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A kind of nuclear cross-linked micelles prepared by a cross-linking agent containing two orthoester five-membered rings and its synthesis method and application

A synthesis method and cross-linking agent technology, which is applied in the field of polymer carriers and slow-release materials, can solve the problems of less research on cross-linked micelles, and achieve good application prospects, good acid sensitivity, and fast release effects

Active Publication Date: 2016-08-24
ANHUI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

pH-responsive cross-linking agents contain acid-sensitive chemical bonds, and the cross-linked micelles with orthoester bonds as sensitive groups are less studied

Method used

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  • A kind of nuclear cross-linked micelles prepared by a cross-linking agent containing two orthoester five-membered rings and its synthesis method and application
  • A kind of nuclear cross-linked micelles prepared by a cross-linking agent containing two orthoester five-membered rings and its synthesis method and application
  • A kind of nuclear cross-linked micelles prepared by a cross-linking agent containing two orthoester five-membered rings and its synthesis method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Preparation of block copolymer micelles:

[0032] The block copolymer PEG-b-PNSM (PEG-b-PNSM 45 , PEG-b-PNSM 90 And PEG-b-PNSM 130 ) 100mg dissolved in 1mL DMSO (add a small amount of triethylamine), then add 10mL of phosphate buffer with a concentration of 50mM and pH 7.4 dropwise with stirring. After the addition is complete, stir vigorously for 1h, and transfer the solution to a dialysis bag with a molecular weight cutoff of 3500 Inside, use distilled water (add a small amount of triethylamine) as dialysate for 48h, then transfer the solution in the bag to a 50mL centrifuge tube, freeze-dry, and obtain block copolymer micelles;

[0033] From block copolymer PEG-b-PNSM 45 , PEG-b-PNSM 90 And PEG-b-PNSM 130 The prepared micelles were named NCLM1, NCLM2 and NCLM3;

[0034] (2) Preparation of block copolymer crosslinked micelles:

[0035] The block copolymer micelles prepared above are dissolved in a mixed solvent of DMSO and water (v:v=1:1), and the crosslinking agent 4,4'-...

Embodiment 2

[0038] The critical micelle concentration of the polymer is determined by fluorescence spectroscopy with Nile Red as a fluorescent probe. The specific operation method is as follows: first add 20μL into the brown vial at a concentration of 1.0×10 -4 mol / L Nile Red acetone solution, place it in the air until the acetone is completely volatilized, and vacuum dry at room temperature for 2 hours. Then use 50mM pH=7.4 phosphate buffer to prepare a concentration of 1×10 -4 ~ 2mg / mL copolymer PEG-b-PNSM solution, add 5mL copolymer solutions of different concentrations into the brown vials previously treated, and after incubating for 12h in the dark, use a fluorescence spectrophotometer to determine the Nile Red in the polymer solution Fluorescence intensity in. The excitation wavelength is set to 550nm, the excitation bandwidth and emission bandwidth are 2.0nm, and the emission spectrum of the copolymer solution sample in the range of 560-720nm is measured. Find the wavelength of eac...

Embodiment 3

[0040] Verification of cross-linked micelles:

[0041] (1) Nuclear magnetic verification.

[0042] The cross-linked micelles are dissolved in deuterated phosphate buffer at pH=7.4 and pH=4. Nuclear magnetic detection shows that under the condition of pH=7.4, only the proton peak of the hydrophilic shell can be observed. Formation, under the condition of pH=, new proton peaks are generated at 8.19 and 8.25ppm, which are presumed to be the degradation peaks of orthoester. Since the free orthoester has been dialyzed out before the crosslinked micelles are lyophilized, it is verified The formation of cross-linked micelles.

[0043] (2) DLS verification

[0044] The cross-linked micelles and uncross-linked micelles were prepared into 0.5 mg / ml micellar solutions in phosphate buffer with pH=7.4, and each solution was diluted 5000 times, and the solution was analyzed in Malvern particle size analyzer (Malvern Zetasizer Nano ZS) measures the size change of micelles before and after dilution...

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Abstract

The invention discloses a nuclear cross-linked micelle prepared by a cross-linking agent of two orthoester five-membered rings, a synthesis method and an application thereof, and belongs to the technical field of polymer carriers and sustained-release materials. The structure of the core cross-linked micelles prepared by two orthoester five-membered ring cross-linking agents is shown in chemical formula I. The amphiphilic block copolymer PEG-b-PNSM is used to self-assemble in aqueous solution to form micelles, and the cross-linked micelles formed by adding a cross-linking agent can deliver poorly water-soluble drugs (such as anti-tumor paclitaxel) in vivo. The nuclear cross-linked micelles of the present invention have good acid sensitivity, biocompatibility and biodegradability, and have good application prospects in the field of targeted therapy. In the formula, X represents a value of 20-200.

Description

Technical field [0001] The invention relates to a nuclear crosslinked micelle prepared from a crosslinking agent containing two orthoester five-membered rings, and a synthesis method and application thereof, and belongs to the technical field of polymer carriers and slow and controlled release materials. Background technique [0002] In recent years, polymer micelles have aroused extensive research interest in the delivery of anti-cancer drugs due to their high efficiency, long-term effect and safety. However, the application of micelles is limited by the instability of nanostructures. After intravenous injection, the concentration of micelles decreases, and the decomposition of micelles occurs when they are below the critical micelle concentration (CMC). Therefore, improving the stability of micelles is a very important research direction. [0003] Nuclear cross-linked micelles can be used as an effective means to fix micelles (Chinese Patent CN 101265311A). However, cross-linked...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/18C08J3/24C08J3/09C08J3/02C08K5/17A61K47/30A61K9/51
Inventor 唐汝培韦兵周晓晶
Owner ANHUI UNIVERSITY
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