Spherical nucleic acid-based constructs as immunostimulatory agents for prophylactic and therapeutic use
Aspects of the invention relate to spherical nucleic acid-based constructs and related methods and compositions thereof. The compositions of the invention are useful for activating agonists of nucleic acid interacting complexes, such as TLRs, stimulating an immune response, and treating diseases such as infectious disease, cancer, allergies, allergic diseases, and autoimmune disease
1. A method of treating a subject, comprising
administering to the subject a nanoscale construct in an effective amount to stimulate an immune response, wherein the nanoscale construct comprises a corona having an exterior shell composed of nucleic acid molecules arranged in a geometrical position around a nanoparticle core, wherein the nucleic acid molecules have a surface density of at least 0.3 pmol/cm 2 , are CpG oligonucleotides, and contain a spacer which comprises an oligoethylene, wherein the nucleic acid molecules do not comprise an oligonucleotide spacer, and wherein the nanoparticle core is about 1 nm to about 40 nm in mean diameter.
2. The method of claim 1 , wherein the subject has cancer.
3. The method of claim 2 , wherein the cancer is biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, an intraepithelial neoplasm, lymphoma, liver cancer, lung cancer, melanoma, neuroblastoma, oral cancer, ovarian cancer, pancreas cancer, prostate cancer, rectal cancer, sarcomas, testicular cancer, thyroid cancer, renal cancer, hairy cell leukemia, chronic myelogenous leukemia, cutaneous T-cell leukemia, multiple myeloma, renal cell carcinoma, lymphoma, bladder cancer, non-small cell lung cancer (NSCLC), or glioblastoma multiforme.
4. The method of claim 2 , wherein the cancer is squamous cell carcinoma.
5. The method of claim 2 , wherein the cancer is skin cancer.
6. The method of claim 1 , wherein the nanoscale construct is administered to the subject through oral, parenteral, intramuscular, intravenous, mucosal, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, dermal or rectal routes of administration.
7. The method of claim 1 , wherein the nanoscale construct is administered to the subject through a subcutaneous route of administration.
8. The method of claim 1 , wherein the nanoscale construct is administered to the subject through direct injection to one or more cancer cells.
9. The method of claim 1 , wherein the oligoethylene is a hexaethylene glycol.
10. The method of claim 1 , wherein the CpG oligonucleotides have a phosphorothioate (PS) backbone.
11. The method of claim 1 , wherein the subject is human.
12. The method of claim 1 , wherein the CpG oligonucleotides comprise the sequence of SEQ ID NO: 30.
13. The method of claim 1 , wherein the surface density is no greater than about 35-40 pmol/cm 2.
14. The method of claim 1 , wherein the CpG oligonucleotides are 6 to 100 nucleotides in length.
15. The method of claim 1 , wherein the nucleic acid molecules are linked to other nucleic acid molecules through a non-covalent linkage.
16. The method of claim 1 , wherein the CpG oligonucleotides have at least one phosphodiester internucleotide linkage.