Novel Compositions for the Delivery of Negatively Charged Molecules

a technology of negatively charged molecules and compositions, applied in the direction of organic chemistry, sugar derivatives, steroids, etc., can solve the problems of high restriction of charged molecules into living cells, inability to introduce chemically synthesized molecules into cells, and limited utility, so as to facilitate the diffusion of the enhancer:polymer complex

Inactive Publication Date: 2010-02-11
SIRNA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0038]In yet another embodiment, the lipid molecules of the invention, such as cationic lipids, are provided as a lipid aggregate, such as a liposome, and co-encapsulated with the compound or polymer to be delivered. Liposomes, which can be unilamellar or multilamellar, can introduce encapsulated material into a cell by different mechanisms. See, Ostro, Scientific American 102, January 1987. For example, the liposome can directly intr

Problems solved by technology

Trafficking of large, charged molecules into living cells is highly restricted by the complex membrane systems of the cell.
Viral vectors can be used to transfer genes efficiently into some cell types, but they cannot be used to introduce chemically synthesized molecules into cells.
Synthetic nucleic acids as well as plasmids may be delivered using the cytofectins, although their utility is often limited by cell-type specificity, requirement for low serum du

Method used

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  • Novel Compositions for the Delivery of Negatively Charged Molecules
  • Novel Compositions for the Delivery of Negatively Charged Molecules
  • Novel Compositions for the Delivery of Negatively Charged Molecules

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Diaminobutyric Acid and Guanidinium-Based Cationic Lipids (FIG. 2)

[0139]Synthesis of palmityloleylamine (1): 1-bromohexadecane (15.27 g, 50 mmol) was rapidly added to oleylamine (26.75 g, 100 mmol) at 100° C. The reaction mixture was heated at 120° C. for 30 minutes and than cooled to room temperature. Chloroform (200 ml) was added followed by 1 N NaOH (50 ml). The mixture was then extracted with H2O (200 ml), the organic layer dried (Na2SO4) and concentrated to a syrup. Silica gel column chromatography using 5-20% gradient methanol in dichloromethane afforded 20.5 g of palmityloleylamine as a syrup (yield, 83%). The identity of the product was confirmed using NMR spectroscopy. 1H NMR (CDCl3) d 5.34 (m, 2H, CH═CH), 2.58 (m, 4H), 2.00 (m, 4H), 1.47 (m, 4H), 1.25 (m, 48H), 0.86 (m, 6H). FAB-MS: 493 [M+H]+. (Other reagents could include oleyl-bromide and hexadecane amine)

[0140]Synthesis of N′-palmityl-N′-oleyl-N-CBZ-glycinamide (2): (1) (2.46 g, 5 mmol) was added to a solu...

example 2

Synthesis of DS 46596 (12)

[0148]Synthesis of Cholesterylamine (10): Referring to FIG. 3, cholesteryl chloride (10 grams, 25 mmol) was partially dissolved in dry methanol (50 ml) and the solution was heated with stirring to 155° C. for 18 hr at 500 psig using a 300 ml Parr bomb apparatus charged with dry ammonia gas. The bomb was cooled to room temperature and the methanol was removed by steam distillation on a rotary evaporator. Compound 10 was purified using E. Merck silica chromatography by eluting with dichloromethane / methanol (4:1 v / v) to yield 4 grams of the ninhydrin positive product (yield, 60%). Identity was confirmed by ES-MS.

[0149]Synthesis of Boc3arginineNHcholesterylamide (11): A 200 mL pear shaped flask with stir bar was charged with a mixture of 10 (1 g, 2.6 mmol), Boc3 arginine (1.2 grams, 2.6 mmol), diisopropylcarbodiimide (450 ul, 2.9 mmol) and dichloromethane (70 mls). The mixture of reagents was stirred at room temperature for two hours. Following the reaction, th...

example 3

Synthesis of PH 55933 (15) and PH 55938 (16)

[0151]Synthesis of (13): Referring to the FIG. 4, to a solution of methylphosphonic dichloride (0.332 g, 2.5 mmol, 31P NMR s, 43.93 ppm) stirring at room temperature under positive pressure argon was added 4-dimethylaminopyridine (DMAP) (0.31 g, 2.5 mmol). The resulting clear, colorless solution was cooled to −70° C. and a solution of cholesterol (0.97 g, 2.5 mmol) suspended in anhydrous dichloromethane (20 ml) was added via syringe with vigorous stirring over a period of one hour. The reaction mixture was allowed to warm to room temperature and was maintained at room temperature for 18 hours at which time 31P NMR analysis of a small aliquot of the reaction mixture indicated complete reaction (d, 39.08 ppm).

[0152]Crude (13) was treated with additional DMAP (0.31 g, 2.5 mmol) and the reaction mixture cooled to −70° C. while stirring under positive pressure argon. H-Lys(Z)-OCH3 (0.66 g, 2.25 mmol) in anhydrous dichloromethane (20 ml) was add...

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Abstract

This invention features permeability enhancer molecules, and methods, to increase membrane permeability of various molecules, such as nucleic acids, polynucleotides, oligonucleotides, enzymatic nucleic acid molecules, antisense nucleic acid molecules, 2-5A antisense chimeras, triplex forming oligonucleotides, decoy RNAs, dsRNAs, siRNAs, aptamers, or antisense nucleic acids containing nucleic acid cleaving chemical groups, peptides, polypeptides, proteins, carbohydrates, steroids, metals and small molecules, thereby facilitating cellular uptake of such molecules.

Description

FIELD OF THE INVENTION[0001]This patent application is a continuation of Beigelman et al., U.S. Ser. No. 09 / 120,520, filed Jul. 21, 1998, entitled “NOVEL COMPOSITIONS FOR THE DELIVERY OF NEGATIVELY CHARGED MOLECULES”, which claims priority from Beigelman et al., U.S. Ser. No. 60 / 053,517, filed Jul. 23, 1997, entitled “NOVEL COMPOSITIONS FOR THE DELIVERY OF NEGATIVELY CHARGED MOLECULES” and Beigelman et al., U.S. Ser. No. 60 / 072,967, filed Jan. 29, 1998, entitled “NOVEL COMPOSITIONS FOR THE DELIVERY OF NEGATIVELY CHARGED MOLECULES”. These applications are hereby incorporated by reference herein in their entirety including the drawings.BACKGROUND OF THE INVENTION[0002]The following is a brief description of the delivery of biopolymers. This summary is not meant to be complete but is provided only for understanding of the invention that follows. This summary is not an admission that all of the work described below is prior art to the claimed invention.[0003]Trafficking of large, charge...

Claims

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Application Information

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IPC IPC(8): C07J43/00A61K47/48C07C237/06C07C237/22C07C279/04C07C279/12C07C279/14C07D213/64C07H19/06C07J1/00C07J41/00C07J51/00C12N15/88
CPCA61K47/48023C12N15/88A61K47/48046C07C237/06C07C237/22C07C279/04C07C279/12C07C279/14C07D213/64C07H19/06C07J1/00C07J41/0005C07J43/003C07J51/00A61K47/48038A61K47/54A61K47/542A61K47/543A61K38/05
Inventor BEIGELMAN, LEONIDCHAUDHARY, NILABHHAEBERLI, PETERKARPEISKY, ALEXANDERMATULIC-ADAMIC, JASENKAMIN, JOHNREYNOLDS, MARKSWEEDLER, DAVID
Owner SIRNA THERAPEUTICS INC
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