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ROS-sensitive tumor-targeted gene delivery system and preparation method thereof

A tumor-targeting, gene-based technology, applied in gene therapy, anti-tumor drugs, pharmaceutical formulations, etc., can solve the problems of tumors that cannot be surgically cut, immune reactions, toxic and side effects, etc., and achieve good tumor treatment effects and biocompatibility Good sex and reduced cytotoxicity

Active Publication Date: 2019-07-09
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] It has been reported in the literature that malignant tumors have become the number one enemy threatening human health. Traditional treatment methods include surgical resection, chemotherapy, and radiotherapy, all of which have their own shortcomings: surgery is difficult to remove completely, and some tumors cannot be surgically cut due to their special location; chemotherapy Often accompanied by systemic toxic side effects and body drug resistance; radiotherapy can also cause damage to normal tissues and bring about certain immune responses
Studies have shown that the effect of gene therapy mainly depends on the delivery efficiency of the delivery carrier. An ideal carrier needs to have the following three points: 1) good biocompatibility; 2) strong gene loading capacity to ensure the stability of in vivo transportation; 3 ) targeted delivery to the lesion while satisfying the above three points is still a challenge for carrier design

Method used

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  • ROS-sensitive tumor-targeted gene delivery system and preparation method thereof
  • ROS-sensitive tumor-targeted gene delivery system and preparation method thereof
  • ROS-sensitive tumor-targeted gene delivery system and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0047] like figure 1 Synthetic steps shown, first synthesize VPBE, add 4-vinylphenylboronic acid, 3-allyloxy-1,2-propanediol and 1 gram of anhydrous sodium sulfate in anhydrous dichloromethane with a molar ratio of 1:1.5 , stirred overnight in a 40-degree oil bath, removed anhydrous sodium sulfate by filtration, and finally separated and purified the final product VPBE by column chromatography on a silica gel column at a ratio of petroleum ether / ethyl acetate 3:1. Then carry out sulfhydryl modification on low molecular weight polyethyleneimine, add polyethyleneimine and propylene sulfide with a molar ratio of 1:2 in an appropriate amount of methanol solution, nitrogen protection, react at 60 degrees for 12 hours, and remove by rotary evaporation Methanol and ether were precipitated and purified three times to obtain mercapto-modified polyethyleneimine. Then, the mercapto-modified polyethyleneimine and VPBE with a molar ratio of 1:5, and a catalytic amount of 2,2-dimethoxy-phe...

Embodiment 2

[0049] Quantitatively weigh the pure uncrosslinked BPEI 1.2K , crosslinked BPEI and SP-crosslinked BPEI, dissolved in pure water to make the final concentration 1mg / mL. The above three materials were dropped into the 200 μg / mL pDNA solution according to the corresponding N / P ratio concentration from 5 to 20, the pipette gun was quickly blown and mixed, vortexed for 30 seconds, and left at room temperature for 30 minutes to prepare each nanometer Particles, the DLS particle size and zeta potential value of the nanoparticles were measured by a Malvern particle size analyzer, such as figure 2 A, B shown. Freshly prepare the nanoparticle solution (N / P=10) according to the above method, drop a drop onto the carbon support film copper grid, dry under the infrared lamp, observe the morphology of the nanoparticle under the TEM microscope, as shown in FIG. figure 2 D shows. It can be seen that when N / P=10, nanoparticles with uniform and stable particle size can be formed.

Embodiment 3

[0051] Place crosslinked BPEI in 1mM H 2 o 2 Treated in aqueous solution for 12 hours, freeze-dried, re-dissolved in heavy water after freeze-drying, NMR comparison H 2 o 2 Changes in hydrogen spectra before and after treatment, such as image 3 As shown in A, it can be seen that the hydrogen displacement on the benzene ring in the cross-linking agent molecule has changed, which proves that the phenyl boronate bond is in the H 2 o 2 Disconnect under existence, show the ROS sensitivity of material; Prepare crosslinked BPEI / pDNA nanoparticle (N / P=10) by the method described in embodiment 2, respectively through different treatments, including H 2 o 2 and heparin, gel electrophoresis results show that the material can completely encapsulate pDNA, and has ROS response release characteristics (such as image 3 Shown in B); H 2 o 2 After the treatment, the particle size of the nanoparticles gradually increased, and in the last 20 hours, it was seen that the particle size exc...

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Abstract

The invention belongs to the field of biotechnology, and relates to an ROS-sensitive tumor-targeted gene delivery system and a preparation method thereof. According to the system, an ROS-sensitive micromolecular crosslinking agent is used for crosslinking low-molecular-weight polyethyleneimine to form an ROS-sensitive cationic polymer, an SP polypeptide is modified to serve as a targeted functional group, nanoparticles are targeted into a breast cancer tumor site after mediating and gene compounding, the crosslinked polymer is responsively dissociated into small molecules under a high-level ROS atmosphere in a tumor cell, load-releasing genes take effects, and finally, effective gene delivery is realized. A new gene delivery platform is provided, the gene transfection effect is good, and the growth of tumors can be effectively inhibited through delivery of therapeutic genes siPlk1.

Description

[0001] Technical field: [0002] The invention belongs to the field of biological technology, and in particular relates to a ROS-sensitive tumor-targeted gene delivery system. [0003] Background technique: [0004] It has been reported in the literature that malignant tumors have become the number one enemy threatening human health. Traditional treatment methods include surgical resection, chemotherapy, and radiotherapy, all of which have their own shortcomings: surgery is difficult to remove completely, and some tumors cannot be surgically cut due to their special location; chemotherapy It is often accompanied by systemic toxic side effects and drug resistance; radiotherapy can also cause damage to normal tissues and bring about certain immune responses. By introducing exogenous genes into host cells, gene therapy is expected to correct or replace the human body's own gene structure or functional disorder, and prevent the further development of the disease. Due to its high sp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61P35/00
CPCA61K48/0041
Inventor 阮春晖孙涛蒋晨
Owner FUDAN UNIV
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