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Polypeptide block polymer and preparation method therefor and use thereof

A polymer and peptide block technology, applied in the fields of polymer chemistry and biomedical engineering, can solve the problems of lack of specificity, instability, killing normal cells, etc., and achieve good biocompatibility, low toxicity, and wide application value effect

Inactive Publication Date: 2015-12-16
河南省眼科研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Malignant tumors have become a major disease that threatens human health. Chemotherapy and gene therapy are the two main clinical treatments. However, the application of antitumor drugs in chemotherapy has many defects: most of them have great toxicity, Lack of specificity, while killing tumor cells, it will kill a large number of normal cells; in gene therapy, non-specific cell absorption of gene drugs, easy to be adsorbed by active substances in the body, easy to be phagocytized by macrophages and decomposed by biological enzymes, etc. Instability during in vivo application also affects its application
At present, there is a lack of multifunctional nanocarriers that can simultaneously achieve chemotherapy, gene therapy and precise positioning in the prior art

Method used

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  • Polypeptide block polymer and preparation method therefor and use thereof
  • Polypeptide block polymer and preparation method therefor and use thereof
  • Polypeptide block polymer and preparation method therefor and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] The synthesis of embodiment 1 polypeptide block polymer

[0049] Polypeptide block polymer, the molecular formula is: PLAsp (DIP) n -b-PLLys m , the structural formula is:

[0050] Wherein, m=25, n=125.

[0051] PLAsp (DIP) n -b-PLLys m Synthetic steps:

[0052] (1) Synthesis of N-ε-benzyloxycarbonyl lysine benzyl ester, reaction mechanism and reaction process are as follows:

[0053]

[0054] Dissolve 18.25g (100mmol) of lysine hydrochloride and 8.0g (200mmol) of NaOH in 80ml of water to form a solution. Under the condition of 30°C, dissolve copper sulfate solution (12.5g of copper sulfate pentahydrate (50mmol) in 40ml of water) Add dropwise to the above solution; lower the reaction system to 0°C, under this condition, add 10gNaHCO 3 (120mmol), then dropwise excess 19ml (130mmol) of benzyl chloroformate, reacted for 3 hours at 0°C, overnight at room temperature; the N-Cbz-Lys-Cu in the reaction system 2+ The blue precipitate of the complex was collected, w...

Embodiment 2

[0076] Example 2 Preparation of blank vesicles and drug-loaded vesicles PALDOX

[0077] Preparation of blank vesicles: weigh 20 mg of the polypeptide block polymer PLAsp (DIP) in Example 1 n -b-PLLys m , dissolved with dilute hydrochloric acid (1%, mass concentration), the pH is about 2.0, stirred for 1h; within 20 minutes, the pH value was slowly adjusted to 5.0 with 0.5M NaOH aqueous solution; then within 20 minutes, with 0.05M NaOH aqueous solution The pH value was slowly adjusted to 6.4; finally, within 30 minutes, the pH value was slowly adjusted from 6.4 to 7.4 with 0.001 M NaOH aqueous solution, and then filtered through a 450 nm filter membrane to finally obtain a blank vesicle solution.

[0078] Drug-loaded vesicles (PALDOX) are prepared using the same method: weigh the polypeptide block polymer PLAsp (DIP) in Example 1 n -b-PLLys m 20 mg and 2 mg of doxorubicin hydrochloride were dissolved with dilute hydrochloric acid (1%, mass concentration), the pH was about 2....

Embodiment 3

[0080] Example 3 Preparation of drug-loaded vesicle PALsiRNA and combined drug-loaded vesicle PAL (DOX / siRNA)

[0081] A certain amount of siRNA (1 μg, purchased from Guangzhou Ruibo Biotechnology Co., Ltd.) was added to a known amount of blank vesicles and drug-loaded vesicles (PALDOX) solution in Example 2, according to the polypeptide block polymer PLAsp (DIP) n -b-PLLys m The molar ratios of amino groups and siRNA phosphate groups are 0.5:1, 1:1, 1.5:1, 2:1, 3:1, 4:1, and 8:1. Make up to the volume required for the experiment with deionized water, shake on a shaker for 30 minutes after mixing, and let stand for 10 minutes to obtain a series of drug-loaded vesicle PALsiRNA solutions and combined drug-loaded vesicle PAL ( DOX / siRNA) solution.

[0082] The particle size and surface potential of the drug-loaded vesicle PALDOX in Example 2 and the combined drug-loaded vesicle PAL (DOX / siRNA) in Example 3 were measured with a dynamic light scattering instrument (DLS), and the...

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Abstract

The invention belongs to the technical field of macromolecular chemical and biomedical engineering and particularly relates to a polypeptide block polymer and a preparation method therefor and use thereof. The molecular formula of the polypeptide block polymer is PLAsp(DIP)<n>-b-PLLys<m>. The preparation method comprises the steps: (1) synthesizing N-epsilon-carbobenzoxy lysine benzyl ester; (2) synthesizing N-epsilon-carbobenzoxy lysine anhydride CBLLys-NCA; (3) synthesizing beta-aspartic acid benzyl ester; (4) synthesizing beta-aspartic acid anhydride BLAsp-NCA; (5) synthesizing Bu-PBLAsp<n>; (6) synthesizing PBLAsp<n>-b-PCBLLys<m>; (7) synthesizing PLAsp(DIP)<n>-b-PCBLLys<m>; and (8) synthesizing PLAsp(DIP)<n>-b-PLLys<m>. The invention further relates to use of the polypeptide block polymer as a drug delivery carrier. The polypeptide block polymer provided by the invention is self-assembled to form a vesicle system which can be used as a medicine combined delivery carrier. The vesicle system is pH sensitive and can deliver chemical medicines and gene medicines at the same time for synergistic interaction; the carrier composed of polypeptide units is good in biocompatibility and small in toxicity. The carrier can be used for delivering two medicines in a combined manner so as to realize integration of carrier positioning, chemotherapy and gene therapy, and has wide application value.

Description

technical field [0001] The invention belongs to the technical field of macromolecule chemistry and biomedical engineering, and specifically relates to a polypeptide block polymer and its preparation method and application. Background technique [0002] Malignant tumors have become a major disease that threatens human health. Chemotherapy and gene therapy are the two main clinical treatments. However, the application of antitumor drugs in chemotherapy has many defects: most of them have great toxicity, Lack of specificity, while killing tumor cells, it will kill a large number of normal cells; in gene therapy, non-specific cell absorption of gene drugs, easy to be adsorbed by active substances in the body, easy to be phagocytized by macrophages and decomposed by biological enzymes, etc. The instability of in vivo application also affects its application. Chemotherapy and gene therapy, two of the most promising cancer treatments, require efficient and safe delivery of vectors...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G69/14C08G69/16A61K47/34A61K9/127A61K48/00A61K45/00A61P35/00
Inventor 李景果栗占荣张俊杰王丽娅
Owner 河南省眼科研究所
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