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Tumor microenvironment response type gene nano-micelle as well as preparation method and application thereof

A tumor microenvironment and nanomicelle technology, applied in tumor microenvironment responsive gene nanomicelles and their preparation, in the field of tumor targeted drug delivery, can solve the specific targeting and low loading efficiency of non-viral gene carriers question

Active Publication Date: 2018-06-22
SHANGHAI INST OF ONCOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to provide a tumor microenvironment-responsive gene nanomicelle and its preparation method and application. The tumor microenvironment-responsive gene n

Method used

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  • Tumor microenvironment response type gene nano-micelle as well as preparation method and application thereof
  • Tumor microenvironment response type gene nano-micelle as well as preparation method and application thereof
  • Tumor microenvironment response type gene nano-micelle as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1P

[0060] Embodiment 1PEI-PBA and PEI-MAH-C225 carrier preparation

[0061] (1) Preparation of polyethyleneimine-phenylboronic acid (PEI-PBA):

[0062]

[0063] The synthetic route of PEI-PBA

[0064] According to the above polymer synthesis route, the specific description is as follows:

[0065] Add 4-(bromomethyl)phenylboronic acid and PEI into anhydrous DMSO, and stir the reaction at 80°C for 24 hours. The ratios of 4-(bromomethyl)phenylboronic acid to PEI were 4:1, 6:1 and 8:1, respectively. Finally, the product was dialyzed and freeze-dried to complete the preparation of PEI-PBA. H NMR spectrum such as Figure 4 , indicating that PEI-PBA was successfully synthesized.

[0066] (2) Preparation of polyethyleneimine-maleic anhydride-cetuximab (PEI-MAH-C225):

[0067]

[0068] The synthetic route of PEI-MAH

[0069] According to the above polymer synthesis route, the specific description is as follows:

[0070] (1) Preparation of PEI-C225: Add C225 to 0.1M MES solutio...

Embodiment 2

[0072] Example 2 Loading microRNA-146a (miR-146a) and cetuximab

[0073] Preparation of PEI-PBA-miR146a / PEI-MAH-C225 Nanomicelles

[0074] Put 5mg PEI-PBA and 2.5mg miR-146a into the aqueous solution to form PEI-PBA-miR-146a nanomicelles loaded with genes, then put 10mg PEI-MAH-C225 into the above nanomicelle solution and stir to form PEI-PBA - miR-146a / PEI-MAH-C225 nanomicelles. The results of nanomicelle by atomic force microscope and transmission electron microscope are as follows: Figure 6 , 7 As shown, the prepared nanoparticles are circular and have good dispersibility, and the particle size is mainly concentrated between 100-200nm, especially the particle size of 150nm.

Embodiment 3

[0075] Example 3 Cytotoxicity of PEI-PBA / PEI-MAH-C225 Nanomicelles

[0076] DU145 prostate cancer cells were plated in a 96-well plate, and the density of cells per well was 1×10 5 a, at 37°C, CO 2 Culture overnight in a cell culture incubator with a volume fraction of 5%. Nanomicelles of different concentrations were added to the 96-well plate (the cell group with only the culture medium was the negative control group), and 5 replicate wells were set for each experimental condition. After 24 hours of culture, 20 μL of cck8 (5 mg / mL) solution was added, and the culture was continued for 2 hours. After that, the culture solution was aspirated, tested at 450 nm in a microplate reader, and the cell survival rate was calculated.

[0077] The experimental results are shown in 8. Compared with the control group, the OD value of the cells incubated with nanoparticles within 24 hours did not change significantly, indicating that the nanoparticles have good biocompatibility.

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Abstract

The invention provides a tumor microenvironment response type gene nano-micelle. The tumor microenvironment response type gene nano-micelle comprises polyethyleneimine-phenylboronic acid and polyethyleneimine-maleic anhydride-target radical, wherein the mass ratio of the polyethyleneimine-phenylboronic acid to the polyethyleneimine-maleic anhydride-target radical ranges from (1 to 1) to (1 to 2).The invention further provides a preparation method of the tumor microenvironment response type gene nano-micelle. The invention further provides application of the tumor microenvironment response type gene nano-micelle to preparation of a medicine for treating cancers and application of the tumor microenvironment response type gene nano-micelle serving as a medicine carrier. The nano-micelle provided by the invention can efficiently load and transmit RNA (Ribonucleic Acid) and a medicine with a microenvironment response type gene enters a tumor cell target to play a role; the tumor microenvironment response type gene nano-micelle is especially suitable for loading the RNA for carrying out gene therapy on malignant tumor. The preparation method is simple and convenient and is suitable forlarge-scale production.

Description

technical field [0001] The invention belongs to the field of bioengineering and relates to a tumor-targeted drug delivery technology, in particular to a tumor microenvironment-responsive gene nanomicelle and its preparation method and application. Background technique [0002] Chemotherapy drugs used clinically have played an important role in tumor treatment, but they also have some serious problems, which limit the further application of drugs. A major problem is that clinically used antitumor drugs lack specificity to tumors, leading to serious dose-dependent toxic and side effects, which greatly limits the antitumor effect of drugs. In recent years, more and more attention has been paid to the treatment of malignant tumors through the delivery of RNA (including siRNA and microRNA). Although RNA has been successfully used in experiments on tumor cells, its in vivo research progress is still slow. The main reason is that exogenous RNA has no targeting and is easily degrad...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K47/32A61K47/42A61K31/7105A61K48/00A61P35/00
CPCA61K9/1075A61K31/7105A61K47/32A61K47/42
Inventor 刘培峰刘红梅马丁吴亮亮孔宪明
Owner SHANGHAI INST OF ONCOLOGY
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