Modular targeted liposomal delivery system

Abstract

A liposome including a fusogenic liposome, a linking moiety and a targeting moiety. The fusogenic liposome is a lipid bilayer encapsulating contents. The linking moiety is electrostatically bound to the lipid bilayer, and the targeting moiety is covalently bound to the linking moiety. The liposome may also include a stabilizing moiety interposed between the linking and targeting moieties, and covalently bound to both. Alternatively, the stabilizing and targeting moieties may be covalently bound to separate linking moieties, the linking moieties being electrostatically bound to the lipid bilayer.

Description

FIELD OF THE INVENTION [0001] The invention relates to a targeted liposome capable of efficient intracellular delivery of one or more bioactive agents, a pharmaceutical composition including the targeted liposome, and a method of delivering the contents of a liposome to an in vivo or in vitro target site such as a tumor cell, site of inflammation or infection. BACKGROUND OF THE INVENTION [0002] Pharmaceutical usefulness of bioactive agents depends upon the ability to position therapeutically-effective quantities of intact agent at the target site in the patient. Delivering intact bioactive agents to target sites can be difficult: In vivo degradation of bioactive agents can occur, as well as absorption / retention of the agent by non-targeted systems. Even if pharmaceutically effective amounts of intact agent can be delivered to the vicinity of the target site, accessing the functional location of the site for the bioactive agent can be challenging, particularly if that location is int...

AI Technical Summary

Benefits of technology

"The invention is a system for delivering bioactive agents to cells using a fusogenic liposome, a linking moiety, and a targeting moiety. The liposome can contain drugs or other bioactive agents, and the targeting moiety can be a molecule or antibody that targets specific cells or receptors. The system can also include a stabilizing moiety that enhances the ability of the liposome to bind to cells and deliver the contents to the target site. The targeting moiety can be a vitamin, transferrin, or other molecule that binds to a cell surface receptor or expresses at a higher frequency on target cells. The system can be used to treat tumors, inflammation, or infection by delivering the liposomal contents to the targeted cells. The invention also includes a method of introducing a bioactive agent into a cell by preparing a targeted liposome, contacting it with a cell, and fusing the liposome with the cell membrane to release the bioactive agent into the cell."

Problems solved by technology

Delivering intact bioactive agents to target sites can be difficult: In vivo degradation of bioactive agents can occur, as well as absorption / retention of the agent by non-targeted systems.

Even if pharmaceutically effective amounts of intact agent can be delivered to the vicinity of the target site, accessing the functional location of the site for the bioactive agent can be challenging, particularly if that location is intracellular: For example, certain polar compounds and many large molecules can not enter cells at all because of their inability to cross target cell membranes.

In addition, dilution of the bioactive agent by non-specific binding to non-target sites reduces the amount of bioactive agent available to the target site.

Yet another challenge in the therapeutic delivery of drugs or bioactive agents is limiting the toxicities often associated with therapeutically effective concentrations of drugs or bioactive agents.

Even when a drug or bioactive agent has no toxicity associated with it, the “loss” of agent through degradation, removal by non-target organs and other delivery failures can significantly and prohibitively increase the cost of the therapy or decrease the efficacy.

While certain cells are known to engulf liposomes, delivery of most liposomes to a target site is not sufficient to deliver the encapsulated contents to the interior of the cell.

However, often these fusogenic liposomes lack stability when incubated in serum.

In addition, most fusogenic liposomes have not heretofore been able to be targeted to the specific site where the bioactive agent or drug is required.

Unfortunately, most known targeting and protecting strategies also generate large steric barriers on the surface of the liposomes that limit or prohibit fusogenic delivery of the liposomal contents into the interior of the cell.

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