Polyethylene glycol-b-polytyrosine-lipoic acid copolymer, polypeptide micelle and preparation method and application thereof

A polyethylene glycol and polytyrosine technology, applied in the field of polytyrosine materials, can solve the problems of poor tumor targeting effect, slow release, easy early release of drugs, etc., and achieve good biocompatibility and high efficiency. Load and prepare simple effects

Active Publication Date: 2018-12-14
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, a variety of polypeptide nanomedicines have entered the clinical trial stage, and the results show that polypeptide nanomedicines can effectively improve the therapeutic effect and reduce side effects; however, the existing polypeptide nanomicelles still have some shortcomings, For example, the drug is easy to release early after injection into the body, the tumor targeting effect is poor, and the drug releases slowly after reaching the tumor tissue, etc.

Method used

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  • Polyethylene glycol-b-polytyrosine-lipoic acid copolymer, polypeptide micelle and preparation method and application thereof
  • Polyethylene glycol-b-polytyrosine-lipoic acid copolymer, polypeptide micelle and preparation method and application thereof
  • Polyethylene glycol-b-polytyrosine-lipoic acid copolymer, polypeptide micelle and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment 1 Synthesis of PEG-PTyr-LA Polypeptide Copolymer

[0056] First, PEG- b -PTyr is based on PEG-NH 2 It is obtained by ring-opening polymerization of Tyr-NCA monomer as a macroinitiator. The details are as follows: Dissolve Tyr-NCA (231.0 mg, 1115.7 μmol) in 2 mL DMF, and slowly add it dropwise under nitrogen until PEG-NH is dissolved 2 (5 KDa , 400.0 mg, 80.0 μmol) in DMF (4 mL) and reacted in an oil bath at 40 °C. After 72 hours, precipitate with excess glacial ether, dissolve with chloroform after centrifugation, and repeat the precipitation twice. The precipitate was collected and dried in a vacuum oven for 24 h to obtain a white powdery polymer PEG- b -PTyr( M n : 7.0 kg / mol).

[0057] PEG- b -PTyr-LA is catalyzed by DMAP through PEG- b The phenolic hydroxyl group on the -PTyr side chain is obtained by esterification. The specific operation is as follows: lipoic acid (LA, 108.5 mg, 526.7 μmol) was dissolved in 3 mL DCM under a nitrogen atmosphere...

Embodiment 2

[0061] Example 2 Synthesis of cRGD-PEG-PTyr

[0062] Under nitrogen atmosphere, allyl-PEG- b -PTyr (200 mg, 28.6 μmol, see Example 1 for the preparation method, PEG-NH 2 (400.0 mg, 80.0 μmol) replaced by allyl-PEG-NH 2 ( M n =5.0 K, 400.0 mg, 80.0 μmol) in DMF solution were added thiol-modified cRGD-SH (33.9 mg, 57.1 μmol) and photosensitizer 2959 (4.0 mg, 17.8 μmol), and the mixed solution was placed in an ice bath React in a UV curing box for 15 min. The reaction solution was dialyzed with a large amount of DMF (Specture / Pore, MWCO 3500) to remove excess cRGD and 2959. Finally, the polymer was precipitated in excess anhydrous ether, and the precipitate was dried in a vacuum oven for 12 hours, yield: 70.5%.

[0063] The above preparation scheme can be expressed as follows:

[0064]

[0065] cRGD-PEG-PTyr NMR characterization see appendix figure 2 , 1 H NMR (400 MH Z , DMSO- d 6 ) 9.07 (1 H, -C 6 h 4 -OH), 7.95 (1 H, -HNCH(CH 2 )CO-), 6.91, 6.54 (4H, -C 6 h...

Embodiment 3

[0066] Example 3 Preparation of cRGD-rPTM-Dox polymer micelles

[0067] cRGD-modified polytyrosine micelles were prepared by dialysis, and the molar ratio of 2:8 cRGD-PEG-PTyr / PEG- b - PTyr-LA and doxorubicin Dox with a designed drug loading of 20% were dissolved in DMF; then 100 μL (10 mg / mL) of the polymer / drug solution was added dropwise to 1 mL of HEPES buffer solution at pH 7.4 , stirring at a speed of 400 rpm while adding dropwise. After stirring, the micelles / drug solution was transferred to a dialysis bag with a molecular weight cut-off of 3.5 K and dialyzed with HEPES buffer solution of pH 7.4 for 8 h, and the dialysis medium was changed every 2 h; 25 μL (1 mg / mL) of DTT solution was added to the solution, and placed in a 37︒C 100 rpm shaker for 12 h to obtain the cross-linked drug-loaded micelles cRGD-rPTM-Dox, that is, nano-drugs; the same method, without adding doxorubicin Dox with a designed drug loading of 20%, to obtain cross-linked empty micelles, denoted as ...

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Abstract

The invention discloses a polyethylene glycol-b-polytyrosine-lipoic acid copolymer, a polypeptide micelle and a preparation method and application thereof. The preparation method comprises the following steps: firstly, carrying out NCA ring opening polymerization and esterification reaction to prepare a PEG-PTyr-LA polypeptide copolymer; and carrying out self-assembly of the polymer to obtain themicelle which is small in grain size, high in stability and high in drug loading amount and has reduction responsiveness, wherein the method is simple and controllable, and the prepared polymer has high biocompatibilitya nd biodegradability. The micelle drug can be circulated for a long time in vivo and penetrates tumor cells better, so that enrichment of the drug at tumors is improved greatly, and therefore, growth of DMA-MB-231 breast carcinoma transplantation tumor is inhibited better.

Description

technical field [0001] The invention relates to a biocompatible and biodegradable polytyrosine material and its application, in particular to the synthesis and application of a polyethylene glycol-polytyrosine diblock polypeptide material grafted with lipoic acid. The application of a small-sized reversibly cross-linked polypeptide micelle prepared by it in the high-efficiency entrapment and targeted delivery of hydrophobic chemotherapeutic drugs. Background technique [0002] Polypeptides have the characteristics of excellent biocompatibility, good degradability, and easy modification, and are increasingly used to construct drug delivery systems. At present, a variety of polypeptide nanomedicines have entered the clinical trial stage, and the results show that polypeptide nanomedicines can effectively improve the therapeutic effect and reduce side effects; however, the existing polypeptide nanomicelles still have some shortcomings, For example, after injection into the bod...

Claims

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Application Information

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IPC IPC(8): C08G69/46C08G69/40A61K47/34A61K47/42A61K47/36A61K9/107A61K31/704A61P35/00
CPCA61K9/1075A61K31/704A61K47/34A61K47/36A61K47/42A61P35/00C08G69/40C08G69/46
Inventor 邓超薛松顾晓雷钟志远
Owner SUZHOU UNIV
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