Methods and compositions for the treatment of cancer
Disclosed herein are compositions for treating cancer comprising a modified veratridine. In certain aspects, the modified veratridine comprises a polyglutamic acid (PLE) or polyethylene glycol/polyglutamic acid (PEG-PLE) conjugated to the 4′ hemiketal thereof. Further disclosed is a method of treating colorectal cancer in a subject comprising administering to a subject an effective amount of the disclosed compositions.
1. A composition comprising a veratridine (VTD) conjugate selected from the group consisting of polyglutamic acid-VTD (PLE-VTD) conjugate and polyethylene glycol/polyglutamic acid-VTD (PEG-PLE-VTD) conjugate.
2. The composition of claim 1 , wherein the composition comprises PLE-VTD conjugate.
3. The composition of claim 1 , wherein the composition comprises PEG-PLE-VTD conjugate.
4. The composition of claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier.
5. The composition of claim 4 , wherein the pharmaceutically acceptable carrier is a nanoparticle.
6. The composition of claim 5 , wherein the nanoparticle carrier is mesoporous silica nanoparticle.
7. The composition of claim 6 , wherein the mesoporous silica nanoparticle further comprises at least one hyaluronic acid, conjugated thereto.
8. The composition of claim 7 , wherein the pores of the mesoporous silica nanoparticle are sealed by a metalloprotein matrix.
9. The composition of claim 8 , wherein the metalloprotein matrix is attached to the nanoparticle surface by an electrochemical or covalent bond.
10. The composition of any previous claim, wherein the composition is unable to cross the blood brain barrier upon systemic administration to a subject.
11. A method for treating colorectal cancer in a subject comprising administering to the subject in need thereof, a composition comprising a veratridine (VTD) conjugate selected from the group consisting of polyglutamic acid-VTD (PLE-VTD) conjugate and polyethylene glycol/polyglutamic acid-VTD (PEG-PLE-VTD) conjugate.
12. The method of claim 11 , wherein the colorectal cancer is metastatic.
13. The method of claim 11 , wherein the wherein the composition selectively binds colorectal cancer cells.
14. The method of claim 13 , wherein the composition selectively binds colorectal cancer cells via hyaluronic acid conjugated to the composition.
15. The method of claim 14 , the composition has reduced neurotoxicity relative to a comparable dose of unmodified veratridine.
16. The method of claim 11 , further comprising administering the composition in conjunction with at least one other treatment or therapy.
17. The method of claim 11 , wherein the composition increases UBXN2A protein levels.
18. The method of claim 11 , wherein the composition reduces the formation of electrophilic ortho-quinones in catechol metabolites the composition has reduced neurotoxicity relative to comparable dose of unmodified VTD.
19. The method of claim 11 , wherein the composition suppresses the mTORC2 pathway.
20. The method of claim 11 , wherein the subject has been shown to be resistant to one or more chemotherapy.
21. A method of preventing colorectal cancer in a subject comprising administering to the subject in need thereof, a composition comprising a veratridine (VTD) conjugate selected from the group consisting of polyglutamic acid-VTD (PLE-VTD) conjugate and polyethylene glycol/polyglutamic acid-VTD (PEG-PLE-VTD) conjugate and a pharmaceutically acceptable carrier thereof.
22. The method of claim 18 , wherein the subject has a high risk of developing colorectal cancer.
23. The method of claim 19 , wherein the subject is obese.