How to improve safety and antitumoral activity of a new platinum (IV) compound.

Cisplatin, carboplatin and oxaliplatin (OXA) are widely used in combined chemotherapy. However, their clinical benefits are seriously limited by severe side-effects attributed to the reactivity of these Pt(II) compounds and inherent or acquired resistance. Pt(IV) complexes with two additional axial groups may have advantages over the reactive Pt(II) species. They are inert in plasma, may reach cancerous lesions in their Pt(IV) form and be activated into their Pt(II) analogs only inside the cancerous cells. Unfortunately, clinical evaluation of several Platinum(IV) complexes showed rapid elimination, less or equal efficacy than Pt (II) drugs and wide inter- and intra-variable oral bioavailability. Therefore, no Pt(IV) drug has yet reached the market. We synthesized [Pt(DACH)(OAc)(OPal)(ox)], oxaliplatin palmitate acetate (OPA), a novel Pt(IV) chemical entity, derived from OXA and containing both lipophilic and hydrophilic axial ligands (1). OPA was found at least 20 times more efficient in killing various cancer cells than OXA. OPA demonstrated significantly higher tumor growth inhibition compared to OXA in both orthotopic and xenograft mice tumor models of ovarian, pancreatic, lung and liver. However, OPA was also prematurely eliminated before cellular uptake. To overcome this drawback, OPA was incorporated in PEGylated liposomes to optimize therapeutic performance. In vitro studies showed OPA-loaded liposomes retain OPA potency against different cancer cell lines. Liposomes significantly extended the systemic exposure, while the maximum tolerated dose in mice was not reached, even at OPA dose of 60mg/kg, twice weekly. Injected OPA liposomes altered PK parameters and biodistribution patterns in favor of the liposome formulations. Intravenous administration of OPA liposomes (60 mg/kg, twice weekly) demonstrated delayed response and higher survival compared to cisplatin in a mice model of liver xenograft (Hep-3B). Furthermore, in 2 identical consecutive orthotopic intraperitoneal models of metastatic ovarian cancer (SKOV3-luc-D3), OPA liposomes administered intravenously at 15 and 30 mg/kg (twice weekly) exhibited delayed response and higher survival compared to Avastin, while a combination of OPA and Avastin showed a significant synergistic effect enlightening the potential of OPA liposomes in the treatment of various cancers.

[1]. Biswas N, Abu Ammar A, et al. Int J Pharm. 2021; 604, doi: 10.1016/j.ijpharm. 2021.120740