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Preparation and application of intracellular triggering reduction sensitive drug linked gene targeted co-carrier

A technology of internal triggering and delivery body, which can be used in drug combination, gene therapy, nanomedicine, etc., and can solve the problems of high cost, complicated preparation, and inability to be used repeatedly in vivo.

Inactive Publication Date: 2014-02-12
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Viral vectors have high transfection efficiency, but there are serious safety problems, and the target gene capacity is small, the preparation is complicated, the cost is high, and it cannot be used repeatedly in vivo

Method used

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  • Preparation and application of intracellular triggering reduction sensitive drug linked gene targeted co-carrier
  • Preparation and application of intracellular triggering reduction sensitive drug linked gene targeted co-carrier
  • Preparation and application of intracellular triggering reduction sensitive drug linked gene targeted co-carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Synthesis and Characterization of Disulfide Bonded Low Molecular Weight Polyethyleneimine

[0032] (1) Synthesis conditions

[0033] Weigh 1 g (0.56 mmol) of polyethyleneimine (Mw=1800), place it in a three-neck round bottom flask, and add 9 ml of methanol-water (80%) to dissolve it. Weigh 0.07g (0.28mmol) of N,N'-bis(acryl)cystamine, add 1ml of methanol-water (80%) to dissolve, and slowly drop it into the three-necked flask. Stir, react at 55°C for 3 days under nitrogen protection and in the dark. Purified by dialysis and freeze-dried to obtain disulfide cross-linked low molecular weight polyethyleneimine.

[0034] (2) Structural characterization

[0035] Take an appropriate amount of disulfide cross-linked low molecular weight polyethyleneimine dry pure product, dissolve in D 2 O, by NMR ( 1 H-NMR) to confirm the results. polyethyleneimine 1 In the H-NMR spectrum, the characteristic peaks are concentrated at 2.5-2.9; while the low molecular weight polyethylenei...

Embodiment 2

[0037] Preparation and Quality Evaluation of Nanoparticles

[0038] (1) Preparation of nanoparticles

[0039] Prepare 20mg / ml disulfide bond crosslinked low molecular weight polyethyleneimine acetone stock solution: weigh 0.2g disulfide bond crosslinked low molecular weight polyethyleneimine, add 0.05g Tween 80, dissolve in 10ml acetone, Protect from light, sonicate to dissolve.

[0040] Organic phase solution preparation: Weigh 0.2 g of polylactide-glycolide copolymer (10,000Da50:50), add 0.1 g of Tween 80, dissolve in 2 ml of dichloromethane, and ultrasonically dissolve. Add 1ml of disulfide bond cross-linked low molecular weight polyethyleneimine acetone stock solution, add acetone to 10ml, and mix well.

[0041] Preparation of aqueous phase solution: Weigh 0.5g of poloxamer 188 and dissolve in 10ml of water.

[0042] The organic phase was added to the aqueous phase, and the mixed solution was sonicated for 15 min using an ultrasonic cell pulverizer. Rotary steam at 45°...

Embodiment 3

[0047] Modification of hyaluronic acid and evaluation in vitro and in vivo

[0048] (1) Hyaluronic Acid Modification

[0049] Non-covalent binding: Take an appropriate amount of drug-loaded nanoparticles, add hyaluronic acid solution, mix and incubate for 15 minutes to obtain hyaluronic acid-modified nanoparticles.

[0050] Covalent binding: mix an appropriate amount of hyaluronic acid solution and drug-loaded nanoparticles, add 1.0mol / L hydrochloric acid, and make the pH of the reactant reach 6.5. Another appropriate amount of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide was dissolved in dimethyl sulfoxide-water (50%), Then slowly add into the reactant solution, stir and mix at room temperature for 24 hours, then adjust the pH with 1.0 mol / L sodium hydroxide. After dialysis, freeze-dry to obtain hyaluronic acid-modified nanoparticles.

[0051] Take an appropriate amount of hyaluronic acid-modified nanoparticles, mix with the siRNA sol...

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Abstract

The invention relates to an intracellular triggering reduction sensitive drug linked gene targeted co-carrier which is a gene and drug double-loaded system and comprises disulfide bond cross-linked polyethylene imine, a poly-lactide glycolide copolymer and a surface modified targeted micromolecule. According to the invention, the surface modified active targeted group of a carrier can target drugs to a tumor part and enrich the drugs; a disulfide bond cross-linked in a polymer can be broken in a cell under the condition of high reduction, and the structure of the carrier is disassembled so that the drugs are released. The intracellular triggering reduction sensitive drug linked gene targeted co-carrier disclosed by the invention can effectively load the gene and the hydrophobic micromolecular drug, ensure the stability of the gene and is degraded and releases the gene and the micromolecular drug under the condition of reduction. An in-vivo experiment shows that the intracellular triggering reduction sensitive drug linked gene targeted co-carrier disclosed by the invention has outstanding targeting on tumors.

Description

technical field [0001] The invention relates to the fields of high molecular polymer gene carrier and gene therapy. In particular, it relates to a polymer for gene carrier and an "intracellular trigger" reduction-sensitive drug-combined gene-targeting cotransporter designed and constructed based on the polymer. The invention relates to the synthesis and characterization of cross-linked polyethyleneimine, the preparation method of co-transfer body and its application. The cotransporter relates to a complex formed by hydrophobic small molecule drugs, genes and nanoparticles, a preparation method and an application. Background technique [0002] According to statistics, in China, malignant tumors are the second largest killer after cardiovascular and cerebrovascular diseases, and the vast majority of patients prefer surgical resection, radiotherapy and chemical drug treatment. These therapies can obtain rapid and effective treatment for patients with early tumors, but for pat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00C08J3/24C08L79/02C12N15/85A61K47/34B82Y5/00A61P35/00
Inventor 沈雁王珏涂家生汪步海张俊玲
Owner CHINA PHARM UNIV
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