Lipid-comprising drug delivery complexes and methods for their production
First Claim
1. A lipid-nucleic acid complex comprising a compacted nucleic acid, a polycation, a targeting factor, and a lipid, wherein:
- a) the targeting factor increases cellular bioavailability of the nucleic acid by a means other than interaction with a specific outer cell surface membrane receptor;
b) the complex does not comprise a protamine or a salt thereof; and
c) the mean diameter of the complex is greater than about 100 nm and less than 400 nm.
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Abstract
Novel stable, concentrated, biologically active and ready-to-use lipid-comprising drug delivery complexes and methods for their production are described. The. complexes of the invention comprise a drug, at least one lipid species, optionally at least one polycation, and at least one targeting factor. The at least one lipid species may comprise a pegylated lipid. The complexes of the invention may provoke lower levels of inflammatory cytokines such as tumor necrosis factor-α (TNF- α). The method described herein provides for the large scale production of lipid-comprising drug delivery systems useful for gene therapy and other applications.
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Citations
94 Claims
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1. A lipid-nucleic acid complex comprising a compacted nucleic acid, a polycation, a targeting factor, and a lipid, wherein:
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a) the targeting factor increases cellular bioavailability of the nucleic acid by a means other than interaction with a specific outer cell surface membrane receptor;
b) the complex does not comprise a protamine or a salt thereof; and
c) the mean diameter of the complex is greater than about 100 nm and less than 400 nm. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 51, 53, 55, 65, 66, 67, 68, 69, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93)
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13. The complex of 12, wherein the polycationic methacrylate polymer is comprised of dimethylamino methacrylate.
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18. The complex of 14, wherein the membrane translocating peptide is selected from the group consisting of H2N-KKAAAVLLPVLLAAP-COOH (Elan094) (SEQ ID NO:
- 2), H2N-KKKAAAVLLPVLLAAP (ZElan094) (SEQ ID NO;
3), H2N-kkkaavllpvllaap (ZElan207) (SEQ ID NO;
4), and H2N-KKKAAAVLLPVLLAAPREDL (ZElan094R) (SEQ ID NO;
5).
- 2), H2N-KKKAAAVLLPVLLAAP (ZElan094) (SEQ ID NO;
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27. A lipid-nucleic acid complex comprising a compacted nucleic acid and at least one lipid species that is fusogenic, wherein:
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a) the complex has an aqueous core; and
b) the mean diameter of the complex is greater than about 100 nm and less than 400 nm. - View Dependent Claims (29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 52, 54, 56, 61, 62, 63, 64, 70, 76, 82, 88, 94)
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28. A lipid-nucleic acid complex comprising a compacted nucleic acid, a polycation, a targeting factor and at least one lipid species, wherein:
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a) the at least one lipid species is an anionic lipid;
b) the complex has an aqueous core;
c) the complex comprises at least one fusogenic moiety;
d) the mean diameter of the complex is greater than about 100 nm and less than 400 nm; and
,wherein the complex does not comprise protamine or a salt thereof.
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57. A method for preparing a lipid-nucleic acid complex comprising a compacted nucleic acid and at least one lipid species that is fusogenic, comprising:
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a) mixing an aqueous micelle mixture comprising a lipid and at least one lipophilic surfactant with a nucleic acid mixture comprising a nucleic acid, wherein the lipid has or assumes fusogenic characteristics, and wherein at least one of the mixtures contains a component that causes the nucleic acid to compact; and
b) after the mixing removing the lipophilic surfactant from mixture resulting from step a). - View Dependent Claims (58, 59, 60)
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Specification