Hyperbranched dendron and methods of synthesis and use thereof
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Abstract
Hyperbranched dendron (HD) polymers are synthesized using low molecular weight polyethyleneimine (BPEI-L) as a core and used for gene delivery. The obtained polymers display low toxicity and efficient gene delivery at low nitrogen-to-phosphate (N/P) ratios. Using successive attachment of ethyleneimine moieties to a PEI core, the polymer has a lower relative ratio of linear-to-branched structures than in the core PEI. The more extensive branching enables the polymer to condense plasmid DNA into nanostructure complexes with a size of less than or equal to about 100 nm. The complexes are stable and efficient in transfecting cells in the presence of serum. Bioluminescent imaging of in vivo gene expression using a luciferase reporter gene performed in live mice showed gene expression in the liver and in submandibular lymph nodes.
42 Citations
77 Claims
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1-27. -27. (canceled)
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28. A complex between a hyperbranched dendron polymer and a nucleic acid molecule comprising:
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a nucleic acid molecule; and
a hyperbranched dendron polymer selected from at least one of the group consisting of (a) a flexible hyperbranched dendron polymer comprising;
a surface defined by the polymer, a polyethyleneimine core within the surface, a plurality of primary amine groups at the surface, and a plurality of secondary and tertiary amine groups positioned at the core.;
(b) a hyperbranched dendron polymer having a randomly branched structure, a molecular weight of about 10 to 25 kD, and a ratio of secondary to tertiary amine groups of less than or equal to about 1.5 to 1; and
(c) hyperbranched dendron polymer made by a process comprising iterative attachment of ethyleneimine moieties to a branched polyethyleneimine core, wherein the process increases the amount of secondary and tertiary amines in the polymer while maintaining a plurality of primary amines on a surface of the polymer. - 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, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76)
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77. A method for manufacturing a medicament for use in delivery of a nucleic acid in vivo comprising:
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providing a nucleic acid molecule; and
combining the nucleic acid molecule with a hyperbranched dendron polymer selected from at least one of the group consisting of (a) a flexible hyperbranched dendron polymer comprising;
a surface defined by the polymer, a polyethyleneimine core within the surface, a plurality of primary amine groups at the surface, and a plurality of secondary and tertiary amine groups positioned at the core.;
(b) a hyperbranched dendron polymer having a randomly branched structure, a molecular weight of about 10 to 25 kD, and a ratio of secondary to tertiary amine groups of less than or equal to about 1.5 to 1.; and
(c) hyperbranched dendron polymer made by a process comprising iterative attachment of ethyleneimine moieties to a branched polyethyleneimine core, wherein the process increases the amount of secondary and tertiary amines in the polymer while maintaining a plurality of primary amines on a surface of the polymer.
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Specification