Oxaliplatin acetate palmitate: a prodrug or a new promising chemical entity for the treatment of cancers

Severe side-effects and acquired resistance by cancer cells limit the use of the widely-prescribed Platinum [Pt (II)] anticancer drugs. One approach to overcome the drawbacks of Pt (II) drugs is to use platinum (IV) compounds. Modification of oxaliplatin (OXA) into lipophilic Pt (IV) complexes containing lipophilic and hydrophilic axial ligands, was applied to improve performance and facilitate incorporation into polymeric nanoparticles. Oxaliplatin palmitate acetate (OPA) among other synthetic asymmetric Pt (IV) molecules, exhibited unique potency against a panel of cancer cells. OPA incorporated nanoparticles (NPs) presented a mean diameter of 146 nm with encapsulation yields above 95% as determined by HPLC. OPA and OPA NPs showed enhanced in vitro cellular Pt accumulation, DNA platination and anti-proliferative effect compared to OXA. Results of a mice orthotopic intraperitoneal model of metastatic ovarian cancer (SKOV-3) showed that the activity of OPA and OPA NPs significantly decreased tumor growth rates compared to control and OXA treatment groups. Furthermore, OPA and OPA NPs were equally and significantly more efficient in tumor growth inhibition than OXA and control, using a SCID-bg xenograft subcutaneous mice model of pancreatic cancer (BxPC-3). More importantly, an organ biodistribution study in the SCID-bg orthotopic metastatic ovarian cancer model showed that both OPA and OPA NPs accumulated in the tumors with a preference to the NPs. The anti-pancreatic and ovarian tumor inhibition of OPA is of major interest especially in view of the lack of activity of OXA suggesting the ability of free OPA to penetrate BxPC-3 and SKOV-3 cells within the tumors at an adequate therapeutic concentration exerting an antiproliferative activity mainly because of the lipophilic character of OPA since there was no difference between OPA and OPA NPs. These findings warrant further development including the use of OPA in combined therapy which is the mainstay treatment of cancer in clinics.