Amphiphilic stellate camptothecin polymer prodrug and preparation method thereof

A technology of camptothecin and polymer, which is applied in the field of amphiphilic star camptothecin polymer prodrug and its preparation, can solve the problems of normal cell and tissue damage, drug release in advance, etc., to improve drug loading, High drug loading capacity, solving water solubility and combining effects of nano drug delivery

Pending Publication Date: 2019-09-13
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently CN103524519A discloses a class of linear camptothecin polymer prodrugs, which realizes the selective release of camptothecin drugs in response to the tumor microenvironment, but is limited by the critical micelle concentration (CMC). The nanomicelles obtained by self-assembly are highly sensitive to the environment (such as: organic solvent, polymer concentration, temperature and pH value, etc.), which can easily lead to early release of drugs and cause unnecessary damage to normal cells and tissues

Method used

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  • Amphiphilic stellate camptothecin polymer prodrug and preparation method thereof
  • Amphiphilic stellate camptothecin polymer prodrug and preparation method thereof
  • Amphiphilic stellate camptothecin polymer prodrug and preparation method thereof

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Embodiment 1

[0037] In the embodiment of the present invention, the steps of preparing the reduction-sensitive CD-PCPT-POEGMA amphiphilic star camptothecin polymer prodrug are as follows:

[0038] (1) Preparation of CD-Br: Under argon (Ar) atmosphere, first dissolve cyclodextrin in N-methylpyrrolidone and cool to 0℃, then dissolve the 2-bromo in N-methylpyrrolidone Isobutyryl bromide was added dropwise to the above cyclodextrin solution under stirring, reacted at 0°C for 2 hours and then at room temperature for 48 hours, and then purified to obtain the product.

[0039] (2) Preparation of MABHD: Under the condition of temperature ≤ 0℃ and argon (Ar) atmosphere, a certain amount of methacrylic acid chloride dissolved in tetrahydrofuran is added dropwise to bis(2-hydroxyethyl) disulfide, triethyl In amine and tetrahydrofuran solution, stir overnight, wash and purify, and column chromatography to obtain pure product. Wherein, the molar ratio of BHD, triethylamine, methacryloyl chloride or acryloy...

Embodiment 2

[0045] In the embodiment of the present invention, preparation of β-CD-PCPT that does not respond to stimulation cc -POEGMA amphiphilic star camptothecin polymer prodrug, the steps are as follows:

[0046] 1) Preparation of CD-Br: Under argon (Ar) atmosphere, first dissolve CD in N-methylpyrrolidone and cool to 0℃, then dissolve 2-bromoisobutyryl in N-methylpyrrolidone Bromine was added dropwise to the CD solution with stirring, reacted at 0°C for 2 hours and then at room temperature for 48 hours, and then purified to obtain the product.

[0047] (2) Preparation of MAHDO: Under the condition of temperature ≤ 0℃ and argon (Ar) atmosphere, methacrylic chloride dissolved in a certain amount of tetrahydrofuran is added dropwise to hexahexanediol (HDO), triethylamine, and tetrahydrofuran In the solution, stir overnight, wash and purify, and column chromatography to obtain a pure product. Wherein, the molar ratio of HDO, triethylamine, methacryloyl chloride or acryloyl chloride is 5:1...

Embodiment 3

[0053] In the embodiment of the present invention, the steps of preparing the reduction-sensitive CD-PCPT-POEGMA amphiphilic star camptothecin polymer prodrug are as follows:

[0054] (1) Preparation of CD-Br: Under argon (Ar) atmosphere, first dissolve cyclodextrin in N-methylpyrrolidone and cool to 0℃, then dissolve the 2-bromo in N-methylpyrrolidone Isobutyryl bromide was added dropwise to the above cyclodextrin solution under stirring, reacted at 0°C for 2 hours and then at room temperature for 48 hours, and then purified to obtain the product.

[0055] (2) Preparation of MABHD: Under the condition of temperature ≤ 0℃ and argon (Ar) atmosphere, a certain amount of methacrylic acid chloride dissolved in tetrahydrofuran is added dropwise to bis(2-hydroxyethyl) disulfide (BHD) , Triethylamine, tetrahydrofuran solution, stir overnight, wash and purify, column chromatography to obtain a pure product. Wherein, the molar ratio of BHD, triethylamine, methacryloyl chloride or acryloyl ...

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Abstract

The present invention discloses an amphiphilic stellate camptothecin polymer prodrug and a preparation method thereof. The preparation method comprises the following steps: preparing a cyclodextrin-based stellate atom transfer radical polymerization (ATRP) initiator (CD-Br), preparing a reduction-sensitive or reduction-insensitive monomer MABHD / MAHDO, preparing a reduction-sensitive or reduction-insensitive CPT precursor, preparing a stellate polymer prodrug CD-PCPT, and then preparing the amphiphilic stellate camptothecin polymer prodrug beta-CD-PCPT-POEGMA. The obtained stellate camptothecinpolymer prodrug can self-assemble to form a drug nanomicelle, can selectively release drugs, has advantages of high micelle stability, high drug loading amount, drug release for stimulating responsecontrols, and effectively solves water solubility of hydrophobic drug molecules and characteristics of combination with nano drug delivery.

Description

Technical field [0001] The invention relates to the synthetic field of medicinal chemistry, in particular to an amphiphilic star camptothecin polymer prodrug and a preparation method thereof. Background technique [0002] Camptothecin (CPT) is a kind of plant anticancer drug extracted from Camptothecin, its CAS number: 7689-03-4, chemical structure: C 20 H 16 N 2 O 4 , Relative molecular weight: 348.43, has a good medical effect on colon cancer, stomach cancer and liver cancer. The drug's mechanism of action is to form a stable ternary dissociable complex through active camptothecin, DNA and topoisomerase I, causing DNA loss and cell death. [0003] Anti-cancer drug molecules including camptothecin generally have problems such as poor water solubility and small molecular size. In the process of drug delivery, there are low drug loading, poor blood circulation stability, low drug bioavailability, strong toxic and side effects, and low medical efficiency. And other issues. In order...

Claims

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Application Information

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IPC IPC(8): A61K47/61A61K9/107A61K31/4745A61P35/00
CPCA61K47/61A61K9/1075A61K31/4745A61P35/00
Inventor 许志刚石潇潇马晓倩白霜康跃军
Owner SOUTHWEST UNIVERSITY
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