Nanoliposomal delivery of cytosolic phospholipase A2 inhibitor arachidonyl trimethyl ketone for melanoma treatment

• DOI: 10.1016/j.nano.2017.12.020
• Publication Date: 2018-01-06T17:25:53Z
• Authors: Raghavendra Gowda; Saketh S. Dinavahi; Soumya Iyer; Shubhadeep Banerjee; Rogerio I. Neves; Colette R. Pameijer; Gavin P. Robertson
• Keywords: 0301 basic medicine; Phospholipase A2 Inhibitors; Mice, Nude; Phospholipases A2, Cytosolic; Arachidonic Acids; 3. Good health; Mice; 03 medical and health sciences; Drug Delivery Systems; Liposomes; Tumor Cells, Cultured; Animals; Humans; Nanoparticles; Female; Melanoma; Cell Proliferation

Drug resistance and toxicity are major limitations of cancer treatment and frequently occurs during melanoma therapy. Nanotechnology can decrease drug resistance by improving drug delivery, with limited toxicity. This study details the development of nanoparticles containing arachidonyl trifluoromethyl ketone (ATK), a cytosolic phospholipase A2 inhibitor, which can inhibit multiple key pathways responsible for the development of recurrent resistant disease. Free ATK is toxic, limiting its efficacy as a therapeutic agent. Hence, a novel nanoliposomal delivery system called NanoATK was developed, which loads 61.7% of the compound and was stable at 4oC for 12 weeks. The formulation decreased toxicity-enabling administration of higher doses, which was more effective at inhibiting melanoma cell growth compared to free-ATK. Mechanistically, NanoATK decreased cellular proliferation and triggered apoptosis to inhibit melanoma xenograft tumor growth without affecting animal weight. Functionally, it inhibited the cPLA2, AKT, and STAT3 pathways. Our results suggest the successful preclinical development of a unique nanoliposomal formulation containing ATK for the treatment of melanoma.