The University of British Columbia

Inex Pharmaceuticals Corporation

Tekmira Pharmaceuticals Corporation

Hana Biosciences, Inc.

Arbutus Biopharma Corporation

Alnylam Pharmaceuticals, Inc.

Talon Therapeutics, Inc.

Sean C Semple

Pieter Rutter Cullis

Michael J Hope

Thomas D Madden

Steven Michial Ansell

Sandra K Klimuk

Peter Scherrer

Troy Harasym

Dan Debeyer

Barbara Mui

Quet F Ahkong

Jianxin Chen

Pieter R Cullis

Marco A Ciufolini

Norbert Maurer

Barbara Low Shoud Mui

Muthiah Manoharan

Kallanthottathil G Rajeev

Patricia M Logan

Murray S Webb

Kim F Wong

Andreas H Sarris

Fernando Cabanillas

Clive T R Burge

James H Goldie

Deirdre McIntosh

Nancy Dos Santos

Barbara L S Mui

Marco A Cuifolini

Barbara Ls Mui

Srinivasulu Masuna

Masunu Srinivasulu

The present invention provides superior compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of specific target proteins at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.

Amino lipids and methods for the delivery of nucleic acids

Methods for the preparation of a lipid-nucleic acid composition are provided. According to the methods, a mixture of lipids containing a protonatable or deprotonatable lipid, for example an amino lipid and a lipid such as a PEG- or Polyamide oligomer-modified lipid is combined with a buffered aqueous solution of a charged therapeutic agent, for example polyanionic nucleic acids, to produce particles in which the therapeutic agent is encapsulated in a lipid vesicle. Surface charges on the lipid particles are at least partially neutralized to provide surface-neutralized lipid-encapsulated compositions of the therapeutic agents. The method permits the preparation of compositions with high ratios of therapeutic agent to lipid and with encapsulation efficiencies in excess of 50%.

Lipid-encapsulated polyanionic nucleic acid

The present invention includes novel liposomes comprising dihydrosphingomyelin. The invention also includes compositions comprising these liposomes and a therapeutic agent, in addition to methods and kits for delivering a therapeutic agent or treating a disease, e.g., a cancer, using these compositions.

Liposomal formulations comprising dihydrosphingomyelin and methods of use thereof

This invention relates to liposomal antineoplastic agents (e.g., camptothecin) compositions and methods of using such compositions for treating neoplasia and for inhibiting angiogenesis. The compositions and methods are useful for modulating the plasma circulation half-life of an active agent.

Liposomal antineoplastic drugs and uses thereof

This invention provides compositions and methods for treating neoplasias in a mammal. In particular, the invention provides liposome-encapsulated vinca alkaloids, e.g., vinorelbine, and methods of treating a mammal using such compositions.

Compositions and methods for treating cancer

This invention relates to improved liposomal camptothecin compositions and methods of manufacturing and using such compositions for treating neoplasia and for inhibiting angiogenesis.

Liposomal camptothecins and uses thereof

Lipidic compositions with superior characteristics for in vivo delivery of oligodeoxynucleotides (ODN) can easily and efficiently be made in the form of small multilamellar vesicles. The compositions contain a population of nucleic acid-containing lipid vesicles in a liquid carrier, and at least a portion of the lipid vesicles are small multilamellar vesicles. The small multilamellar vesicles are made from a lipid component including 20-30 mol % of an ionizable amino lipid such as DODAP, and a steric barrier lipid such as PEG-CerC ; and an oligodeoxynucleotide contained in the lumen or interlamellar spaces of the small multilamellar vesicles. The ODN and lipid components are preferably present in the small multilamellar vesicles in a mole ratio of from 0.15 to 0.25. The compositions of the invention can be made by preparing two solutions: a lipid mixture with 20-30 mol % of the ionizable amino lipid, the steric barrier lipid and additional lipid components selected from among neutral lipids and sterols in an ethanolic solvent; and a solution of oligodeoxynucleotide in an aqueous solvent having a pH at which the ionizable amino lipid is positively charged. The lipid mixture is added to the solution of oligodeoxynucleotide to form a mixture containing lipid vesicles which is then massed through a filter to produce sized lipid vesicles in a solution containing ethanol. The ethanol is then removed, for example by dialysis. Then, the pH of the solution surrounding the sized lipid vesicles is increased to reduce the net positive charge on the exterior of the sized lipid vesicles.

Composition containing small multilamellar oligodeoxynucleotide-containing lipid vesicles

Lipid-therapeutic agent particles are prepared containing a charged therapeutic agent encapsulated in lipid portion containing at least two lipid components including a protonatable or deprotonatable lipid such as an amino lipid and a lipid that prevents particle aggregation during lipid-therapeutic agent particle formation such as a PEG-modified or polyamide oligomer-modified lipid. Other lipid components may also be present and these include a neutral lipid such as DSPC, POPC, DOPE or SM, and a sterol such as Chol. The therapeutic agent is encapsulated by combining a mixture of the lipids with a buffered aqueous solution of a charged therapeutic agent to form an intermediate mixture containing lipid-encapsulated therapeutic agent particles, and changing the pH of the intermediate mixture to neutralize at least some surface charges on the particles. The method permits high ratios of therapeutic agent to lipid and encapsulation efficiencies in excess of 50%. The method is particularly useful for preparing lipid-encapsulated nucleic acids such as an antisense polyanionic nucleic acid having exclusively phosphodiester linkages. The encapsulated nucleic acid can be contacted with a cell to introduce the nucleic acid into the cell such as for treatment or prevention of a disease characterized by aberrant expression of a gene. A pharmaceutical composition may be prepared containing the lipid-encapsulated therapeutic agent particles and a carrier.

Charged therapeutic agents encapsulated in lipid particles containing four lipid components

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Vancouver, Canada

Sean C Semple