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Autophagy siRNA-Fingolimod co-delivered nano drug delivery system for targeting liver cancer

A nano-drug-loading and drug-loading system technology, which is applied in the direction of anti-tumor drugs, drug combinations, and pharmaceutical formulations, can solve problems such as adverse reactions, normal cell apoptosis, and difficulty in achieving it, and achieve the effect of synergistically inducing apoptosis of liver cancer cells

Active Publication Date: 2019-01-04
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, problems have been encountered in the process of applying FTY720 and SiRNA targeting autophagy. First, if FTY720 and SiRNA targeting autophagy are administered directly, the poor targeting in vivo will induce normal cell apoptosis and cause serious adverse effects. In addition, due to the negative charge of SiRNA and the dependence of FTY720 on solvent, it is difficult to deliver FTY720 and SiRNA targeting autophagy at the same time with one administration

Method used

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  • Autophagy siRNA-Fingolimod co-delivered nano drug delivery system for targeting liver cancer
  • Autophagy siRNA-Fingolimod co-delivered nano drug delivery system for targeting liver cancer
  • Autophagy siRNA-Fingolimod co-delivered nano drug delivery system for targeting liver cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation and Characterization of the Nano Drug Loading System LCP-II for Co-loading siRNA and FTY720 1. Preparation, Characterization and Drug Release Experiment

[0029] 1. Preparation and characterization of nano-drug loading system LCP-II

[0030] The molecules that need to be co-loaded and delivered in the present invention are SiRNA and Fingolimod (FTY720, Fingolimod). The target protein of the SiRNA molecule is beclin1, which is used to knock down beclin1 to inhibit autophagy.

[0031] First, 300 μL CaCl 2 (500mM) and 100μL siRNA (2mg / mL) were dispersed in 15ml cyclohexane / surfactant (Igepal CO-520) mixture (71 / 29V / V) to prepare water-in-oil microemulsion. Next, 300 μL Na 2 HPO 4 (25mM pH=9.0) was dispersed in another 15ml of cyclohexane / surfactant (Igepal CO-520) mixture (71 / 29V / V), and 200μL of DOPA (20mg / mL) dissolved in chloroform was added , to prepare the phosphoric acid phase. Then, the two were mixed and stirred for 20 minutes, 30 mL of a...

Embodiment 2

[0040] Example 2 Anti-tumor experiment of co-delivery nano-drug delivery system in vitro

[0041] 1. Materials

[0042] 1,2-dioleoyl-3-trimethylammoniumpropane (DOTAP), dioleoylphosphatidic acid (DOPA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[ Methoxyl (polyethylene glycol 2000)] ammonium salt (DSPE-PEG) was purchased from Avanti Polar lipids in the United States. DSPE-PEG-FA was purchased from Xi'an Ruixi Biotechnology Co., Ltd. Cholesterol was purchased from Sigma. Fluorescence-labeled (FAM) beclin1 siRNA (target sequence 5'-CAGTTTGGCACAATCAATA-3') and control siRNA (target sequence 5'-AAT TCT CCGAACGTGTCACGT-3') were purchased from Shanghai Gemma Gene Company.

[0043] 2. Cells and cell culture

[0044] The human liver cancer cell line SMMC-7721 was purchased from the Cell Bank of the Chinese Academy of Sciences in Shanghai. The cells were cultured in complete medium, DMEM medium was added with 10% fetal bovine serum and 100u / ml penicillin (purchased from ...

Embodiment 3

[0066] Example 3 In vivo anti-tumor experiment of co-delivery nano-drug delivery system

[0067] 1. Experiment Mice and in vivo tumor studies

[0068] 1. In vivo tumor research in nude mice

[0069]All animal studies were approved in accordance with the guidelines and regulations of the Animal Ethics Committee of Nanjing Drum Tower Hospital. 4-6 week old male nude mice (BALB / c nude mice) were purchased from the Experimental Animal Center of Shanghai Academy of Sciences. The SMMC-7721 cells were resuspended in PBS, and the nude mice were infiltrated and anesthetized with isoflurane, and the cells were injected into the right axilla of the mice (25 mice, 5 in each group) (200 μL of PBS for each mouse contained 1× 10 7 cells). Tumor volume is about 100mm after two weeks 3 , the mice were randomly divided into 5 groups (PBS control group, LCP-II negative control group, LCP-II-FTY720 group, LCP-II-FTY720-sibeclin1 without FA group, LCPII-FTY720-sibeclin1 with FA group) And di...

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Abstract

The invention belongs to the field of pharmaceutical technology, and in particular relates to the field of targeted delivery pharmaceutical preparation, in particular to autophagy siRNA-Fingolimod co-delivered nano drug delivery system for targeting liver cancer, and a preparation method and use. The autophagy siRNA-Fingolimod co-delivered nano drug delivery system is disclosed. The preparation method of a siRNA co-carrying autophagy protein beclin1 and a nano drug-carrying system LCP-II-sibeclin1-FTY720 for actively targeting liver cancer are disclosed. Pharmacological experiments show that the nano drug-carrying system simultaneously carries the siRNA of beclin 1 and the FTY720, actively targets the liver cancer and delivers the siRNA into the liver cancer cell, and is released under theacidic environment in the liver cancer cell, has the function of resisting liver cancer, and has the value of developing the anti-liver cancer medicament.

Description

technical field [0001] The invention relates to the field of pharmacy, especially the field of drug preparations for targeted delivery, in particular to an autophagy siRNA-Fingolimod co-delivery nano-drug delivery system targeting liver cancer, its preparation method and application. Background technique [0002] Our research found that Fingolimod (FTY720, Fingolid) can effectively induce the apoptosis of liver cancer cells, and if it can inhibit the autophagy of liver cancer cells at the same time, the effect of FTY720 on liver cancer will be better, so the simultaneous application of FTY720 and targeting autophagy Phagocytic siRNA has synergistic anti-hepatocarcinogenesis effect. However, problems have been encountered in the process of applying FTY720 and SiRNA targeting autophagy. First, if FTY720 and SiRNA targeting autophagy are administered directly, the poor targeting in vivo will induce normal cell apoptosis and cause serious adverse effects. In addition, due to th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/137A61K31/713A61K48/00A61K47/54A61K47/02A61P35/00
CPCA61K47/02A61K47/545A61P35/00A61K31/137A61K31/713A61K2300/00
Inventor 吴俊华吴俊艺江春平王忠夏强光辉屈振纪安来马丁张广
Owner NANJING UNIV
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