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Drug delivery system of small interfering RNA drug and preparation

A drug and copolymer technology, applied in the field of small interfering RNA drug delivery systems and preparations, can solve the problems of difficult to meet clinical applications, low siRNA encapsulation rate, and low drug loading, and achieve the encapsulation rate and drug loading. High effect, low potential toxicity, simple preparation method

Inactive Publication Date: 2015-03-11
SUZHOU RIBO LIFE SCIENCE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Such nanoparticles are generally prepared by using polylactic acid, polyglycolic acid, or a copolymer of the two. The disadvantage is that the encapsulation efficiency of siRNA is very low (less than 30%), and the drug loading is very low, which is difficult to meet the requirements of clinical application. Require

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  • Drug delivery system of small interfering RNA drug and preparation
  • Drug delivery system of small interfering RNA drug and preparation
  • Drug delivery system of small interfering RNA drug and preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1, the preparation of siRNA delivery system and preparation

[0061] siRNA-loaded nanoparticles were prepared by a double-emulsion method using amphiphilic block polymers and cationic lipids. The polyethylene glycol-polylactic acid or polyethylene glycol-poly(lactic acid glycolic acid) diblock / triblock copolymer used is the above-mentioned polymer PEG 550 -PLA 28600 、PEG 2000 -PLA 12500 、PEG 5000 -PLA 5000 、PEG 5000 -PLA 25000 、PEG 5000 -PLA 51000 、PEG 10000 -PLA 15000 、PEG 10000 -PLGA 10000(50 / 50) 、PEG 10000 -PLGA 50000(75 / 25) , PLA 6300 -PEG 1200 -PLA 6300 , PLA 4800 -PEG 5000 -PLA 4800 , PLA 4800 -PEG 10000 -PLA 4800 (Subscripts are molecular weight and ratio). The cationic lipids used were the above-mentioned BHEM-Chol, DOTAP, and DOTMA, respectively. The siRNA drug delivery system with different properties is prepared by changing the quality of the added cationic lipid, the quality of the added siRNA, the type of polymer used, an...

Embodiment 2

[0109] Embodiment 2, the evaluation of the effect of this drug delivery system at the cellular level

[0110] According to Example 1, when siRNA / cationic lipid / polymer=0.2 / 1.0 / 25.0, the obtained siRNA drug delivery system has higher siRNA encapsulation efficiency and drug loading capacity. Therefore, this example is used to illustrate the biological effect of this drug delivery system. The polymer used is PEG 550 -PLA 28600 、PEG 2000 -PLA 12500 、PEG 5000 -PLA 5000 、PEG 5000 -PLA 25000 、PEG 5000 -PLA 51000 、PEG 10000 -PLA 15000 、PEG 10000 -PLGA 10000(50 / 50) 、PEG 10000 -PLGA 50000(75 / 25) , PLA 6300 -PEG 1200 -PLA 6300 , PLA 4800 -PEG 5000 -PLA 4800 , PLA 4800 -PEG 10000 -PLA 4800 , the cationic lipid used is BHEM-Chol.

[0111] 1. Biocompatibility evaluation of nanoparticles prepared from different polymers

[0112] Nanoparticles not loaded with siRNA were prepared by the method described in Example 1. The toxicity of nanoparticles to human liver cance...

Embodiment 3

[0166] Embodiment 3, the biological effect evaluation of this drug delivery system at animal level

[0167] It can be seen from the experiment at the cell level that when the method described in Example 1 is used to prepare nanoparticles loaded with siRNA, when the ratio of each component is siRNA / cationic lipid / polymer=0.2 / 1.0 / 25.0, the cationic lipid used is BHEM-Chol, the polymer used is PEG 5000 -PLA 25000 When the prepared nanoparticles loaded with siRNA can effectively enter the cells, and can significantly silence the expression of the target gene, this formula is used to prepare the nanoparticles loaded with siRNA NP (PEG 5000 -PLA 25000 ) as an example to study the biological effects of this drug delivery system at the animal level.

[0168] 1. Inhibition of firefly luciferase expression by tumor cells implanted in liver orthotopically implanted with siLuci nanoparticles

[0169] Luciferase is firefly luciferase, which can catalyze the emission of visible light th...

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Abstract

A delivery system and preparation of siRNA, with nanoparticles enclosing siRNA as an active ingredient, wherein the nano-particles are formed by a polymer and a cationic lipid, the polymer is a di-block or tri-block copolymer of polyethylene glycol-polylactic acid or polyethylene glycol-poly(lactic acid-glycolic acid), the cationic lipid is N,N-dihydroxyethyl-N-methyl-N-2-(cholesteroloxy carbonylamino) ethylammonium bromide or (2,3-dioleyloxy propyl) trimethylammonium chloride. The nanoparticle and preparation can desirably deliver siRNA to a cell and effectively silence expression of a target gene. Moreover, after being modified by a ligand or antibody, the siRNA delivery system can desirably silence the target gene at both a cellular level and an animal level.

Description

technical field [0001] The present invention relates to a polyethylene glycol-polylactic acid or polyethylene glycol-poly(lactic acid-glycolic acid) diblock / triblock copolymer (amphiphilic high molecular polymer) and a cationic lipid material co-prepared Drug delivery systems and formulations of small interfering RNA (siRNA). Background technique [0002] Small interfering RNA has the ability to specifically inhibit the expression of disease-causing genes, as well as its high efficiency and diverse characteristics. In recent years, it has shown good application prospects in the treatment of a large number of diseases such as hepatitis, AIDS, age-related macular degeneration, avian influenza, and cancer. . For example, the RNA interference-based CALAA-01 preparation developed by Calendo Pharmaceuticals has shown the effect of treating cancer in a phase I clinical trial after systemic administration. There is reason to believe that siRNA-based RNA interference therapy may be...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K48/00A61K47/34A61P35/00
CPCC12N15/88A61K9/5153A61P35/00
Inventor 不公告发明人
Owner SUZHOU RIBO LIFE SCIENCE CO LTD
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