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

Vaibhav Mundra, Yang Peng, Virender Kumar, Wei Li, Duane Miller, Ram I. Mahato

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)199-208
Number of pages10
JournalDrug Delivery and Translational Research
Volume5
Issue number3
DOIs
StatePublished - Jun 1 2015

Fingerprint

Tubulin Modulators
Nanoparticles
Melanoma
Solubility
Neoplasm Metastasis
Lung
Poly(ADP-ribose) Polymerases
G2 Phase
Cell Cycle Checkpoints
Particle Size
Cell Division
Gel Chromatography
Neoplasms
Oils
Cell Proliferation
Drug Therapy
Water
Therapeutics
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Systemic delivery of nanoparticle formulation of novel tubulin inhibitor for treating metastatic melanoma. / Mundra, Vaibhav; Peng, Yang; Kumar, Virender; Li, Wei; Miller, Duane; Mahato, Ram I.

In: Drug Delivery and Translational Research, Vol. 5, No. 3, 01.06.2015, p. 199-208.

Research output: Contribution to journalArticle

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