A Lipophilic Pt(IV) Oxaliplatin Derivative Enhances Antitumor Activity.
Side effects and acquired resistance by cancer cells limit the use of platinum anticancer drugs. Modification of oxaliplatin (OXA) into a lipophilic Pt(IV) complex [Pt(DACH)(OAc)(OPal)(ox)] (1), containing both lipophilic and hydrophilic axial ligands, was applied to improve performance and facilitate incorporation into polymeric nanoparticles. Complex 1 exhibited unique potency against a panel of cancer cells, including cisplatin-resistant tumor cells. [Pt(DACH)(OAc)(OPal)(ox)] incorporated nanoparticles (2) presented a mean diameter of 146 nm with encapsulation yields above 95% as determined by HPLC. Complexes 1 and 2 showed enhanced in vitro cellular Pt accumulation, DNA platination, and antiproliferative effect compared to OXA. Results of an orthotopic intraperitoneal model of metastatic ovarian cancer (SKOV-3) and a xenograft subcutaneous model of colon (HCT-116) tumor in SCID-bg mice showed that the activity of 1 and 2 significantly decreased tumor growth rates compared to control and OXA treatment groups. Consequently, these findings warrant further development toward clinical translation.
The Hebrew University of Jerusalem , Institute for Drug Research of the School of Pharmacy, Faculty of Medicine, POB 12065, Jerusalem 9112100, Israel.
Aiman
A
Abu Ammar
The Hebrew University of Jerusalem , Institute for Drug Research of the School of Pharmacy, Faculty of Medicine, POB 12065, Jerusalem 9112100, Israel.
Raji
R
Raveendran
The Hebrew University of Jerusalem , Institute for Drug Research of the School of Pharmacy, Faculty of Medicine, POB 12065, Jerusalem 9112100, Israel.
Dan
D
Gibson
The Hebrew University of Jerusalem , Institute for Drug Research of the School of Pharmacy, Faculty of Medicine, POB 12065, Jerusalem 9112100, Israel.
Taher
T
Nassar
The Hebrew University of Jerusalem , Institute for Drug Research of the School of Pharmacy, Faculty of Medicine, POB 12065, Jerusalem 9112100, Israel.
Simon
S
Benita
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D055808:Drug Discovery; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy; D000077150:Oxaliplatin
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin