Systemic delivery of nanoparticle formulation of novel tubulin inhibitor for treating metastatic melanoma

作者：Mundra, Vaibhav; Peng, Yang; Kumar, Virender; Li, Wei; Miller, Duane D.; Mahato, Ram I.^*

来源：Drug Delivery and Translational Research, 2015, 5(3): 199-208.

DOI：10.1007/s13346-015-0226-2

• Metastatic melanoma
• Tubulin inhibitor
• Nanoparticles
• Lung metastasis

Clinical translation of tubulin inhibitors for treating melanoma is limited by multidrug efflux transporters, poor aqueous solubility, and dose-limiting peripheral toxicities. Tubulin inhibitors with efficacy in taxane-resistant cancers are promising drug candidates and can be used as single agent or in conjunction with other chemotherapy. Systemic therapy of such a novel tubulin inhibitor, 2-(1H-indol-5-yl) thiazol-4-yl) 3,4,5-trimethoxyphenyl methanone (abbreviated as LY293), is limited by its poor aqueous solubility. The objective of this study was to design a polymeric nanocarrier for systemic administration of LY293 to improve tumor accumulation and reduce side effects of tubulin inhibitor in a lung metastasis melanoma mouse model. Methoxy polyethylene glycol-b-poly(carbonate-co-lactide) (mPEG-b-P(CB-co-LA)) random copolymer was synthesized and characterized by H-1 NMR and gel permeation chromatography (GPC). Polymeric nanoparticles were formulated using oil/water (o/w) emulsification methodwith amean particle size of 150 nm and loading efficiency of 7.40 %. Treatment with LY293-loaded nanoparticles effectively inhibited the proliferation of melanoma cells in vitro and exhibited concentration-dependent cell cycle arrest in G2/M phase. Mitotic arrest activated the intrinsic apoptotic machinery by increasing the cellular levels of cleaved poly ADP ribose polymerase (PARP) and fraction of sub-G1 cells. In vivo, LY293-loaded nanoparticles significantly inhibited the proliferation of highly aggressive metastasized melanoma in a syngeneic lung metastasis melanoma mouse model without toxicity to vital organs. In conclusion, we have designed a promising polymeric nanocarrier for systemic delivery of LY293 for treating metastatic melanoma while minimizing the toxicity associated with the administration of cosolvents.

• 出版日期2015-6