Nanostructures for drug delivery
The present invention provides compositions, preparations, formulations, kits, and methods useful for treating subjects having cancer or at risk of developing cancer. Some embodiments of the invention may comprise a composition comprising a plurality of particles comprising a platinum(IV) therapeutically active precursor.
1. A method of making a composition for the delivery of a hydrophilic drug comprising:
providing a hydrophobic drug precursor comprising a substantially hydrophilic small molecule drug bound to a compatibilizing moiety, and
forming a particle comprising a hydrophobic interior,
wherein the hydrophobic drug precursor is encapsulated in the particle in an amount of at least 0.1% by weight based on the weight of the particle.
2. The method of claim 1 further comprising:
providing a solution comprising the hydrophobic drug precursor and a polymeric base component, and
contacting the solution with a base component nonsolvent to form the particle.
3. The method of claim 1 , wherein the drug comprises a platinum metal compound.
4. The method of claim 3 , wherein the drug comprises a platinum (IV) compound or a platinum (II) compound.
5. The method of claim 4 , wherein the drug comprises a platinum (IV) compound having the formula
wherein,
R 1 , R 2 , R 3 , and R 4 can be the same or different and each is a group comprising at least one of ammonia, an amine, a heterocycle including at least one nitrogen, an aryl group, or a leaving group, any being optionally substituted, or any two or three of R 1 , R 2 , R 3 , and R 4 can be joined together to form a bidentate ligang or a tridentate ligand, any being optionally substituted, and
R 5 and R 6 can be the same or different and comprise the formula -QR 7 , wherein R 7 is an alkyl, an alkenyl, an alkynyl, a heteroalkyl, a heteroalkynyl, an aryl, a heteroaryl, or CO(CH 2 ) n CH 3 , wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and Q is O or N.
6. The method of claim 5 , wherein R 7 is CO(CH 2 ) n CH 3 , wherein n is an integer from 0 to 10.
7. The method of claim 5 , wherein the platinum(IV) compound is
8. The method of claim 5 , wherein drug precursor comprises an inorganic metal compound and the compatibilizing moiety is a ligand bound to a metal of the inorganic compound.
9. The method of claim 3 , wherein the platinum metal compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, [cis-Pt(diaminocyclohexane)Cl 2 ], nedaplatin, stratoplatin, paraplatin, platinol, cycloplatin, dexormaplatin, enloplatin, iproplatin, lobaplatin, ormaplatin, spiroplatin, and zeniplatin.
10. The method of claim 1 , wherein the drug is selected from the group consisting of dexamethasone phosphate, nicardipine hydrochloride, methylsalicylic acid, nitroglycerine, hydrophilic serotonin 5-HT3 receptor antagonists, and anthracyclines.
11. The method of claim 1 , wherein the drug or drug precursor comprises inorganic or organometallic drugs selected from the group consisting of platinum compounds, ruthenium compounds, cobalt compounds, copper compounds, and iron compounds.
12. The method of claim 1 , wherein the compatibilizing moiety comprises at least one of an alkyl, a cycloalkyl, an aryl, or an arylalkyl group.
13. The method of claim 1 , further comprising associating the compatibilizing moiety with the drug via a linker prior to forming the particle.
14. The method of claim 13 , wherein the linker is selected from the group consisting of CO, SiO, C(O)O, NHC(O)O, and NHCO.
15. The method of claim 2 , wherein the polymeric base component is an amphiphilic polymer.
16. The method of claim 2 , wherein the polymeric base component comprises a polymer selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(alkylene glycols), polyhydroxyalkanoates, poly(orthoesters), poly(caprolactones), polylysine, poly(acrylic acid), poly(ethyleneimine), and copolymers thereof.
17. The method of claim 2 , wherein the polymeric base component comprises a polymer selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(ethylene glycol), and copolymers thereof.
18. The method of claim 2 , further comprising associating a targeting moiety with the particle prior to, during, or after formation of the particle.
19. The method of claim 18 , wherein the targeting moiety is selected from the group consisting of proteins, peptides, antibodies, and nucleic acids.
20. The method of claim 18 , wherein the targeting moiety is prostate specific membrane antigen.
21. The method of claim 1 , wherein the particles have an average diameter from about 10 nm to about 200 nm.
22. The method of claim 1 , wherein the drug or drug precursor has a molecular weight of not more than about 800 g/mol.