Polyconjugates for in vivo delivery of polynucleotides
AssigneeArrowhead Madison Inc.
InventorsDavid B. Rozema, James E. Hagstrom, Jason Klein, David L. Lewis, Sean D. Monahan, Darren H. Wakefield, Jon A. Wolff, So Wong
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Abstract
The present invention is directed to compounds, compositions, and methods useful for delivering polynucleotides or other cell-impermeable molecules to mammalian cells. Described are polyconjugates systems that incorporate targeting, anti-opsonization, anti-aggregation, and transfection activities into small biocompatible in vivo delivery vehicles. The use of multiple reversible linkages connecting component parts provides for physiologically responsive activity modulation.
Claims27
A conjugate delivery system for delivering an RNA interference polynucleotide to a liver cell in vivo comprising:
- wherein,
- P is a membrane active polyamine,
- L2 is a disubstituted maleamate linkage,
- M1 is a masking agent containing a galactose derivative,
- M2 is a masking agent containing a polyethyleneglycol,
- N is an RNA interference polynucleotide,
- L1 is a physiologically labile covalent linkage that is orthogonal to L2,
- y and z are integers greater than 1 wherein the value of y and z together is greater than 50% on amines of P,
- positive charge of P is neutralized and membrane activity of P is reversibly inhibited by modification of greater than 50% of P amines by attachment of M1 and M2 through the physiologically pH-labile linkages L2, and
- cleavage of L2 restores membrane activity of P.
A conjugate delivery system for delivering an RNA interference polynucleotide to a liver cell in vivo formed by the process comprising:
- a) forming a membrane active polyamine;
- b) forming a first masking agent comprising a disubstituted maleic anhydride containing a galactose derivative;
- c) forming a second masking agent comprising a disubstituted maleic anhydride containing a polyethyleneglycol;
- d) linking the RNA interference polynucleotide to the polyamine via a physiologically labile covalent bond that is orthogonal to a maleamate linkage;
- e) 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 polyethyleneglycols to the membrane active polymer via physiologically pH-labile disubstituted maleamate linkages.
Dependencies are inferred from the claim text.