期刊
JOURNAL OF CONTROLLED RELEASE
卷 200, 期 -, 页码 201-211出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2014.12.027
关键词
beta-Lapachone; Prodrug therapy; Polymeric micelles; Non-small cell lung cancer; Cancer nanomedicine
资金
- Cancer Prevention Research Institute of Texas [RP120897]
- National Institutes of Health [5 R01 CA102792]
Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, beta-lapachone (beta-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of beta-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of beta-lap prodrug nanotherapeutics consisting of diester derivatives of beta-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(D, Llactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of beta-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered beta-lap-dC(3) and -dC(6) prodrugs were converted to beta-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintained NAD(P) H: quinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of beta-lap-dC(3) micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over beta-lap-dC(6) micelles or beta-lap-HP beta CD complexes. Improved therapeutic efficacy of beta-lap-dC(3) micelles correlated with higher area under the concentration-time curves of beta-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation,.H2AX, and ATP depletion). beta-Lap-dC(3) prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy. (C) 2014 Elsevier B.V. All rights reserved.
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