IPA-3-loaded liposomes and methods of use thereof
Lipid-based delivery vehicles are provided. Nanoparticulate compositions typically including a p21 activated kinase (PAK) inhibitor and a lipid-based delivery vehicle are also provided. In preferred embodiments, the lipid-based delivery vehicle is a liposome, most preferably a sterically-stabilized liposome. Typically the lipid-based delivery vehicle includes one or more phospholipids, and optionally a sterol. In some embodiments, at least one of the phospholipids is PEGylated. In particular embodiments, the lipid-based delivery vehicle includes DSPC, DSPE-PEG2000, and cholesterol. In specific embodiments, the ratio of DSPC, DSPE-PEG, and cholesterol is 9:1:5. The nanoparticulate composition typically includes a PAK inhibitor, preferably a PAK-1 inhibitor such as IPA-3 or a derivative, prodrug, or pharmaceutically acceptable salt thereof. Methods of use, for example methods of treating cancer, particularly prostate and breast cancer by administering the composition to subjects in need thereof, are also provided.
1. A nanoparticulate composition comprising a p21 activated kinase (PAK) inhibitor and a lipid-based delivery vehicle,
wherein the p21 activated kinase (PAK) inhibitor is Inhibitor targeting P21-activated kinase-1 (PAK1) activation-3 (IPA-3), a prodrug, or a pharmaceutically acceptable salt thereof, and
wherein the lipid-based delivery vehicle is a liposome which consists essentially of: (1) 1, 2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC) and/or 1, 2-distearoyl -sn-glycero-3-phosphatidylethanolamine (DSPE); (2) at least one pegylated lipid; and (3) cholesterol.
2. The nanoparticulate composition of claim 1 , wherein the at least one pegylated lipid is pegylated 1, 2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE).
3. The nanoparticulate composition of claim 1 , wherein the liposome is a sterically-stabilized liposome.
4. The nanoparticulate composition of claim 1 , having a polydispersity index (PDI) of about 0.05 to about 0.139, a zeta potential of about -28.1v, or a combination thereof.
5. The nanoparticulate composition of claim 1 , having a diameter of about 75 nm to about 500 nm.
6. The nanoparticulate composition of claim 1 , wherein the at least one pegylated lipid is DSPE-PEG2000.
7. The nanoparticlate composition of claim 1 , wherein the ratio of DSPC and/or DSPE, at least one pegylated lipid, and cholesterol is 9:1:5.
8. The nanoparticulate composition of claim 1 , wherein the PAK-1 inhibitor is Inhibitor targeting P21-activated kinase-1 (PAK1) activation-3 (IPA-3) or pharmaceutically acceptable salt thereof.
9. The nanoparticulate composition of claim 8 wherein the PAK-1 inhibitor is IPA-3.
10. A pharmaceutical composition comprising the nanoparticulate composition of claim 1 and a pharmaceutically acceptable carrier.
11. A dosage unit comprising the composition of claim 10 in an effective amount to treat cancer in a subject in need thereof for 2 to 5 days.
12. A method of treating cancer comprising administering a subject in need thereof the pharmaceutical composition of claim 10 in an effective amount to treat cancer.
13. The method of claim 12 , wherein the cancer comprises cancer cells that express PAK-1 at a higher expression level than normal cells of the same type.
14. The method of claim 12 , wherein the cancer is prostate cancer or breast cancer.
15. The method of claim 12 , wherein the pharmaceutical composition is administered to the subject between 1 and 3 times per week.
16. The method of claim 15 , wherein the pharmaceutical composition is administered 2 times per week.
17. A method of treating prostate cancer comprising administering a subject with prostate cancer an effective amount of the dosage unit of claim 11 to treat the subject for 2-5 days.
18. The nanoparticulate composition of claim 1 , wherein the lipid-based delivery vehicle is a liposome which consists of: (1) 1, 2-distearoyl-sn -glycero-3-phosphatidylcholine (DSPC) and/or 1, 2-distearoyl-sn-glycero-3-phosphatidylethanolamine (DSPE); (2) at least one pegylated lipid; and (3) cholesterol.
19. The nanoparticulate composition of claim 18 , wherein the at least one pegylated lipid is pegylated 1, 2-distearoyl-sn-glycero -3-phosphatidylethanolamine (DSPE).
20. The nanoparticulate composition of claim 18 , wherein the liposome is a sterically-stabilized liposome.