Anti-tumor compositions and methods
Disclosed herein are oligonucleotide sequences that generate innate immunity in cells within tumors upon its delivery into tumors. In certain embodiments, these oligonucleotides are specifically delivered into tumors through nanoparticles displaying targeting peptides that confer specific binding of the nanoparticle to receptors on the surface of tumor cells and allow for uptake of the nanoparticle into the tumor cells.
1. A composition for targeting tumor cells and inhibiting tumor growth by activating a subject's innate immune response, the composition comprising:
an isolated double stranded oligonucleotide comprising a strand comprising the nucleic sequence of SEQ ID NO: 1 and a strand comprising the nucleic sequence of SEQ ID NO: 2;
a tumor cell-targeting moiety; and
a pharmaceutically acceptable salt thereof,
wherein said oligonucleotide activates a subject's innate immune response through activation of one or more toll-like receptors (“TLRs”).
2. The composition of claim 1 , wherein said tumor cell-targeting moiety is a protein, a peptide, or an aptamer.
3. The composition of claim 1 , wherein said composition further comprises a nanoparticle.
4. The composition of claim 3 , wherein said nanoparticle comprises lipids, cyclodextrin, chitosan, carbohydrate polymers, elastin-like polypeptides (ELP), calcium phosphate polymers, or combinations thereof.
5. The composition of claim 3 , wherein said nanoparticle is PEGylated.
6. The composition of claim 3 , wherein the nanoparticle is ELP-L.
7. The composition of claim 1 , wherein the composition is encapsulated in a liposome.
8. The composition of claim 7 , wherein the liposome is PEGylated.
9. A pharmaceutical composition comprising:
the composition of claim 1 ; and
a pharmaceutically acceptable carrier, excipient or adjuvant.
10. The pharmaceutical composition of claim 9 , further comprising a chemotherapeutic drug or agent.
11. The pharmaceutical composition of claim 9 , further comprising an immune checkpoint inhibitor.
12. A method for inhibiting tumor growth, comprising:
contacting the tumor with the composition of claim 1 in an amount sufficient to inhibit tumor growth.
13. A method for activating a subject's innate immune response specifically in the tumor of the subject, the method comprising:
obtaining an isolated double stranded oligonucleotide comprising a strand comprising the nucleic sequence of SEQ ID NO: 1 and a strand comprising the nucleic sequence of SEQ ID NO: 2;
contacting the oligonucleotide with a tumor cell-targeting moiety to form a composition, such that the composition will specifically deliver the oligonucleotide to the tumor in the subject; and
administering a pharmaceutically effective amount of the composition to the subject, wherein the oligonucleotide within the composition activates a subject's innate immune response by activating one or more TLRs.
14. The method of claim 12 or 13 , wherein the tumor is a human bladder tumor, a human breast tumor, a human colon tumor, a human liver tumor, a human lung tumor, a human neuroblastoma tumor, a human ovarian tumor, a human pancreatic tumor, a human prostate tumor, or a human skin tumor.
15. The composition of claim 1 , wherein the composition is encapsulated in a nanoparticle.
16. The composition of claim 1 , wherein the tumor cell-targeting moiety comprises a peptide that binds L1 cell adhesion molecule (L1CAM).
17. The composition of claim 1 , wherein the tumor cell-targeting moiety is the cell targeting domain of ELP-L.
18. A method for reducing the number of tumors disseminated from a primary tumor by contacting the tumor with the composition of claim 1 in an amount sufficient to reduce the number of tumors.
19. The composition of claim 1 , wherein at least one activated TLR is TLR-3.
20. The method of claim 13 , wherein at least one activated TLR is TLR-3.