Lipid-derived neutral nanoparticles
AssigneeShire Human Genetic Therapies, Inc.
InventorsFrank DeRosa, Braydon Charles Guild, Michael Heartlein
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Abstract
Disclosed herein are novel lipids and liposomal compositions prepared using such compounds and related methods of neutralizing or otherwise modifying such liposomal compositions. The lipids described herein are useful for example, as liposomal vehicles to facilitate the delivery of encapsulated polynucleotides to target cells and the subsequent transfection of such target cells. In certain embodiments, one or more of the compounds that comprise the liposomal delivery vehicle may be neutralized or further modified such that the properties of the liposomal delivery vehicle are modified.
Claims32
A method of neutralizing a lipid nanoparticle, wherein the lipid nanoparticle comprises at least one lipid having a releasable polar head-group, the method comprising the step of contacting the lipid nanoparticle with one or more agents such that the polar head-group is released from the lipid and the lipid nanoparticle thereby neutralized.
10-38. (canceled)
A method of encapsulating one or more therapeutic agents in a neutral lipid nanoparticle, such method comprising the steps of:
- (a) loading a lipid nanoparticle comprising at least one reducible cationic lipid with the one or more therapeutic agents;
- and (b) contacting the lipid nanoparticle with one or more reducing agents such that the lipid nanoparticle is neutralized.
45-67. (canceled)
A method of neutralizing a lipid nanoparticle, wherein the lipid nanoparticle comprises at least one lipid having a releasable polar head-group, the method comprising the step of contacting the lipid nanoparticle with one or more agents such that the polar head-group is released from the lipid to thereby neutralize the lipid nanoparticle;
- wherein
- the lipid has the structure:
- R1 is the releasable polar head-group and is selected from the group consisting of imidazole, guanidinium, imine, enamine, amino, an optionally-substituted alkyl amino and an optionally-substituted pyridyl;
- R2 is selected from the group consisting of an optionally substituted, variably saturated or unsaturated alkyl, an optionally substituted, variably saturated or unsaturated acyl, an optionally substituted pyridyl,
- R3 and R4 are each independently selected from the group consisting of an optionally substituted, variably saturated or unsaturated C6-C20 alkyl and an optionally substituted, variably saturated or unsaturated C6-C20 acyl;
- x is a cleavable linker group selected from the group consisting of disulfide, ester, hydrazone, imine, acetal, ketal, cis-aconityl, ortho-ester, anhydride, beta-thiopropionate, vinyl ether, phosphoramidate, GLFG, Val-Cit, GG, AA, GGGF and PVGLIG;
- and
- n is zero or any positive integer.
71-80. (canceled)
The method of claim 71, wherein the one or more agents are enzymes.
83-87. (canceled)
89-99. (canceled)
A method of modulating the surface charge of a liposomal vehicle, wherein the liposomal vehicle comprises at least one lipid comprising a releasable polar head-group;
- the method comprising a step of contacting the liposomal vehicle with at least one agent, wherein upon contacting the liposomal vehicle with the at least one agent the polar head-group is released from the lipid, and the surface charge of the liposomal vehicle thereby modulated.
101-110. (canceled)
Dependencies are inferred from the claim text.