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Co-delivery nano-carrier of drug and gene, preparation method and application thereof

A nanocarrier, co-delivery technology, applied in gene therapy, drug combination, pharmaceutical formulation, etc., can solve problems such as delivery difficulties, and achieve the effect of promoting release, reducing the effect of plasma proteins, and reducing toxic and side effects

Active Publication Date: 2015-07-08
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is relatively difficult to deliver siRNA, a negatively charged biomacromolecule, into tumor cells. Therefore, the preparation of a suitable carrier is a key link to effectively realize the function of RNA silencing

Method used

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  • Co-delivery nano-carrier of drug and gene, preparation method and application thereof
  • Co-delivery nano-carrier of drug and gene, preparation method and application thereof
  • Co-delivery nano-carrier of drug and gene, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] The synthesis scheme of the TCPL polymer prodrug is as follows: Triphenylphosphine (TPP) and 6-bromohexanoic acid are fed at a molar ratio of 1:1.05, dissolved in anhydrous acetonitrile, reacted for 16 hours under nitrogen protection, and recrystallized to obtain TPP- COOH. Take an appropriate amount of TPP-COOH, dissolve in anhydrous DMSO, add dicyclohexylcarbodiimide DCC and N-hydroxysuccinimide NHS (molar ratio DCC:NHS:TPP-COOH=1.5:1.5:1), stir at room temperature React for 12 hours, centrifuge to remove the precipitate, mix the supernatant with PEI-containing anhydrous DMSO solution, stir and react at room temperature for 12 hours to obtain a reaction solution. Take an appropriate amount of LND, dissolve in anhydrous DMSO, add DCC and NHS (molar ratio DCC:NHS:TPP-COOH=1.5:1.5:1), stir and react at room temperature for 12 hours, centrifuge to remove the precipitate, supernatant and reaction solution (TPP- COOH and polyethyleneimine PEI reaction) were mixed evenly, a...

Embodiment 2

[0060] Structural elucidation of TCPL polymers.

[0061] The structure of TCPL polymer was identified by H NMR and IR spectroscopy. figure 1 (A), the results of hydrogen spectrum show: on the hydrogen spectrum of TCPL, the chemical shift value of 7.75-7.91ppm is the characteristic peak of hydrogen on the TPP benzene ring, and the chemical shift value of 2.27-2.55ppm is the peak of methylene on PEI The characteristic peak of hydrogen, the chemical shift value of 5.84ppm is the characteristic peak of the hydrogen of the methylene on the LND, and the chemical shift value of 3.71-3.81ppm is the characteristic peak of the hydrogen of the methylene on the oxidized chitosan sugar chain, the above characteristics The peaks were all displayed, indicating that the synthesis of polymer TCPL was successful.

[0062] figure 1 (B), infrared spectrum results show: TCPL at 1404cm -1 There are C=N stretching vibration peaks, indicating the formation of Schiff base bonds.

Embodiment 3

[0064] The synthesis scheme of PPX polymer is as follows: Take folic acid FA as an example. Weigh FA 0.1mmol, dissolve in 0.1M Na 2 CO 3 solution, then add 0.2mmol EDC and NHS respectively, stir, and activate for 30min, transfer to the solution containing 0.1mmol H 2 N-PEG-NH 2 0.1M Na 2 CO 3 solution, stirred, and reacted at room temperature for 2h. Dialyzed with a dialysis bag with a molecular weight cut-off of 1000, 0.01M Na 2 CO 3 The solution is a dialysate, which is dialyzed until there is no FA in the external liquid (ultraviolet detection), and then dialyzed with distilled water for 24 hours. PEG-FA was obtained after freeze-drying. Weigh an appropriate amount of polyacrylic acid, dissolve it in sodium carbonate solution, add EDC and NHS with a polyacrylic acid carboxyl molar weight of 4%, after 30 minutes, add PEG-FA, react at room temperature for 2 hours, lyophilize after dialysis to obtain PPX (PPF), Keep away from light.

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Abstract

The invention discloses a co-delivery nano-carrier of drugs and genes, a preparation method and an application thereof; and particularly relates to a co-delivery nano-carrier TCPL-siRNA-PPX which can carry a chemotherapeutic drug and a genetic drug simultaneously. The drug delivery system is composed of a polymer prodrug carrier TCPL, siRNA and a multifunctional polyanionic polyer PPX through electrostatic adsorption among the components in a self-assembly manner. The co-delivery nano-carrier can achieve targetedly delivery of the drug and the gene to the same tumor cell, release the siRNA at the cytoplasm, silence Bcl-2 protein, promote apotosis and relieve inhibition of the Bcl-2 on lonidamine, and can deliver the chemotherapeutic drug, lonidamine, which is mitochondrion-acted to mitochondria so that the chemotherapeutic drug and the gene can synergistically trigger the apotosis of a mitochondrial pathway and kill tumor cells cooperatively. Through in-vivo and in-vitro activity evaluation, the drug delivery system is proved to be better than drug delivery carriers which deliver single components respectively at the same time, can significantly improve the anti-cancer activity of the drug and the gene and has a definite synergistic treatment effect.

Description

technical field [0001] The present invention relates to a nanocarrier for co-delivery of drugs and genes, in particular to a co-delivery hierarchical targeted drug delivery system for simultaneously loading chemotherapeutic drugs and gene drugs. The drug delivery system of the present invention can target tumor cells and deliver gene drugs to reach The cytoplasm and the delivery of chemotherapeutic drugs to the mitochondria, the two synergistically trigger the apoptosis of the mitochondrial pathway, and achieve the purpose of synergistically treating tumors, and belong to the technical field of pharmaceutical preparations. Background technique [0002] Cancer is a serious threat to human health, and it is generally difficult to achieve the best curative effect with a single method of treatment. Synergistic effect of two or more therapeutic approaches is one of the effective strategies for tumor treatment. Chemotherapy, also known as chemotherapy, is the main means of clinic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61K31/713A61K47/48C08G81/00C08G73/04C08B37/08C08G81/02C08G65/48A61P35/00A61K31/416
CPCA61K31/416A61K31/713C08G65/33396C08G73/0206C08G81/00C08G81/025
Inventor 姜虎林张兵锋邢磊
Owner CHINA PHARM UNIV
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