Compositions for Targeted Delivery of siRNA
First Claim
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1. A conjugate delivery system 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
31 Claims
- 1. A conjugate delivery system for delivering an RNA interference polynucleotide to a liver cell in vivo comprising:
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20. The composition of 1 wherein L2 is a maleamate linkage.
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21. The composition of 20 wherein L2 is a disubstituted maleamate linkage.
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22. The composition of 1 wherein N is linked to A via a physiologically labile linkage L1.
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23. The composition of 22 wherein L1 is a physiologically labile covalent linkage that is orthogonal to L2.
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24. The composition of 1 wherein A contains a hydrophobic group having 20 or more carbon atoms.
- 25. The composition of 1 wherein A contains a galactose trimer.
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29. A composition for delivering an oligonucleotide to a liver cell in vivo comprising:
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a) an oligonucleotide covalently linked to a galactose trimer; and
,b) a reversibly masked and targeted amphipathic polymer comprising a terpolymer synthesized from amine-containing monomers, lower hydrophobic group-containing monomers, and higher hydrophobic group-containing monomers to which a plurality of galactose derivatives and PEG groups are individually linked to said polymer via pH labile disubstituted maleamic bonds and wherein cleavage of said pH labile disubstituted maleamic bonds yields amine groups thereby generating a membrane active polyamine.
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30. 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 terpolymer synthesized from amine-containing monomers, lower hydrophobic group-containing monomers, and higher hydrophobic group-containing monomers to which a plurality of galactose derivatives and PEG groups are individually linked to said polymer via pH labile disubstituted maleamic bonds and wherein cleavage of said pH labile disubstituted maleamic bonds yields amine groups thereby generating a membrane active polyamine.
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31. 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) 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 the first and second masking agents thereby linking a plurality of galactose derivatives and a plurality of polyethylene glycols to the membrane active polymer via physiologically pH-labile disubstituted maleamate linkages; and
,e) linking the RNA interference polynucleotide to galactose trimer or 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