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.