Biodegradable mixed polymeric micelles for gene delivery

A polymer and polyester technology, applied in gene therapy, use of microcapsules, applications, etc., can solve the problems of replicating host immune responses, cytotoxic complaints, and only orientation.

Inactive Publication Date: 2001-01-24
三阳有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, their application in vivo is very limited
Their disadvantages include: targeting only to dividing cells, random insertion into the host genome, risk of replication, and possible host immune response
However, transfection efficiency with cationic lipids remains low compared to viral vectors, and its cytotoxicity has drawn increasing complaints

Method used

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  • Biodegradable mixed polymeric micelles for gene delivery
  • Biodegradable mixed polymeric micelles for gene delivery

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] This example describes poly(L-lactic acid)-poly(L-serine ester) diblock copolymers and poly(L-lactic acid)-poly(N-lactosyl-L-serine ester) diblock copolymers Process for preparing mixed polymeric micelles.

[0037] Poly(N-benzyloxycarbonyl-L-serine ester) diblock copolymer. First, according to the steps described in Macromolecules, No. 23, 1990, pages 65-70 (incorporated herein for reference), equimolar amounts of 4-(dimethylamino)pyridine and p-toluenesulfonic acid were added in the absence of React in water and benzene to obtain 4-(dimethylamino)pyridinium 4-methylbenzenesulfonate. Put 2.392 grams of N-benzyloxycarbonyl (N-CBZ) serine into a double-necked round-bottomed flask equipped with a stirring bar, a nitrogen pipeline and a rubber septum, under nitrogen protection, add 30 milliliters of tetrahydrofuran with a syringe, and dissolve it dissolve. A solution of 2.94 g of 4-(dimethylamino)pyridinium 4-toluenesulfonate and diisopropylcarbodiimide in 80 ml of dichl...

Embodiment 2

[0043] This example describes poly(L-lactic acid)-poly(L-serine ester) diblock copolymers and poly(L-lactic acid)-poly(N-lactosyl-L-serine ester) diblock copolymers Process for preparing mixed polymeric micelles.

[0044] The procedure is the same as in Example 1, except that the amine-terminated poly(L-lactic acid) is prepared by ring-opening polymerization of L-lactide initiated by N-trityl ethanolamine. At room temperature, 3 g of trityl chloride was stirred in 20 ml of ethanolamine to obtain N-trityl ethanolamine. After filtration, the product was separated out, and the product was recrystallized in methanol-water (9:1) for purification. The polymerization of L-lactide was initiated with N-trityl ethanolamine in refluxing toluene in the presence of a catalytic amount of stannous octoate. Poly(L-lactic acid) was precipitated with a large excess of diethyl ether. Trityl groups were removed with 0.1 M trifluoroacetic acid in dioxane.

Embodiment 3

[0046] This example describes poly(L-lactic acid)-poly(L-lysine) graft copolymers and poly(L-lactic acid)-poly(N-lactosyl-L-lysine) graft copolymers Process for preparing mixed polymeric micelles.

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Abstract

A biodegradable, mixed polymeric micelle used to deliver a selected nucleic acid into a targeted host cell contains an amphiphilic polyester-polycation copolymer and an amphiphilic polyester-sugar copolymer. The polyester-polycation copolymer forms an electrostatic interaction with polyanionic nucleic acids, and the polyester-sugar copolymer directs the micelle-nucleic acid complex to cells in vivo. Additional copolymers with similar properties may also be included. The composition improves delivery efficiency by providing a particulate gene carrier for which particle size and charge density are easily controlled by multivariate means. Various kinds of ligands and other functional compounds may be also be introduced using the composition. The composition may be used in a method for transforming a targeted host cell with a selected nucleic acid.

Description

[0001] INTERNATIONAL REFERENCE TO RELATED APPLICATIONS This application claims the benefit of US Provisional Patent Application No. 60 / 069,551 (filed December 12, 1997). Background of the invention [0002] The present invention relates to systems for gene delivery into eukaryotic cells. In particular, the present invention relates to compositions and methods for delivering selected nucleic acids into host cells via biodegradable mixed polymeric micelles containing amphiphilic polyester-polycationic copolymers and amphiphilic polyester-sugars copolymer. [0003] As early as the mid-1950s, methods for the delivery of nucleic acids into tissue culture cells were established, see H.E. Alexander et al., Virology, Vol. 5, pp. 172-173 (1958). Since then, steady progress has been made in improving the in vivo and in vitro delivery of functional DNA, RNA and antisense oligonucleotides (inhibitors of RNA function). In the late 1970s, due to the integration of transfection technology ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N11/06A61K9/107A61K9/127A61K9/51A61K31/7088A61K47/34A61K48/00C12N15/88
CPCA61K48/00Y10S977/916A61K9/1075C12N15/88Y10S977/907A61K48/0041C12N11/06
Inventor Y·K·乔伊J·S·基姆
Owner 三阳有限公司
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