Nanoparticle mediated delivery of siRNA
View Patent ↗The invention provides multifunctional supramolecular self-assembled nanoparticles (SSNPs) comprising a set of rationally designed components that collectively facilitate efficient intestinal absorption of siRNA. The nanoparticles can induce potent TNF-α silencing in macrophages. Single gavage of SSNPs in mice depleted systemic TNF-α production at an siRNA dose as low as 50 μg/kg, and protected the mice from lipopolysaccharide-induced hepatic injury.
1. A nanoparticle comprising:
a) siRNA;
b) oley trimethly chitosan (OTMC);
c) poly(γ-(4-(((2-(piperidin-1-yl)ethyl)amino)methyl)benzyl- L -glutamate) (PVBLG-8);
d) oleyl-PEG-mannose(OPM);
e) oleyl-PEG-cysteamine(OPC); and
f) sodium tripolyphosphate(TPP);
wherein the OTMC/TPP components of the nanoparticle are present in a ratio of about 8:1(w/w), the OTMC/OPM/OPC components of the nanoparticle are present in a ratio of about 1:1:1(w/w); and the nanoparticle has a diameter of about 100 nm to about 140 nm.
2. A pharmaceutical composition comprising a plurality of nanoparticles of claim 1 in combination with a pharmaceutically acceptable diluent, excipient, or carrier.
3. A method for orally delivering siRNA to a subject comprising orally administering the pharmaceutical composition of claim 1 to a subject, wherein the siRNA is delivered to cells of the lining of the digestive system of the subject.
4. The method of claim 3 wherein the siRNA is TNF-α siRNA.
5. The method of claim 4 wherein the endogenous production of tumor necrosis factor (TNF)-α in the subject is reduced by at least 50%.
6. The method of claim 5 wherein the administration treats or reduces the symptoms of an inflammatory disease.
7. The method of claim 6 wherein the inflammatory disease is lipopolysaccharide (LPS)-induced hepatic injury.
8. A method for TNF-α silencing in macrophages in a subject comprising administering to a subject an effective TNF-α silencing amount of a composition comprising a plurality of nanoparticles of claim 1 , wherein the siRNA of the nanoparticles is delivered into macrophages of the subject and endogenous production of TNF-α in the subject is reduced by at least 50%.
9. A pharmaceutical composition for the oral delivery of siRNA comprising a plurality of siRNA-containing nanoparticles, wherein the nanoparticles comprise
a) siRNA;
b) oleyl trimethyl chitosan (OTMC);
c) poly(γ-(4-(((2-(piperidin-1-yl)ethyl)amino)methyl)benzyl- L -glutamate) (PVBLG-8);
d) oleyl-PEG-mannose(OPM);
e) oleyl-PEG-cysteamine(OPC); and
f) sodium tripolyphosphate(TPP);
wherein the OTMC/PVBLG/siRNA componments of the nanoparticle are present in a ratio of about 100:20:1(w/w); the OTMC/TPP components of the nanoparticle are present in a ratio of about 8:1(w/w), the OTMC/OPM/OPC components of the nanoparticle are present in a ratio of about 1:1:1(w/w); and the nanoparticle has a diameter of about 100 nm to about 140 nm.
10. A pharmaceutical composition comprising a plurality of nanoparticles of claim 1 in combination with a pharmaceutically acceptable diluent, excipient, or carrier, wherein at least one diluent, excipient, or carrier is selected from water, ethanol, and a polyol.
11. A method for orally delivering siRNA to a subject comprising orally administering the pharmaceutical composition of claim 9 to a subject, wherein the siRNA is delivered to cells of the lining of the digestive system of the subject.
12. The method of claim 11 wherein the siRNA is TNF-α siRNA.
13. The method of claim 12 wherein the endogenous production of tumor necrosis factor (TNF)-α in the subject is reduced by at least 50%.
14. The method of claim 13 wherein the administration treats or reduces the symptoms of an inflammatory disease.
15. The method of claim 14 wherein the inflammatory disease is lipopolysaccharide (LPS)-induced hepatic injury.
16. A method for TNF-α silencing in macrophages in a subject comprising administering to a subject an effective TNF-α silencing amount of the composition of claim 9 , wherein the siRNA of the nanoparticles is delivered into macrophages of the subject and endogenous production of TNF-α in the subject is reduced by at least 50%.
17. The pharmaceutical composition of claim 9 comprising water.