Liposome composition for improved intracellular delivery of a therapeutic agent
First Claim
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1. A liposome composition for intracellular delivery of a therapeutic agent, comprising liposomes consisting essentially of (i) a pH-sensitive lipid;
- (ii) between 1-20 mole percent of a lipid derivatized with a hydrophilic polymer, said polymer attached to said lipid by a bond effective to release the hydrophilic polymer in response to an existing or an induced physiologic condition;
(iii) a targeting ligand; and
(iv) an entrapped therapeutic agent;
wherein said composition is adapted to bind to a target cell and to release said entrapped agent to achieve at least a two-fold increase in intracellular concentration of the agent, when compared to intracellular concentration of the agent delivered by similar liposomes lacking said releasable bond and/or said targeting ligand.
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Abstract
A liposomal composition and a method of using the same for achieving intracellular delivery of a liposome-entrapped agent is described. The liposomes are composed of a pH sensitive lipid and include a targeting ligand to direct the liposomes to a target cell. The liposomes also include a stabilizing component, such a polymer-derivatized lipid, where the polymer is attached to the lipid by a releasable linkage. Administration of the liposomes results in cellular internalization and destabilization of the liposome for intracellular delivery of the entrapped agent.
19 Citations
29 Claims
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1. A liposome composition for intracellular delivery of a therapeutic agent, comprising liposomes consisting essentially of (i) a pH-sensitive lipid;
- (ii) between 1-20 mole percent of a lipid derivatized with a hydrophilic polymer, said polymer attached to said lipid by a bond effective to release the hydrophilic polymer in response to an existing or an induced physiologic condition;
(iii) a targeting ligand; and
(iv) an entrapped therapeutic agent;
wherein said composition is adapted to bind to a target cell and to release said entrapped agent to achieve at least a two-fold increase in intracellular concentration of the agent, when compared to intracellular concentration of the agent delivered by similar liposomes lacking said releasable bond and/or said targeting ligand. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
- (ii) between 1-20 mole percent of a lipid derivatized with a hydrophilic polymer, said polymer attached to said lipid by a bond effective to release the hydrophilic polymer in response to an existing or an induced physiologic condition;
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10. A method for increasing intracellular cytotoxicity of a liposome-entrapped agent, comprising
providing liposomes consisting essentially of (i) a pH-sensitive lipid; - (ii) between 1-20 mole percent of a lipid derivatized with a hydrophilic polymer, said polymer attached to said lipid by a bond effective to release the hydrophilic polymer in response to an existing or an induced physiologic condition;
(iii) a targeting ligand; and
(iv) an entrapped therapeutic agent;
administering said liposomes to achieve (i) cleavage of the releasable bond, thereby releasing said hydrophilic polymer chain;
(ii) binding of said ligand to a target cell, where said binding occurs prior to or subsequent to said cleavage; and
(iii) internalization of said liposome by said target cell;
whereby said administering is effective to achieve at least a two-fold higher intracellular cytotoxicity of said agent, relative to intracellular concentration of the agent delivered by similar liposomes lacking said releasable bond and/or said targeting ligand. - View Dependent Claims (11, 12, 13, 14, 15, 16, 17, 18)
- (ii) between 1-20 mole percent of a lipid derivatized with a hydrophilic polymer, said polymer attached to said lipid by a bond effective to release the hydrophilic polymer in response to an existing or an induced physiologic condition;
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19. The method of claim 19, wherein said disulfide linkage is a dithiobenzyl bond.
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20. A method for increasing accumulation of a therapeutic agent into cellular nuclei, comprising
providing liposomes consisting essentially of (i) a pH-sensitive lipid; - (ii) between 1-20 mole percent of a lipid derivatized with a hydrophilic polymer, said polymer attached to said lipid by a bond effective to release the hydrophilic polymer in response to an existing or an induced physiologic condition;
(iii) a targeting ligand; and
(iv) an entrapped therapeutic agent;
administering said liposomes to achieve (i) cleavage of the releasable bond, thereby releasing said hydrophilic polymer chain;
(ii) binding of said ligand to a target cell, where said binding occurs prior to or subsequent to said cleavage; and
(iii) internalization of said liposome by said target cell;
whereby said administering is effective to achieve at least a two-fold higher accumulation of said agent in the nucleus of the target cell, when compared to intracellular concentration of the agent delivered by similar liposomes lacking said releasable bond and/or said targeting ligand. - View Dependent Claims (21, 22, 23, 24, 25, 26, 27, 28, 29)
- (ii) between 1-20 mole percent of a lipid derivatized with a hydrophilic polymer, said polymer attached to said lipid by a bond effective to release the hydrophilic polymer in response to an existing or an induced physiologic condition;
Specification
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Current AssigneeSamuel Zalipsky, Shi Kun Huang, Theresa M. Allen
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Original AssigneeSamuel Zalipsky, Shi Kun Huang, Theresa M. Allen
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InventorsZalipsky, Samuel, Allen, Theresa M., Huang, Shi Kun
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Application NumberUS11/472,140Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current424/144.100CPC Class CodesA61K 47/6913 the liposome being modified...A61K 9/1271 Non-conventional liposomes,...A61K 9/1272 with substantial amounts of...
