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PH response type anti-tumor prodrug by using polyethylene glycol-b-poly-epsilon-caprolactone as vector and preparation method thereof

A polyethylene glycol and anti-tumor drug technology, applied in the field of biomedicine, can solve the problems of low drug bioavailability, high drug loading capacity of polymer carriers, good biocompatibility, etc. Release, good biocompatibility

Inactive Publication Date: 2015-08-26
XIANGTAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] For anti-tumor drugs such as polymer carrier anti-tumor prodrugs synthesized in the prior art, they can only be bonded to the terminal functional groups of the carrier, and the prepared prodrugs have low drug loading, especially the existing prodrugs are generally linked by ester bonds. On the polymer carrier, there is slow hydrolysis in the tumor microenvironment, which leads to the low bioavailability of the drug by the human body. A bond-linked pH-responsive anti-tumor prodrug, which is acid-responsive and can be released quickly in the tumor microenvironment, greatly improving the utilization efficiency of anti-tumor drugs, and the polymer carrier has high drug loading and degradability Good, good biocompatibility

Method used

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  • PH response type anti-tumor prodrug by using polyethylene glycol-b-poly-epsilon-caprolactone as vector and preparation method thereof
  • PH response type anti-tumor prodrug by using polyethylene glycol-b-poly-epsilon-caprolactone as vector and preparation method thereof
  • PH response type anti-tumor prodrug by using polyethylene glycol-b-poly-epsilon-caprolactone as vector and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] 1. Preparation of α-bromo ε-caprolactone monomer

[0073] Weigh 38.14g of bromosuccinimide (NBS), 20.00g of cyclohexanone, 1.54g of ammonium acetate, and 300mL of anhydrous ether into a 1000mL round bottom flask, add a magnet to stir, and react at room temperature for 1h. After the reaction is completed, filter, wash with distilled water three times, and separate through a column to obtain the product α-position bromocyclohexanone. Weigh 17.70 g of the obtained α-position bromocyclohexanone and 20.64 g of m-chloroperoxybenzoic acid (m-CPBA) and dissolve them in a 500 mL single-necked flask with 300 mL of dichloromethane, stir and react at room temperature for 48 h; filter after the reaction, and the filtrate Place in the refrigerator overnight and then filter out the precipitated m-chlorobenzoic acid. The filtrate was washed three times with saturated sodium thiosulfate, sodium bicarbonate and distilled water respectively. After the organic phase was dried and concentra...

Embodiment 2

[0081] Steps 1 and 2 The method for synthesizing polyethylene glycol-b-poly α-position brominated ε-caprolactone amphiphilic block copolymer is the same as that of Example 1.

[0082] 3. Functionalization of antitumor drug doxorubicin

[0083] Weigh 116mg of doxorubicin hydrochloride and dissolve it in 50mL of anhydrous methanol, dissolve 48mg of 3-mercaptopropionylhydrazide in 2mL of anhydrous methanol, add it dropwise into the reaction bottle under the protection of argon, and react for 24 hours at room temperature in the dark, and the resulting functionalized Doxorubicin was settled with anhydrous ether, and centrifuged to obtain a dark red solid (NMR see Image 6 ).

[0084] 4. Preparation of pH-responsive doxorubicin prodrug

[0085] Weigh 75 mg of polyethylene glycol-b-polyα-bromoε-caprolactone amphiphilic block copolymer, 75 mg of functionalized doxorubicin, dissolve in 5 mL of anhydrous DMF, add triethylene glycol dropwise under argon protection Amine 12mg, reaction...

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Abstract

The invention discloses a pH response type anti-tumor prodrug by using polyethylene glycol-b-poly-epsilon-caprolactone as a vector and a preparation method thereof. The preparation method of the pH response type anti-tumor prodrug comprises the following steps: using methoxypolyethylene glycol as an initiator, and triggering ring opening polymerization of alpha-site bromo-epsilon-caprolactone to obtain a polyethylene glycol-b-poly-alpha-bromo-epsilon-caprolactone amphipathic segmented copolymer; further enabling the obtained copolymer to take a thio-bromine click reaction with mercapto-functionalized antitumor drug molecules to obtain the pH response type anti-tumor prodrug. The pH response type anti-tumor prodrug has the amphipathic structure, can be assembled to form stable nanomicelles, and meanwhile is high in drug loading capacity, good in biodegradability and good in biocompatibility; particularly, the antitumor drug is connected with a polymer carrier through an acylhydrazone bond; the pH response type anti-tumor prodrug has the acid responsiveness, can be quickly released in the tumor microenvironment, and greatly improves the utilization efficiency of the antitumor drug; in addition, the preparation method of the prodrug is simple, mild in process conditions, free of introducing a high-toxicity catalyst in the preparation process, and low in toxic and side effects.

Description

technical field [0001] The invention relates to a preparation method of a pH-responsive anti-tumor prodrug using polyethylene glycol-b-polyε-caprolactone amphiphilic block copolymer as a carrier, and belongs to the technical field of biomedicine. Background technique [0002] Paclitaxel is an antineoplastic drug extracted from Pacific yew tree and yew tree. It is one of the most widely used antineoplastic drugs at present. It is mainly used in the treatment of breast cancer, ovarian cancer and bladder cancer in clinical practice. Traditional paclitaxel preparations are used for tumor chemotherapy. Although the drug has a certain inhibitory or killing effect on tumor tissues or cells, it also causes damage to normal human tissue cells because it cannot distinguish between normal tissues and tumor tissues, resulting in toxic side effects. In addition, paclitaxel also has disadvantages such as strong hydrophobicity and short half-life, which greatly limit its clinical applicati...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K45/06A61K31/704A61K31/337A61P35/00C08G65/48A61K47/59
Inventor 张雪飞李德珊
Owner XIANGTAN UNIV
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