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Publication Number
US-9636406-B2
Publication Date
2017-05-02
Expiration Date
Abstract
The invention provides a method for treating cancer using a coadministration strategy that combines local codelivery of a therapeutic agent and an intracellular penetration enhancing agent, and optionally in further combination with local administration of an immunotherapeutic agent, such as a cancer vaccine or NKT agonist. The invention also provides a method for treating cancer using an intracellular penetration enhancing agent. The methods of the invention aim to substantially kill and/or destroy the target tumor cells, as well as those cancerous cells that have metastasized to other parts of the body.
Core Innovation
The disclosed invention provides a method of treating cancer in a subject by locally/regional administration of a pharmaceutical composition comprising a therapeutically effective amount of a therapeutic agent and an intracellular permeation enhancing agent. The intracellular permeation enhancing agent facilitates the intracellular transport of the therapeutic agent across an intact cell membrane of the tumor while not having therapeutic activity. The therapeutic agent is not associated with a liposomal vesicle and is not covalently bound to the intracellular permeation enhancing agent.
In key embodiments, the composition is administered intratumorally as a solution containing the therapeutic agent and a selected intracellular permeation enhancing agent. The intracellular permeation enhancing agent is selected from 6-Oxo-6-phenylhexanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, N-[8-(2-hydroxybenzoyl)aminooctanoic acid], a functionally effective salt of any of the foregoing, or any combination thereof.
The disclosed system is directed to improving intracellular drug transport across intact tumor cell membranes using non-liposomal, non-covalently bound therapeutic agents, including chemotherapeutic agents, interfering RNA, therapeutic proteins, and therapeutic antibodies. The partial content further describes optional or combined use with immunotherapeutic agents to further enhance tumor shrinkage and destruction and reduce metastasis.
Claims Coverage
One independent claim is provided. Across the independent claim, three core inventive aspects are: intratumoral administration of a solution containing both a therapeutic agent and an intracellular permeation enhancing agent, a defined functional relationship where the permeation enhancing agent increases intracellular transport across intact tumor cell membranes without therapeutic activity, and a defined selection of permissible permeation enhancing agents and structural/association constraints on the therapeutic agent.
Intratumoral solution with non-therapeutic intracellular permeation enhancer
Intratumorally administering a pharmaceutical composition as a solution comprising a therapeutically effective amount of a therapeutic agent and an intracellular permeation enhancing agent that facilitates intracellular transport of the therapeutic agent across an intact cell membrane of the tumor and does not have therapeutic activity.
Therapeutic agent not in a liposomal vesicle and not covalently bound
Using a therapeutic agent that is not associated with a liposomal vesicle and is a chemotherapeutic agent, an interfering RNA, a therapeutic protein, or a therapeutic antibody, wherein the therapeutic agent is not covalently bound to the intracellular permeation enhancing agent.
Selected intracellular permeation enhancing agents (acids/salts/mixtures)
Selecting the intracellular permeation enhancing agent from 6-Oxo-6-phenylhexanoic acid, 8-Cyclohexyl-8-oxooctanoic acid, N-[8-(2-hydroxybenzoyl)aminooctanoic acid], a functionally effective salt of any of the foregoing, and/or any combination thereof.
The independent claim covers treating cancer by intratumorally administering a solution that pairs a therapeutically effective, non-liposomal, non-covalently bound therapeutic agent with a non-therapeutic intracellular permeation enhancing agent that promotes intracellular transport across intact tumor cell membranes, using a defined set of ketoacid-like enhancer compounds and salts.
Stated Advantages
Facilitates intracellular transport of the therapeutic agent across intact tumor cell membranes.
Optionally combined use with immunotherapeutic agents to further enhance tumor shrinkage and destruction and reduce metastasis.
Documented Applications
Treating solid tumors in a subject by intratumoral administration of a pharmaceutical composition comprising a therapeutic agent and an intracellular permeation enhancing agent.
Combining the approach with immunotherapeutic agents (e.g., cancer vaccines and NKT agonists such as α-Gal glycolipids or β-mannosylceramide) to enhance tumor shrinkage and destruction and reduce metastasis.
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