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Releasable polymeric lipids for nucleic acids delivery systems

A technology of polymers and compounds, applied in the directions of liposome delivery, application, drug combination, etc., can solve problems such as nucleic acid therapy limitations, and achieve the effects of coordination, enhanced bioavailability, and high transfection efficiency

Inactive Publication Date: 2011-11-02
ENZON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, therapeutics using nucleic acids have so far been limited due to difficulties associated with the delivery and stability of such therapeutic nucleic acids

Method used

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  • Releasable polymeric lipids for nucleic acids delivery systems
  • Releasable polymeric lipids for nucleic acids delivery systems
  • Releasable polymeric lipids for nucleic acids delivery systems

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0941] Example 1. Conventional NMR method

[0942] Unless otherwise specified, using a Varian Mercury 300NMR spectrometer and deuterium chloroform as solvent at 300MHz 1 H NMR spectrum and acquired at 75.46MHz 13 C NMR spectrum. Partial parts per million (ppm) chemical shifts (δ) downfield from tetramethylsilane (TMS) are reported.

Embodiment 2

[0943] Embodiment 2. Conventional HPLC method

[0944] by Beckman Coulter System Gold HPLC equipment monitored the purity of the reaction mixture and intermediate and final products. It uses a ZORBAX with a 168 diode array UV detector 300SB C8 reverse phase column (150×4.6mm) or Phenomenex Jupiter 300A C18 reverse phase column (150x4.6mm) using a gradient of 10-90% acetonitrile in 0.05% TFA at a flow rate of 1 mL / min or a gradient of 25-35% acetonitrile in 50 mM TEAA buffer at a flow rate of 1 mL / min. Anion exchange chromatography was run on an AKTA detector 100A from GE healthcare (Amersham Biosciences) using Poros 50HQ strong anion exchange resin from Applied Biosystems packed with water in AP empty glass columns. Desalting (for PEG-Oligo) was achieved by using a HiPrep 26 / 10 desalting column from Amersham Biosciences.

Embodiment 3

[0945] Example 3. Conventional mRNA downregulation procedures

[0946] 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 Wash the cells once and add 400 μL Opti-MEM to each well . Then, a nanoparticle solution containing oligonucleotides or Lipofectamine2000 was added to each well . Cells were incubated for 4 hours, after which 600 [mu]L of medium per well was added 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 quantified by RT-qPCR. Normalize mRNA expression levels.

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Abstract

The present invention relates to polymer conjugated releasable lipids and nanoparticle compositions containing the same for the delivery of nucleic acids and methods of modulating gene expression using the same. In particular, this invention relates to releasable polymeric lipids containing an acid-labile linker based on a ketal or acetal-containing linker, or an imine-containing linker.

Description

[0001] Related Applications Cited [0002] This application claims priority to US Provisional Patent Application Nos. 61 / 115,371 and 61 / 115,379, filed December 17, 2008, the contents of which are incorporated herein by reference. Background of the invention [0003] Therapy using nucleic acids has been proposed for the treatment of a variety of diseases. One such proposed nucleic acid therapy is antisense therapy, in which a therapeutic gene selectively regulates the expression of disease-associated genes and minimizes the side effects associated with other therapeutic approaches to treating the disease. [0004] However, therapy using nucleic acids has so far been limited due to difficulties associated with the delivery and stability of such therapeutic nucleic acids. Several gene delivery systems have been proposed to overcome the aforementioned difficulties to efficiently introduce therapeutic genes into target regions, such as cancer cells or other cells or tissues in vit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/04
CPCC07C233/49C07C237/22C07C251/24A61K31/785A61K47/48815A61K47/6911A61P29/00A61P31/12A61P35/00A61P43/00
Inventor 赵洪彦魏丽史连军乌德春
Owner ENZON PHARM INC