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Co-delivery of lipid nanoparticles with autophagy siRNA-fingolimod targeting liver cancer

A lipid nanoparticle and autophagy technology, which is applied in the fields of genetic material components, medical preparations with non-active components, and medical preparations containing active components, etc., can solve problems such as adverse reactions, difficult to achieve, and normal cell apoptosis. , to achieve the effect of synergistically inducing apoptosis of liver cancer cells

Active Publication Date: 2019-08-20
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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  • Co-delivery of lipid nanoparticles with autophagy siRNA-fingolimod targeting liver cancer
  • Co-delivery of lipid nanoparticles with autophagy siRNA-fingolimod targeting liver cancer
  • Co-delivery of lipid nanoparticles with autophagy siRNA-fingolimod targeting liver cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation and Characterization of Nano Drug Delivery System LCP-II for Co-loading siRNA and FTY720

[0029] 1. Preparation, characterization and drug release experiment

[0030] 1. Preparation and characterization of nano drug delivery system LCP-II

[0031] The molecules that need to be co-loaded and delivered in the present invention are SiRNA and Fingolimod (FTY720, Fingolid), and the target protein of the SiRNA molecule is beclin1, which is used to knock down beclin1 to achieve the purpose of inhibiting autophagy.

[0032] First, 300μLCaCl 2 (500mM) and 100μL of siRNA (2mg / mL) were dispersed in 15ml of cyclohexane / surfactant (Igepal CO-520) mixture (71 / 29V / V) to prepare a water-in-oil microemulsion. Next, 300μL Na 2 HPO 4 (25mM pH=9.0) Disperse in another 15ml cyclohexane / surfactant (Igepal CO-520) mixture (71 / 29V / V), and add 200μL of DOPA dissolved in chloroform (20mg / mL) , In order to prepare the phosphoric acid phase. Then, the two were mixed and stirred fo...

Embodiment 2

[0041] Example 2 In vitro anti-tumor experiment of co-delivery of nano drug delivery system

[0042] 1. Material

[0043] 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), dioleoyl phosphatidic acid (DOPA) and per1,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-[ Methoxy (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 Biological Technology 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 Gema Gene Company.

[0044] 2. Cells and cell culture

[0045] Human hepatocellular carcinoma cell line SMMC-7721 was purchased from the Shanghai Chinese Academy of Sciences Cell Bank. The cells were cultured in complete medium. DMEM medium was supplemented with 10% fetal bovine serum and 100u / ml penicillin (purch...

Embodiment 3

[0067] Example 3 In vivo anti-tumor experiment of co-delivery of nano drug delivery system

[0068] 1. Experiment Mice and in vivo tumor studies

[0069] 1. Tumor research in nude mice

[0070] All animal studies were approved in accordance with the guidelines and regulations of the Animal Ethics Committee of Nanjing Gulou Hospital. Male nude mice (BALB / c nude mice) aged 4-6 weeks 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 anesthetized by isoflurane infiltration. The cells were injected into the right armpit of the mice (25 mice, 5 mice in each group) (each mouse 200μL PBS containing 1× 10 7 Cells). The 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 inject different compounds ...

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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 present invention relates to the field of pharmacy, in particular to the field of targeted delivery of pharmaceutical preparations, in particular to autophagy siRNA-Fingolimod co-delivery lipid nanoparticles for targeting liver cancer, and a preparation method and application thereof. Background technique [0002] Our research found that Fingolimod (FTY720, Fingolid) can effectively induce apoptosis of liver cancer cells, and if it can simultaneously inhibit the autophagy of liver cancer cells, FTY720 will have a better anti-liver cancer effect. Therefore, both FTY720 and targeted autophagy Phagocytic SiRNA has a synergistic effect on liver cancer. However, there are problems in the application of FTY720 and SiRNA targeting autophagy. First, if FTY720 and SiRNA targeting autophagy are directly administered, poor targeting in the body will induce normal cell apoptosis and cause serious adverse effects. Reaction; In addition, due to the negative charge o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/137A61K31/713A61K48/00A61K47/54A61K47/02A61P35/00
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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