Two-block double-sensitive camptothecin polymer prodrug taking benzeneboronic ester as connecting unit and preparation method of two-block double-sensitive camptothecin polymer prodrug

A technology of phenylboronic acid ester and linking unit, which is applied in the field of nanomedicine and new materials, and biomedical technology, and can solve problems such as unfavorable cell endocytosis

Inactive Publication Date: 2019-07-09
EAST CHINA NORMAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0006] The drug-loaded micelles constructed by traditional block polymers usually use polyethylene glycol (PEG) as the hydrophilic segment, which can make full use of the high permeability and long retention effect (EPR effect) of solid tumors to enrich the drug in the tumor. However, due to the presence of PEG shells, this ty

Method used

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  • Two-block double-sensitive camptothecin polymer prodrug taking benzeneboronic ester as connecting unit and preparation method of two-block double-sensitive camptothecin polymer prodrug
  • Two-block double-sensitive camptothecin polymer prodrug taking benzeneboronic ester as connecting unit and preparation method of two-block double-sensitive camptothecin polymer prodrug
  • Two-block double-sensitive camptothecin polymer prodrug taking benzeneboronic ester as connecting unit and preparation method of two-block double-sensitive camptothecin polymer prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Synthesis of PEG-3,4-DA

[0089] Weigh 3,4-dihydroxyphenylacetic acid (0.126g, 0.750mmol) and dissolve it in 25mL of anhydrous dichloromethane, disperse it by ultrasonic to form a suspension, add 1-ethyl-(3-dimethylamino Propyl)carbodiimide hydrochloride (0.154g, 0.800mmol), 1-hydroxybenzotriazole (0.108g, 0.800mmol), N,N-diisopropylethylamine (0.260mL, 1.500mmol ), after 0.5h, add PEG-NH under nitrogen protection 2 (1.000g, 0.500mmol), the reaction device was protected from light, reacted overnight at room temperature, concentrated, added pure water to dissolve, extracted several times with dichloromethane, dried the organic phase with anhydrous sodium sulfate, concentrated the filtrate and mixed the sample and purified it through a silica gel column. The mobile phase was mixed with dichloromethane and methanol in a certain volume ratio (30:1). After the purified product was concentrated, it was added to glacial ether to precipitate, and the white precipitate was obt...

Embodiment 2

[0094] Synthesis of PEG-BC

[0095] Weigh 3-aminophenylboronic acid (0.191g, 1.390mmol) and 200mL redistilled toluene into a 500mL single-necked flask, ultrasonically promote its dissolution, add PEG-3,4-DA (0.300g, 0.139mmol) under nitrogen protection , react at 120°C for 5 hours, concentrate the reaction solution, add 30 mL of anhydrous tetrahydrofuran to dissolve, transfer the tetrahydrofuran solution to a dialysis bag with a molecular weight cut-off of 1000, dialyze the anhydrous tetrahydrofuran for 5 hours, add it dropwise to 100 mL of ice ether, wash and filter After three times, 0.360 g of light yellow powder PEG-BC was obtained with a yield of 87%.

[0096] The structural formula of the PEG-BC is shown in formula (2);

[0097]

[0098] Among them, x=44.

Embodiment 3

[0100] Synthesis of CPT-ss-OH

[0101] Weigh camptothecin (700mg, 2mmol), triphosgene (414mg, 1.4mmol) and 100mL of anhydrous dichloromethane in a reaction flask, after 0.5h, add 4-dimethylaminopyridine (1.464g , 12mmol) and 2,2'-dithiodiethanol (1.540g, 10mmol), after reacting at room temperature for 5h, the reaction solution became clear. Extract three times with saturated NaCl aqueous solution, dry the organic phase with anhydrous NaSO4, after filtering, the filtrate is concentrated and mixed and purified by a silica gel column. The mobile phase is that dichloromethane and methanol are mixed in a certain volume ratio (300:1). Pale yellow powder CPT-ss-OH 0.95g, yield 90%.

[0102] The structural formula of the Boc-(Glu-ss-CPT)-OtBu is shown in formula (3);

[0103]

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Abstract

The invention discloses a two-block double-sensitive camptothecin polymer prodrug taking benzeneboronic ester as a connecting unit and a preparation method of the two-block double-sensitive camptothecin polymer prodrug. The two-block double-sensitive camptothecin polymer prodrug takes benzeneboronic catechol ester (BC) as the connecting unit, polyethylene glycol-polyglutamate disulfide ethanol camptothecin two-block polymer (PEG-BC-PGlu-ss-CPT) is synthesized, thereby constructing a self-assembly prodrug nano micelle, namely PEG-BC@PGlu-ss-CPT; PEG-BC is taken as a macroinitiator an initiatorto perform an open-loop polymerization reaction on a reduction-sensitive camptothecin monomer to obtain the two-block double-sensitive camptothecin polymer prodrug PEG-BC-PGlu-ss-CPT taking the benzeneboronic ester as the connecting unit. The prepared prodrug micelle can improve the solubility of camptothecin and improve the stability of a camptothecin lactone ring so as to overcome the limitationof camptothecin clinical treatment, and the prodrug micelle has a good drug release property and dual sensitive properties of acid sensitivity and reduction sensitivity.

Description

technical field [0001] The invention belongs to the fields of biomedical technology, nanomedicine and new materials, and specifically relates to a synthesis method of a two-block bisensitized camptothecin polymer prodrug with phenylboronic acid ester as a connecting unit and a self-assembled prodrug nano-micelle Preparation method and application. Background technique [0002] Traditional chemotherapy drugs have achieved great success in the treatment of tumors, but there are many limitations that limit the further improvement of their clinical efficacy, such as serious side effects, poor selectivity, and tumor cells are prone to drug resistance. Camptothecin (CPT) is a tryptophan-terpene alkaloid anticancer drug, which has a significant effect on the treatment of various malignant tumors. It inhibits DNA by interacting with DNA topoisomerase I. replication, transcription and mitosis. The closed lactone ring form in its molecular structure is an effective form with tumor s...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K31/4745A61K47/64A61P35/00C08G65/334C08G65/337C08G65/333C08G65/332
CPCA61K9/1075A61K31/4745A61K47/64A61P35/00C08G65/3326C08G65/33306C08G65/33396C08G65/3348C08G65/337
Inventor 余家会黄钰淑徐艳昀伍彦仟尤东磊
Owner EAST CHINA NORMAL UNIVERSITY
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