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

JOURNAL OF CONTROLLED RELEASE

卷:200

Article

Ma, Xinpeng¹  Huang, Xiumei²  Moore, Zachary²  Huang, Gang¹  Kilgore, Jessica A.³  Wang, Yiguang¹  Hammer, Suntrea⁴  Williams, Noelle S.³  Boothman, David A.²  Gao, Jinming¹ 

[1] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[2] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[3] Univ Texas SW Med Ctr Dallas, Dept Biochem, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Pathol, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

关键词: beta-Lapachone;    Prodrug therapy;    Polymeric micelles;    Non-small cell lung cancer;    Cancer nanomedicine;   

DOI  :  10.1016/j.jconrel.2014.12.027

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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