Esterase-activatable ?-lapachone prodrug micelles for NQO1-targeted lung cancer therapy.

ABSTRACT: Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, ?-lapachone (?-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 ?-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 ?-lap prodrug nanotherapeutics consisting of diester derivatives of ?-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of ?-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered ?-lap-dC3 and -dC6 prodrugs were converted to ?-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintainedquinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of ?-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over ?-lap-dC6 micelles or ?-lap-HP?CD complexes. Improved therapeutic efficacy of ?-lap-dC3 micelles correlated with higher area under the concentration-time curves of ?-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, ?H2AX, and ATP depletion). ?-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy.

SUBMITTER: Ma X 

PROVIDER: S-EPMC4803448 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature