated glucan intermediate (DEX- COOH);

[0051](2) 1000 mg of deoxycholic acid (DOCA) was dissolved in 20 ml of tetrahydrofuran, and 381 mGNHS and 628 mg DCC were added. After 12 h, the white precipitate was removed, and the additional cyclohexane was added to produce a precipitate, and the white precipitate was collected by filtration. Cholic acid-activated ester intermediate; Take 1000 mg of the activated ester intermediate dissolved in 5 mln, N-di...

Embodiment 3

[0055]Carboxylated glucan-FAPα response peptide-lauryl (DEX-PEPTIDE-C12The preparation method is as follows:

[0056](1) 2000 mg of glucan was dissolved in dimethyl sulfoxide to obtain a dextran solution; 427 mg of adipic anhydride, 10 mgDMAP was added to the glucan solution, and the temperature was attenuated for 24 h. The reaction liquid was added dropwise to the excess of icy ethanol to form a precipitate, and the precipitate was collected three times using ice ethanol, and after reconstituted, dialysis (MWCO = 7000) 72h, lyophilized, ie, carboxylated glucan intermediate (DEX- COOH);

[0057](2) Take 167 mgboc protected peptide connection arms BOC-ILE-GLY-PRO-ALA, dissolved in 10 mLDMF; 74 mg of lauryride, 55 mgHobt and 77 mgedc, reaction for 24 h, mixed with reaction mixture, mixed with reaction mixture, extract of ethyl acetate The product was washed three times with dilute hydrochloric acid, sodium hydrogencarbonate solution and saturated brine. After deposurizing sodium sulfate and...

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Abstract

The invention provides an amphiphilic dextran derivative carrier for targeting tumor-associated fibroblasts and preparation and application of a pharmaceutical composition of the amphiphilic dextran derivative carrier. The amphiphilic dextran derivative carrier comprises a derivative skeleton modified by hydrophilic dextran carboxyl, an FAP-alpha responsive peptide fragment connecting arm and a hydrophobic group molecule. The amphiphilic derivative is self-assembled in an aqueous solution to form nanoparticles, and molecules with pharmacological activity can be physically loaded for tumor treatment. The amphiphilic dextran derivative carrier is mainly characterized in that: (1) after the nanoparticles reach a focus part, a specific peptide fragment connecting arm can be subjected to enzyme digestion by FAP-alpha which is specifically and highly expressed on the surface of tumor-associated fibroblasts, so that the nanoparticles are rapidly degraded; and (2) the pharmacological active molecules which are physically loaded are quickly released from the disintegrated nanoparticles, tumor-associated fibroblasts can be effectively killed or the function thereof can be inhibited, the physical barrier of a tumor matrix can be weakened, and the permeation of an anti-tumor preparation can be promoted when the nano-particles are combined with other anti-tumor preparations, so that the treatment effect of the anti-tumor preparation can be effectively improved.

Description

Technical field[0001]The present invention belongs to the field of pharmaceutical preparations, and is involved in the preparation and application of the amphiphilic glucan derivative carrier to target tumor-related fibroblasts and their pharmaceutical compositions.Background technique[0002]The occurrence and development of tumors is a dynamic process of tumor cells and their microenvironmental interactions. Cancer-Associated Fibroblasts (CAFS) is the main composition ingredient of tumor microenvironment, which has promoted various common cancers through secretion cytokines, including pancreatic cancer, ovarian cancer, colorectal cancer and breast cancer. Wait. In addition, tumor-associated fibroblasts are the main producers of extracellular matrix (fibronectin, collagen, and α smooth myocardin), which constitutes a dense physical barrier around tumor cells, and severely hinders the penetration of clinical chemotherapy drugs. Cause chemotherapy resistance. Therefore, there is a deve...

Claims

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Application Information

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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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