Lipids, lipid compositions, and methods of using them

Abstract

Disclosed are formulation and optimization protocols for delivery of therapeutically effective amounts of biologically active agents to liver, tumors, and/or other cells or tissues. Also provided are compositions and uses for cationic lipid compounds of formula (I).

The invention also relates to compositions and uses for stealth lipids of formula (XI).

Also provided are processes for making such compounds, compositions, and formulations, plus methods and uses of such compounds, compositions, and formulations to deliver biologically active agents to cells and/or tissues.

Description

[0001]This application claims benefit under 35 U.S.C. §119(e) of U.S. Provisional Application 61 / 284,787, filed 23 Dec. 2009, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]This invention relates to cationic lipid compounds, stealth lipid compounds and to compositions comprising such compounds. The invention also relates to processes for making such compounds and compositions, and to methods and uses of such compounds and compositions, e.g., to deliver biologically active agents to cells and tissues. The invention describes optimized pKa ranges for cationic lipids for use in lipid formulations to deliver biologically active agents to specific cell types, including especially liver and tumors, and methods for optimizing the formulations.BACKGROUND TO THE INVENTION[0003]The delivery of biologically active agents (including therapeutically relevant compounds) to subjects is often hindered by difficulties in the compounds reachin...

AI Technical Summary

Benefits of technology

[0021]The invention provides novel cationic lipids and stealth lipids, and formulations containing them, and their methods of use. Also provided are formulations for use of such lipids for delivery of therapeutically effective amounts of drugs, including especially RNAi constructs, for delivery to subject in need thereof. Particular formulations containing cationic lipids with a pKa within specific ranges are provided for administering therapeutically effective amounts of drugs to the liver and / or to tumor in the somatic tissues of a subject. As a general rule (to which there are exceptions), formulations that are the most effective for delivery to tumors (as described in greater detail below) contain cationic lipids with a pKa of about 6.1 or below, although particular ranges include from about 5.0 to about 6.7, including especially from about 5.2 to about 6.3, or from about 5.4 to about 6.2, or from about 5.8 to about 6.1, depending on tumor type; whereas formulations that are the most effective for delivery to liver (as described in greater detail below) contain cationic lipids with a pKa of about 6.1 or above, although particular ranges include from about 5.1 to about 7.4, including from about 5.3 to about 7.3, and including especially from about 5.9 to about 7.0, and in one embodiment is from about 6.2 to about 6.8.

Problems solved by technology

The delivery of biologically active agents (including therapeutically relevant compounds) to subjects is often hindered by difficulties in the compounds reaching the target cell or tissue.

In particular, the trafficking of many biologically active agents into living cells is highly restricted by the complex membrane systems of the cells.

These restrictions can result in the need to use much higher concentrations of biologically active agents than is desirable to achieve a result, which increases the risk of toxic effects and side effects.

One class of biologically active agents that is particularly difficult to deliver to cells is a biotherapeutic (including nucleosides, nucleotides, polynucleotides, nucleic acids and derivatives).

Viral vectors can be used to transfer genes efficiently into some cell types, but they generally cannot be used to introduce chemically synthesized molecules into cells.

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