Nanogels for cellular delivery of therapeutics

1. A nanogel-based delivery system comprising: a nanogel comprising a crosslinked polymer particle and a crosslinked polymer shell, disposed substantially around the crosslinked polymer particle; and an active agent contained substantially within the nanogel, wherein the active agent is non-covalently associated with the nanogel; wherein the crosslinked polymer particle comprises poly(N-isopropylmethacrylamide) and N,N′-methylenebis(acrylamide), and the crosslinked polymer shell comprises a functionalization agent.

2. The nanogel-based delivery system of claim 1 , wherein the crosslinked polymer shell comprises poly(N-isopropylmethacrylamide), N,N′-methylenebis(acrylamide), and aminopropylmethacryamide.

3. The nanogel-based delivery system of claim 2 , wherein the active agent is a small interfering ribonucleic acid (siRNA).

4. The nanogel-based delivery system of claim 3 , wherein the siRNA comprises substantial sequence identity to a target gene expressed in a neoplastic disease.

5. The nanogel-based delivery system of claim 1 , wherein the nanogel further comprises a targeting moiety, wherein the targeting moiety is attached to the crosslinked polymer shell through the functionalization agent, and wherein the targeting moiety is displayed on at least a portion of the crosslinked polymer shell.

6. The nanogel-based delivery system of claim 5 , wherein the targeting moiety comprises a peptide having the amino acid sequence YSAYPDSVPMMSC (SEQ ID NO: 1).

7. The nanogel-based delivery system of claim 6 , wherein the active agent comprises a siRNA having substantial sequence identity to a gene encoding epidermal growth factor receptor.

8. A method of delivering an active agent into a cell, the method comprising:

contacting a nanogel with a cell, the nanogel comprising

a crosslinked polymer particle wherein the crosslinked polymer particle comprises poly(N-isopropylmethacrylamide) and N,N′-methylenebis(acrylamide),

a crosslinked polymer shell disposed substantially around the crosslinked polymer particle and comprising a functionalization agent, and

the active agent contained substantially within the nanogel, wherein the active agent is non-covalently associated with the nanogel; and

delivering the active agent to the cell.

9. The method of claim 8 , wherein the active agent comprises a siRNA.

10. The method of claim 9 , wherein the nanogel further comprises a targeting moiety and the crosslinked polymer shell comprises poly(N-isopropylmethacrylamide), N,N′-methylenebis(acrylamide), and aminopropylmethacryamide, wherein the targeting moiety is attached to the crosslinked polymer shell through the functionalization agent, and wherein the targeting moiety is displayed on at least a portion of the crosslinked polymer shell.

11. The method of claim 10 , further comprising reducing expression of a target gene, wherein the siRNA has substantial sequence identity to the target gene.

12. The method of claim 11 , wherein the target gene encodes one or more of an anti- apoptotic molecule, a growth factor, a growth factor receptor, a mitotic spindle protein, a cell cycle protein, an angiogenic factor, an oncogene, an intracellular signal transducer, or a molecular chaperone.

13. The method of claim 12 , wherein the targeting moiety comprises a peptide having the amino acid sequence YSAYPDSVPMMSC (SEQ ID NO: 1), and wherein the active agent is a siRNA having substantial sequence identity to the target gene, the target gene encoding epidermal growth factor receptor.

14. A method for treating neoplastic disease comprising:

administering to a subject having neoplastic disease an effective amount of a nanogel comprising

a crosslinked polymer particle;

a crosslinked polymer shell comprising a functionalization agent, wherein the crosslinked polymer shell is disposed substantially around the crosslinked polymer particle;

a targeting moiety comprising a peptide having the amino acid sequence YSAYPDSVPMMSC (SEQ ID NO: 1), wherein the targeting moiety is attached to the crosslinked polymer shell through the functionalization agent, and wherein the targeting moiety is displayed on at least a portion of the crosslinked polymer shell; and

an active agent contained substantially within the nanogel, wherein the active agent is non-covalently associated with the nanogel;

wherein the neoplastic disease comprises cells expressing the EphA 2 receptor.

15. The method of treating neoplastic disease of claim 14 , wherein the crosslinked polymer particle comprises poly(N-isopropylmethacrylamide) and N,N′-methylenebis (acrylamide), and wherein the crosslinked polymer shell comprises poly(N-isopropylmethacrylamide), N,N′-methylenebis(acrylamide), and aminopropylmethacryamide.

16. The method of treating neoplastic disease of claim 15 , further comprising reducing expression of a target gene, wherein the active agent is a siRNA, the siRNA having substantial sequence identity to the target gene, and wherein the target gene encodes one or more of an anti-apoptotic molecule, a growth factor, a growth factor receptor, a mitotic spindle protein, a cell cycle protein, an angiogenic factor, an oncogene, an intracellular signal transducer, or a molecular chaperone.

17. The method of treating neoplastic disease of claim 16 , wherein the target gene encodes epidermal growth factor receptor.

18. The method of treating neoplastic disease of claim 17 , further comprising increasing sensitivity of the subject to a chemotherapeutic agent.

19. The method of treating neoplastic disease of claim 18 , wherein the chemotherapeutic agent comprises paclitaxel or docetaxel.