Abstract
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 1H NMR and gel permeation chromatography (GPC). Polymeric nanoparticles were formulated using oil/water (o/w) emulsification method with a mean 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.
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Acknowledgments
This work is supported by NIH/NCI grant R01CA148706 to WL. We would also like to thank Dr. Yuri Sheinin of the Department of Pathology & Microbiology of the University of Nebraska Medical Center for his assistance in interpreting the histopathology data.
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All authors declare that there are no potential conflicts of interest.
Animal studies
All institutional and national guidelines for the care and use of laboratory animals were followed.
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Mundra, V., Peng, Y., Kumar, V. et al. Systemic delivery of nanoparticle formulation of novel tubulin inhibitor for treating metastatic melanoma. Drug Deliv. and Transl. Res. 5, 199–208 (2015). https://doi.org/10.1007/s13346-015-0226-2
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DOI: https://doi.org/10.1007/s13346-015-0226-2