RNAi CONJUGATES, PARTICLES AND FORMULATIONS THEREOF
Particles, including nanoparticles and microparticles, and pharmaceutical formulations thereof, comprising conjugates of an RNAi agent attached to a targeting moiety via a linker have been designed which can provide improved temporospatial delivery of the RNAi agent and/or improved biodistribution. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer or infectious diseases.
1 . A conjugate comprising an RNA interference (RNAi) agent coupled to a targeting moiety by a linker, wherein the RNAi agent is a small interfering RNA (siRNA) and wherein the targeting moiety is an Hsp90 inhibitor.
2 . The conjugate of claim 1 , wherein the conjugate comprises a formula selected from the group X—Y—Z, X—Y—Z—Y—X, X—(Y—Z) n , (X—Y) n —Z, X—Y—Z n , and (X—Y—Z—Y) n —Z;
wherein X is the targeting moiety,
Y is the linker,
Z is the RNAi agent, and
n is an integer between 2 and 1,000.
3 . The conjugate of claim 1 , wherein the conjugate comprises the formula X—Y—Z;
wherein X is the targeting moiety,
Y is the linker, and
Z is the RNAi agent.
4 . The conjugate of claim 1 , wherein the linker is not a cleavable linker.
5 . The conjugate of claim 1 , wherein the linker is a cleavable linker.
6 . The conjugate of claim 5 , wherein the linker is cleavable in cytoplasm,
endosome or lysosome.
7 . The conjugate of claim 1 , wherein the linker comprises an ester bond,
disulfide, amide, acylhydrazone, ether, carbamate, carbonate, or urea.
8 . The conjugate of claim 1 , wherein the linker comprises a cell-penetrating peptide.
9 . The conjugate of claim 1 , wherein the RNAi agent is a double-stranded RNA (dsRNA).
10 . The conjugate of claim 1 , wherein the targeting moiety is selected from peptides, antibody mimetics, aptamers, antibodies, glycoproteins, small molecules, carbohydrates, or lipids.
11 . The conjugate of claim 1 , wherein the conjugate has a molecular weight of less than 50,000 Da.
12 . A polymeric particle comprising the conjugate of claim 1 and at least one polymeric matrix.
13 . The particle of claim 12 , wherein the polymeric matrix comprises one or more polymers selected from the group consisting of hydrophobic polymers, hydrophilic polymers, and copolymers thereof.
14 . The particle of claim 12 , wherein the polymeric matrix comprises one or more polymers selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(ethylene oxide), poly(ethylene glycol), poly(propylene glycol), and copolymers thereof.
15 . The particle of claim 12 , wherein the particle has a diameter between 10 nm and 5000 nm.
16 . The particle of claim 12 , wherein the conjugate is present in an amount between 0.05% and 50% (w/w) based upon the weight of the particle.
17 . A pharmaceutical formulation comprising the conjugate of claim 1 and at least one pharmaceutically acceptable excipient.
18 . A method of treating a subject in need thereof comprising administering a therapeutically effective amount of the formulation of claim 17 .
19 . A method of making a particle of claim 12 , comprising the steps of:
A. forming the conjugate, and
B. forming the particle comprising a polymeric matrix encapsulating the conjugate.