Compositions for targeted delivery of siRNA
First Claim
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1. A composition for delivering an RNA interference polynucleotide to a liver cell in vivo comprising:
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Abstract
The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted delivery polymers. Delivery polymers provide membrane penetration function for movement of the RNAi polynucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness to the delivery polymers.
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Citations
27 Claims
- 1. A composition for delivering an RNA interference polynucleotide to a liver cell in vivo comprising:
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25. A composition for delivering an oligonucleotide to a liver cell in vivo comprising:
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a) an oligonucleotide covalently linked to a hydrophobic group having at least 20 carbon atoms; and
,b) a reversibly masked and targeted amphipathic polymer comprising a polymer synthesized from amine-containing monomers and lower hydrophobic group-containing monomers to which a plurality of galactose derivatives are linked to said polymer via pH labile disubstituted maleamate bonds and wherein cleavage of said pH labile disubstituted maleamate bonds yields amine groups thereby generating a membrane active polyamine. - View Dependent Claims (26)
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27. A method of manufacturing an RNA oligonucleotide delivery composition comprising:
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a) forming a membrane active polyamine; b) forming a first masking agent comprising a charge neutral disubstituted maleic anhydride containing a galactose derivative; c) optionally forming a second masking agent comprising a charge neutral disubstituted maleic anhydride containing a polyethylene glycol; d) reversibly inhibiting membrane activity of the membrane active polyamine wherein the inhibiting consists of modifying 50% or more of the amines on the polyamine by reacting the polyamine with a plurality of first masking agents and optionally at least one second masking agent thereby linking a plurality of galactose derivatives and optionally at least one polyethylene glycol to the membrane active polymer via physiologically pH-labile disubstituted maleamate linkages; and
,e) linking the RNA interference polynucleotide to a hydrophobic group having at least 20 carbon atoms; f) providing the RNA interference polynucleotide and the reversibly inhibited membrane active polyamine in solution suitable for administration in vivo.
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Specification