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Block polymer with benzeneboronic acid ester as connecting unit, synthesis method and application thereof

A technology of block polymers and phenylboronic esters, which is applied in the field of nanomedicine and new materials, and biomedical technology, can solve the problems of unfavorable cell endocytosis, and achieve good drug release, low cytotoxicity, and good cell phagocytosis Effect

Inactive Publication Date: 2016-01-27
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 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 type of micelles is not conducive to endocytosis, and it is difficult for antineoplastic drugs to reach the intracellular targets in sufficient doses. The endocytosis of such micelles is usually done by adding folic acid, folic acid, and Targeting groups such as galactose or antibody modification for receptor-mediated endocytosis

Method used

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  • Block polymer with benzeneboronic acid ester as connecting unit, synthesis method and application thereof
  • Block polymer with benzeneboronic acid ester as connecting unit, synthesis method and application thereof
  • Block polymer with benzeneboronic acid ester as connecting unit, synthesis method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment one, PEG-3, the synthesis of 4-DA

[0058] Weigh 3,4-dihydroxyphenylacetic acid (0.126g, 0.750mmol), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.154g, 0.800mmol), 1-Hydroxybenzotriazole (0.108g, 0.800mmol), N,N-diisopropylethylamine (0.260ml, 1.500mmol), PEG-NH 2 (1.000g, 0.500mmol) and 30ml of anhydrous dichloromethane in a reaction flask, protected by nitrogen, reacted at room temperature for 12h, concentrated and then added ultrapure water to dissolve, extracted several times with dichloromethane, and the concentrated solution was mixed and purified by column (two Chloromethane:methanol=30:1). The purified product was concentrated and added dropwise to 50 ml of glacial ether, filtered and washed several times and then dried to obtain 0.840 g of white powder PEG-3,4-DA with a yield of 78%.

[0059] The structural formula of the PEG-3,4-DA is as shown in formula (5);

[0060]

Embodiment 2

[0061] Embodiment two, the synthesis of PEG-BC

[0062] Weigh PEG-3,4-DA (0.430g, 0.200mmol), 3-aminophenylboronic acid (0.137g, 1.000mmol), and 100ml redistilled toluene, place in Dean-Stark water removal device, heat at 120°C 8h, after concentrating, add 10ml of anhydrous tetrahydrofuran to dissolve, transfer to a dialysis bag with a molecular weight cut-off of 2000, dialyze in anhydrous tetrahydrofuran solvent for 24h, add dropwise to 50ml of glacial ether, filter and wash several times, and dry to obtain light yellow powder PEG- BC0.360g, yield 80%.

[0063] The structural formula of the PEG-BC is shown in formula (6);

[0064]

Embodiment 3

[0065] Embodiment three, the synthesis of PEG-BC-PBLG

[0066] Weigh PEG-BC (0.897g, 0.400mmol), 5-benzyl ester-L-glutamic acid-N-carboxy anhydride (BLG-NCA) (0.500g, 2.000mmol), and 30ml of anhydrous tetrahydrofuran in the reaction In the bottle, protected by nitrogen, reacted at room temperature for 12 hours, concentrated, transferred to a dialysis bag with a molecular weight cut-off of 3500, and dialyzed for 12 hours, concentrated the dialysate and added it dropwise to 50ml ice ether, filtered and washed several times, and dried to obtain the final product PEG- BC-PBLG 1.244g, yield 95%.

[0067] The structural formula of the PEG-BC-PBLG is shown in the following formula (I);

[0068]

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Abstract

The invention discloses a diblock polymer with benzeneboronic acid ester as the connecting unit. Benzeneboronic acid catechol ester (BC) is adopted as the connecting unit to synthesize PEG-BC-PBLG diblock polymer so as to construct doxorubicin loaded micelle (PEG-BC@PBLG.Dox). The invention also discloses a preparation method of the diblock polymer, and the method includes: (1) preparing the dopa derivative PEG-3, 4-DA of PEG-NH2; (2) subjecting PEG-3, 4-DA and 3-aminophenylboronic acid to dehydration condensation so as to synthesize the benzeneboronic acid ester derivative PEG-BC of PEG; and (3) using PEG-BC to perform ring opening on 5-benzyl ester-L-glutamic acid-N-carboxyanhydride (BLG-NCA), thus obtaining the diblock polymer PEG-BC-PBLG with benzeneboronic acid ester as the connecting unit. The diblock polymer prepared by the method provided by the invention can be used for construction of a nano-micelle, and has the advantages of good drug release, low cytotoxicity and good cell phagocytosis.

Description

technical field [0001] The invention belongs to the fields of biomedical technology, nanomedicine and new materials, and specifically relates to the synthesis and assembly of a two-block polymer with phenylboronic acid ester as a connecting unit and its application to the preparation of a smart drug with enhanced endocytic properties for liver cancer cells. Use of nanomicelle carriers. 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. Nano-drug carriers provide an effective way to achieve fixed-point and rapid release of chemotherapy drugs in tumor tissues, reduce damage to normal tissues and organs, and avoid drug resistance of tumor cells caused by insufficient doses of effective drugs. The intelligent nano-drug carrier s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G83/00A61K47/34A61K9/107A61K31/4745A61K31/704A61K31/7068A61K31/337A61P35/00
Inventor 余家会徐琰徐艳昀高雅
Owner EAST CHINA NORMAL UNIV
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