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Chitosan-platinum (IV) prodrug conjugate and preparation method thereof

A prodrug, chitosan technology, used in drug combinations, pharmaceutical formulations, antitumor drugs, etc., can solve problems such as drug concentration fluctuations, toxic side effects, etc., to enhance tissue effects, reduce toxic side effects, and improve blood circulation time. Effect

Inactive Publication Date: 2015-05-06
YANCHENG INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Traditional small molecule drugs, including metal platinum drugs, are easily eliminated by metabolism after diffusion and distribution in the body, resulting in fluctuations in drug concentration in the body and corresponding toxic and side effects

Method used

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  • Chitosan-platinum (IV) prodrug conjugate and preparation method thereof
  • Chitosan-platinum (IV) prodrug conjugate and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Example 1 Chitosan-platinum (IV) prodrug conjugate

[0027] 1) Synthesis of 4-pentynoic acid modified chitosan (alkynyl-CS)

[0028] Under the action of the combined catalyst, the amino group of chitosan and the carboxyl group of 4-pentynoic acid form an amide bond through amide chemical reaction to obtain alkynyl functionalized chitosan:

[0029] Weigh chitosan (degree of deacetylation 89%, M w =10kDa) 0.5g (2.73mmol amino) and 0.268g (2.73mmol) of 4-pentynoic acid are dissolved in 50mL 0.1M PBS (pH=5) solution, degassed, protected by nitrogen, and then slowly added EDC 0.55 g (2.73mmol) and NHS 0.32g (2.73mmol). After stirring and reacting at room temperature for 18 hours, the reaction solution was transferred to a dialysis bag with a molecular weight cut-off of 3000Da, and then dialyzed with double distilled water for 48 hours at low temperature, and then lyophilized to obtain 0.55g Target product (87%).

[0030] 2) Synthesis of azide anhydride functionalized platinum (IV) ...

Embodiment 2

[0034] Example 2 Chitosan-platinum (IV) prodrug conjugate

[0035] 1) Synthesis of 4-pentynoic acid modified chitosan (alkynyl-CS)

[0036] Under the action of the combined catalyst, the amino group of chitosan and the carboxyl group of 4-pentynoic acid form an amide bond through amide chemical reaction to obtain alkynyl functionalized chitosan:

[0037] Weigh chitosan (degree of deacetylation 89%, M w =10kDa) 1.0g (5.5mmol amino) and 0.73g (8.2mmol) of 4-pentynoic acid are dissolved in 50mL 0.1M PBS (pH=6) solution, degassed, protected by nitrogen, and then slowly added EDC 1.7 g (8.2mmol) and NHS1.0g (8.2mmol). After stirring and reacting at room temperature for 20 hours, the reaction solution was transferred to a dialysis bag with a molecular weight cut-off of 3000 Da, dialyzed with double distilled water at low temperature for 48 hours, and lyophilized to obtain 0.97 g Target product (83%).

[0038] 2) Synthesis of azide anhydride functionalized platinum (IV) prodrug

[0039] Weig...

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Abstract

The invention belongs to the technical field of polymer drugs, and particularly relates to a chitosan-platinum (IV) prodrug conjugate and a preparation method thereof. The method comprises the following steps: firstly, carrying out amide chemical reaction on chitosan and 4-pentyne acid under the action of a combined catalyst NHS / EDC to obtain alkynyl functionalized chitosan, and then carrying out click chemistry reaction together with a nitrine-modified Pt (IV) coordination compound to obtain the chitosan-platinum (IV) prodrug conjugate. The preparation method provided by the invention has the advantages of mild reaction condition, good selectivity, high efficiency and controllability; the drug leakage caused by incomplete reaction can be reduced; the obtained conjugate enters a tumor cell, and is transformed into a Pt (II) coordination compound under the action of reducing substances in the cell, so as to relatively well act on DNA to kill the tumor cells; and meanwhile, a simple and effective pathway is provided for preparation of targeted controllable light-response polymer drug conjugates.

Description

Technical field [0001] The invention belongs to the technical field of polymer medicines, and specifically relates to a chitosan-platinum (IV) prodrug conjugate and a preparation method thereof. Background technique [0002] Cancer is a major disease threatening human life and health. At present, the main treatment methods for cancer patients are surgery, radiotherapy and chemotherapy. Chemotherapy is an important treatment method. Among various chemotherapy drugs, platinum anti-cancer drugs occupy a very important role. The annual usage of cisplatin accounts for more than half, and the platinum anticancer drug with relatively large clinical usage is cisplatin. Cisplatin, a platinum (II) complex, is a non-cell cycle specific anti-cancer drug that can bind to DNA to form adducts, disrupt DNA replication, and lead to cell apoptosis. And it has a strong broad-spectrum anti-cancer effect, which can be used in synergy with other anti-tumor drugs, such as ovarian cancer, prostate canc...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/282A61P35/00
Inventor 张怀红孙柏旺孙玉仓辉蔡照胜
Owner YANCHENG INST OF TECH
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