co-delivery of aurora-a inhibitor xy-4 and bcl-xl sirna enhances antitumor efficacy for melanoma therapy

Xingmei Duan,1,2,* Minjie Mu,3,* Junfeng Yan,1 Lan Bai,1 Lei Zhong,1 Yuxuan Zhu,1 Haixia Pan,1 Mei Zhang,3 Jianyou Shi1,3 1Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People`s Hospital, Chengdu, 2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 3Key Laboratory Standardization of Chinese Herbal Medicines of Ministry of Education, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Medicine (TCM), Chengdu, People’s Republic of China *These authors contributed equally to this work Background: The newly synthesized Aurora-A kinase inhibitor XY-4 is a potential anti-cancer agent, but its hydrophobicity and limited efficiency restrict further application. Nanotechnology based combined therapy provides an optimized strategy for solving these issues.Methods: In this study, the newly synthesized Aurora-A kinase inhibitor XY-4 and Bcl-xl targeted siRNA were co-delivered by cationic liposomes, creating an injectable co-delivery formulation. The anti-cancer ability and mechanisms of XY-4/Bcl-xl siRNA co-loaded cationic liposomes were studied both in vitro and in vivo.Results: The prepared liposomes had a mean particle size of 91.3±4.5 nm with a zeta potential of 38.5±0.5 mV and were monodispersed (Polydispersity index =0.183) in water solution, with high drug loading capacity and stability. Intriguingly, the positive charges of co-delivery liposomes not only facilitated gene delivery, but also obviously enhanced drug uptake. The XY-4/Bcl-xl siRNA co-loaded cationic liposomes demonstrated enhanced anti-cancer effects on B16 melanoma cells in vitro by activation mitochondrial apoptosis pathway. Moreover, intratumoral injection of this co-delivery formulation efficiently inhibited the growth of a B16 melanoma xenograft model in vivo.Conclusion: By co-delivering Aurora-A kinase inhibitor XY-4 and Bcl-xl targeting siRNA in a nanoformulation, our study supplied a potential combination strategy for melanoma therapy. Keywords: RNA interference, Aurora-A kinase inhibitor, liposome, co-delivery, melanoma, apoptosis