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

Xinpeng Ma, Xiumei Huang, Zachary Moore, Gang Huang, Jessica A. Kilgore, Yiguang Wang, Suntrea Hammer, Noelle S. Williams, David A. Boothman, Jinming Gao

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, β-lapachone (β-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 β-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 β-lap prodrug nanotherapeutics consisting of diester derivatives of β-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 β-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered β-lap-dC3 and -dC6 prodrugs were converted to β-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 β-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over β-lap-dC6 micelles or β-lap-HPβCD complexes. Improved therapeutic efficacy of β-lap-dC3 micelles correlated with higher area under the concentration-time curves of β-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γH2AX, and ATP depletion). β-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy.

Original languageEnglish (US)
Pages (from-to)201-211
Number of pages11
JournalJournal of Controlled Release
Volume200
DOIs
StatePublished - Feb 28 2015

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Prodrugs
Micelles
Esterases
Lung Neoplasms
Ethylene Glycol
Therapeutics
Non-Small Cell Lung Carcinoma
Hemolytic Anemia
Caspases
Heterografts
Pharmaceutical Preparations
NAD
Neoplasms
Cell Cycle
Oxidoreductases
Pharmacokinetics
Adenosine Triphosphate
Safety

Keywords

  • Cancer nanomedicine
  • Non-small cell lung cancer
  • Polymeric micelles
  • Prodrug therapy
  • β-Lapachone

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy. / Ma, Xinpeng; Huang, Xiumei; Moore, Zachary; Huang, Gang; Kilgore, Jessica A.; Wang, Yiguang; Hammer, Suntrea; Williams, Noelle S.; Boothman, David A.; Gao, Jinming.

In: Journal of Controlled Release, Vol. 200, 28.02.2015, p. 201-211.

Research output: Contribution to journalArticle

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AU - Moore, Zachary

AU - Huang, Gang

AU - Kilgore, Jessica A.

AU - Wang, Yiguang

AU - Hammer, Suntrea

AU - Williams, Noelle S.

AU - Boothman, David A.

AU - Gao, Jinming

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AB - Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, β-lapachone (β-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 β-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 β-lap prodrug nanotherapeutics consisting of diester derivatives of β-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 β-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered β-lap-dC3 and -dC6 prodrugs were converted to β-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 β-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over β-lap-dC6 micelles or β-lap-HPβCD complexes. Improved therapeutic efficacy of β-lap-dC3 micelles correlated with higher area under the concentration-time curves of β-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γH2AX, and ATP depletion). β-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy.

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