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Branched cationic lipids for nucleic acids delivery system

A cationic lipid and branched chain technology, which is applied in liposome delivery, organic chemistry, special delivery, etc., can solve the problem of not showing in vivo activity and achieve high transfection efficiency

Inactive Publication Date: 2011-10-12
ENZON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, they did not show significantly improved in vivo activity (especially in organs other than the liver) compared to using naked oligonucleotides

Method used

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  • Branched cationic lipids for nucleic acids delivery system
  • Branched cationic lipids for nucleic acids delivery system
  • Branched cationic lipids for nucleic acids delivery system

Examples

Experimental program
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preparation example Construction

[0284] B. Preparation of Cationic Lipids of Formula (I)

[0285] The method of preparing cationic lipids of formula (I) described herein involves reacting amine-functionalized cholesterol (functionalized cholesterol) with 1H-pyrazole-1-carboxamidine to provide a guanidinium moiety. The amines attached to the cholesterol can be primary and / or secondary and the amines in the 1H-pyrazole-1-carboxamidine can be unsubstituted or substituted.

[0286] figure 1 An illustrative example of the preparation of cholesteryl cationic lipids is shown in . Activated cholesterol carbonate, such as cholesteryl chloroformate, cholesteryl NHS carbonate, or cholesteryl PNP carbonate, is reacted with a nucleophilic amine, followed by deprotection of the Boc group to prepare compound 3 (with a band-encapsulated amine-terminated difunctional linker cholesterol). The blocked amine was further reacted with lysine to prepare cholesterol with branched moieties (compound 4). Compound 5 was prepared by...

Embodiment 1

[0677] Example 1. General NMR methods.

[0678] Unless otherwise stated, using a Varian Mercury 300NMR spectrometer, acquired at 300MHz 1 H NMR spectrum, 13C NMR spectrum was acquired at 75.46 MHz and deuterated chloroform was used as solvent. Chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS).

Embodiment 2

[0679] Example 2. General mRNA downregulation procedures.

[0680] Cells were maintained in complete medium (F-12K or DMEM supplemented with 10% FBS). Each well contains 2.5 x 10 5 A 12-well plate of cells was incubated overnight at 37°C. Use Opti-MEM The cells were washed once and 400 μL Opti-MEM added to each well. The cells were then treated with a solution of nanoparticles encapsulating nucleic acids or a solution of free nucleic acids (naked oligonucleotides) without nanoparticles (as a control). Cells were incubated for 4 hours, then 600 [mu]L of medium was added to each well and incubated for 24 hours. After 24 hours of treatment, intracellular mRNA levels of target genes such as human ErbB3 and housekeeping genes such as GAPDH were measured by RT-qPCR. Expression levels of mRNA were normalized to that of GAPDH.

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Abstract

The present invention is directed to cationic lipid for the delivery of oligonucleotides and methods of modulating an expression of a targeted gene using the nanoparticle compositions. In particular, the invention relates to cholesterol and its derivatives having multiple positively charged moieties via branching spacers, and nanoparticle compositions of oligonucleotides encapsulated in a mixture of a cationic lipid, a fusogenic lipid and a PEG lipid.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to US Provisional Patent Application Serial No. 61 / 115,307, filed November 17, 2008, the contents of which are incorporated herein by reference. field of invention [0003] The present invention relates to cationic lipids for oligonucleotide delivery and nanoparticle compositions containing the cationic lipids, as well as methods of modulating gene expression using the nanoparticle compositions. Background of the invention [0004] Therapies using nucleic acids have been proposed over the past few years as an attempt to treat various diseases. Therapies such as antisense therapy are powerful tools in the treatment of disease because therapeutic genes can selectively regulate the expression of genes associated with the disease and minimize the side effects that occur when using other therapeutic methods. [0005] However, therapeutics using nucleic acids are limited due t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/88C07J9/00
CPCA61K9/1272A61K31/7088A61P29/00A61P31/12A61P35/00A61P35/04C07J41/0055C12N15/111C12N15/113C12N15/1138C12N15/88C12N2310/11C12N2310/315C12N2310/3231C12N2310/3341C12N2320/32
Inventor 赵洪彦魏丽史连军乌德春
Owner ENZON PHARM INC
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