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Brain-targeted drug delivery system for improving microenvironment of drug-resistant glioma and reverse drug resistance

A brain glioma and lipid technology, applied in the field of new brain-targeted drug delivery system, can solve the problems of dosage toxicity, reduction of PEI compression siRNA, and large molecular weight of PEI

Active Publication Date: 2019-10-22
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are a large number of protonated amino groups in PEI, which can effectively compress siRNA through electrostatic interaction, but PEI has obvious toxicity due to its high molecular weight and large dosage. Although reducing the molecular weight of PEI can reduce the toxicity of PEI, the same Also reduces the ability of PEI to compress siRNA

Method used

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  • Brain-targeted drug delivery system for improving microenvironment of drug-resistant glioma and reverse drug resistance
  • Brain-targeted drug delivery system for improving microenvironment of drug-resistant glioma and reverse drug resistance
  • Brain-targeted drug delivery system for improving microenvironment of drug-resistant glioma and reverse drug resistance

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Embodiment Construction

[0027] 1 Research method:

[0028] 1.1 siPD-L1 base pair sequence activity screening

[0029] Design and synthesize siPD-L1 with different sequences, and use lipofactamine 2000 transfection reagent to transfect siPD-L1 with different sequences into C 6 In / TR cells, western blot was used to examine each siPD-L1 sequence pair C 6 silencing of PD-L1 in / TR cells.

[0030] 1.1.1 Drug handling

[0031] Take C in the logarithmic growth phase 6 For / TR cells, wash with PBS buffer, add 2ml of 0.25% trypsin solution, digest for 1min, discard the trypsin solution, add 4ml of DMEM complete culture solution, blow off the cells, use a cell counting plate to calculate the cell concentration, add DMEM for complete culture solution to dilute the cell concentration to 1x10 6 pc / ml, add to six-well plate, add 2ml to each well, incubate in carbon dioxide constant temperature incubator for 24h, discard the culture medium, add siPD-L1@lipofactamine 2000 compound with siPD-L1 concentration of...

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Abstract

The invention discloses a brain-targeted drug delivery system for improving the microenvironment of drug-resistant glioma and reverse drug resistance. A small molecular weight polyethyleneimine (PEI)was grafted onto the side chain of polyaspartic acid (PASP) via a disulfide bond to synthesize a new cationic polymer, PASP-g-PEI, for compression of siPD-L1. The complex formed by siPD-L1 and PASP-G-PEI is used as the core, and the lipid film composed of 2-deoxyglucose (Glu) modified distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG), cholesterol and dioleoylphosphatidylethanolamine (DOPE) is used as the outer shell. A core-shell lipid polymer nanoparticle TMZ / siPD-L1@GLPN (PASP-g-PEI) co-loaded with siPD-L1 and TMZ is prepared by thin film dispersion method. The nanoparticlespass through the blood-brain barrier and enter drug-resistant glioma cells via glucose transporter, release naked siPD-L1 and TMZ rapidly under the condition of high GSH concentration in the cytoplasmof drug-resistant glioma cells, silence the expression of PD-L1 in TMZ resistant glioma cells, block the PD-1 / PD-L1 pathway in TMZ resistant glioma cells, and activate the killing effect of body immune system on glioma. At the same time, the expression of MGMT is decreased and the sensitivity of TMZ resistant glioma cells to TMZ is increased. By the above two ways, the growth of drug-resistantglioma was inhibited.

Description

technical field [0001] The invention relates to a novel brain-targeted drug delivery system, which can not only silence the expression of PD-L1 in drug-resistant glioma cells, improve the immune microenvironment of drug-resistant glioma, but also reduce drug resistance The content of MGMT in glioma cells can reverse the resistance of drug-resistant glioma to temozolomide. Background technique [0002] Malignant glioma is the most common central nervous system tumor. Clinical studies have shown that after 3 courses of temozolomide (TMZ) are given in standard treatment, gliomas will develop obvious drug resistance to TMZ, which is the main reason for the failure of chemotherapy. It is an urgent clinical need to develop new methods that can effectively treat TMZ-resistant glioma. [0003] Studies have shown that the overexpression of O6-methylguanine-DNA-methyltransferase (MGMT), base excision repair (BER) and DNA mismatch repair (MMR) are important reasons for the resistance...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K47/34A61K47/24A61K47/26A61K31/7105A61K48/00A61K31/4188A61P35/00C12N15/113
CPCA61K9/5123A61K9/5146A61K31/4188A61K31/7105A61P35/00C12N15/113C12N2310/14A61K2300/00
Inventor 周四元刘道洲成颖刘苗乔赛张邦乐纪奇峰
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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