Taher Nassar

The Hebrew University of Jerusalem, Israel

Title: How to improve safety and antitumoral activity of a new Platinum (IV) compound

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Biography

Dr Taher Nassar endeavours to apply his accumulated experience in the field of new Platinum(IV) complexes containing lipophilic moieties as novel anticancer prodrugs and using nanotechnology as a delivery system tool to improve its stability and safety

Abstract

Cisplatin, carboplatin and oxaliplatin (OXA) are widely used in chemotherapy. However, their clinical benefits are limited by side-effects attributed to the reactivity of these Pt(II) compounds and acquired resistance. Pt(IV) complexes with two different axial groups may have advantages over the reactive Pt(II) species. They are inert in plasma, reach cancerous lesions in their Pt(IV) form, and activate their Pt(II) analogs inside the cancerous cells. Unfortunately, clinical evaluation of Platinum(IV) complexes showed rapid elimination, less or equal efficacy than Pt (II) drugs. Therefore, no Pt(IV) drug has reached the market. We synthesized oxaliplatin palmitate acetate (OPA), a novel Pt(IV) chemical entity derived from OXA and containing both lipophilic and hydrophilic axial ligands. OPA was found 20 times more efficient in killing various cancer cells than OXA. Furthermore, OPA demonstrated significantly higher tumour growth inhibition than OXA in orthotopic and xenograft mice tumour models of ovarian, pancreatic, lung and liver. However, OPA was also eliminated before cellular uptake. OPA was incorporated in PEGylated liposomes to overcome this drawback to optimize therapeutic performance. In vitro studies showed OPA-loaded liposomes retain OPA potency against di?erent cancer cell lines.

Furthermore, liposomes altered PK parameters and biodistribution patterns favouring the liposome formulations and significantly extended the systemic exposure. Intravenous administration of OPA liposomes (60 mg/kg, twice weekly) demonstrated delayed response and higher survival than cisplatin in a mouse liver xenograft model (Hep-3B). Furthermore, in two identical orthotopic intraperitoneal models of metastatic ovarian cancer (SKOV3-luc-D3), OPA liposomes were administered intravenously at 15, and 30 mg/kg (twice weekly) exhibited delayed response and higher survival compared to Avastin. At the same time, a combination of OPA and Avastin showed a significant synergistic effect enlightening the potential of OPA liposomes in the treatment of various cancers.