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A polylipopeptide vesicle with negatively charged inner membrane and its preparation method and application

A technology of polyester and vesicles, which is applied in the fields of polymer materials and applied chemistry, can solve the problems of low protein loading efficiency and achieve high protein loading, good stability, and good application prospects

Active Publication Date: 2022-02-25
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the encapsulation efficiency of conventional polymersomes for proteins is very low

Method used

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  • A polylipopeptide vesicle with negatively charged inner membrane and its preparation method and application
  • A polylipopeptide vesicle with negatively charged inner membrane and its preparation method and application
  • A polylipopeptide vesicle with negatively charged inner membrane and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Polyethylene glycol-b-poly(2-aminohexadecanoic acid)-b-poly(β-benzyl-L-aspartic acid) (PEG-b-PAPA-b-PBLA) three Synthesis of Block Copolymers

[0038] The PEG-b-PAPA-b-PBLA triblock copolymer was prepared in the form of PEG-NH in DMF solution under nitrogen 2 2-aminohexadecanoic acid-N-carboxylate anhydride monomer (APA-NCA) and β-benzyl-L-aspartic acid-N-carboxylate anhydride monomer (BLA- NCA) prepared by ring-opening polymerization. The specific synthesis steps are as follows: under a nitrogen atmosphere, a DMF solution of 10 mL of APA-NCA (0.52 g, 1.76 mmol) was rapidly added to PEG-NH 2 DMF (2 mL) solution, after reacting at 35° C. for 72 hours, the second monomer BLA-NCA was added, and then the reaction was continued for 72 hours. After the reaction, the reaction solution was precipitated in 20 times excess glacial ether for several times, and finally vacuum-dried to obtain a white solid product. Yield: 83%.

[0039] The NMR spectrum of PEG-b-PAPA-...

Embodiment 2

[0040] Embodiment 2: Synthesis of PEG-b-PAPA-b-PAsp copolymer

[0041]PEG-b-PAPA-b-PAsp triblock copolymer was obtained by deprotecting PEG-b-PAPA-b-PBLA in HBr. The specific steps are as follows: HBr (33wt.% HOAc, 0.3mL, 1.66mmol) was added to a solution of PEG-b-PAPA-b-PBLA (0.3g, 0.015mmol) in trifluoroacetic acid (3mL) and reacted at 0°C 2 hours. After the reaction was finished, precipitation was repeated several times with excess glacial ether, and finally vacuum-dried to obtain a white solid product. Yield: 80%.

[0042] The NMR spectrum of PEG-b-PAPA-b-PAsp is attached figure 2 , 1 H NMR (600MHz, CDCl 3 / CF 3 COOH(9 / 1,v / v), figure 2 ,δ):4.50(1H,-COCHNH-),3.72(4H,-OCH 2 CH 2 O-),3.47(3H,-OCH 3 ),2.99(2H,-COCH 2 -),1.82(2H,-CH(NH)CH 2 CH 2 -),1.24(24H,-CH 2 (CH 2 ) 12 CH 3 ),0.85(3H,-CH 2 CH 3 ).

[0043] Table 1. Characterization of PEG-b-PAPA-b-PBLA triblock copolymers

[0044]

[0045] a Depend on 1 Calculated by H NMR. b Measured by GPC (m...

Embodiment 3

[0046] Example 3: Preparation of Polylipopeptide Vesicles with Asymmetric Membrane Structure and Determination of its Critical Aggregation Concentration (CAC)

[0047] cRGD-modified polylipopeptide vesicles (cRGD-CLP) were prepared by solvent displacement method. The brief steps are as follows: 0.2 mL of 2 mg / mL containing 20 mol.% cRGD-PEG-b-PAPA (M n =6.0-11.3kg / mol) and 80mol.% mPEG-b-PAPA-b-PAsp (M n =5.0-10.1-1.4kg / mol) was added dropwise to 0.8mL of PB buffer medium (10mM, pH 7.4), and then dialyzed in PB for 8 hours, changing the dialysis medium every 2 hours. The critical aggregation concentration (CAC) of polylipopeptide vesicles was measured by fluorescence method using pyrene as fluorescent probe. The concentrations of cRGD-CLP and CLP ranged from 1.2 × 10 -5 to 0.1 mg / mL and the concentration of pyrene in each sample was 0.6 μM. Fluorescence intensity at 372 nm and 383 nm was recorded by a fluorescence spectrophotometer under excitation at 330 nm. The inflecti...

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Abstract

The invention discloses a polylipopeptide vesicle whose inner membrane is negatively charged, a preparation method and application thereof, and belongs to the technical field of polymer materials and applied chemistry. Firstly, the present invention simply prepares PEG-b-PAPA-b-PAsp triblock copolymer through NCA ring-opening polymerization and deprotection; the prepared cRGD-CLP has the characteristics of small size, good stability and high protein loading capacity ; cRGD‑CLP (SAP‑cRGD‑CLP) loaded with saporin protein can specifically target α v beta 3 Integrin overexpressed tumor cells, and showed strong cytotoxicity to A549 lung cancer cells; cRGD-CLP can circulate in the body for a long time, thereby promoting the enrichment of protein drugs in tumor sites, and completely inhibiting the growth of A549 lung cancer in situ. Therefore, the vesicles are simple to prepare, have high protein loading capacity, and good tumor targeting, and have great potential in protein therapy of tumors.

Description

technical field [0001] The invention relates to a polylipopeptide vesicle whose inner membrane is negatively charged, a preparation method and application thereof, and belongs to the technical field of polymer materials and applied chemistry. Background technique [0002] Protein drugs have shown unique advantages in cancer treatment. Compared with traditional small-molecule chemotherapy drugs, therapeutic protein drugs such as monoclonal antibodies, enzymes, and hormones have the characteristics of strong specificity and high activity. However, their inherent structural instability, easy degradation and inactivation during in vivo circulation, poor cell penetration and immunogenicity have greatly hindered the clinical transformation of protein drugs. Therefore, how to safely and efficiently deliver therapeutic proteins that need to function in cells to cancer cells is a major challenge in the field of protein therapy. Polymeric vesicles have a huge hydrophilic inner cavit...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G69/40C08G69/08A61K9/127A61K47/34A61P35/00
CPCA61K47/34A61P35/00A61K9/1273C08G69/08C08G69/40
Inventor 邓超邱敏钟志远
Owner SUZHOU UNIV
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