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Esterase-activatable β-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, 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.
AuthorsXinpeng Ma, Xiumei Huang, Zachary Moore, Gang Huang, Jessica A Kilgore, Yiguang Wang, Suntrea Hammer, Noelle S Williams, David A Boothman, Jinming Gao
JournalJournal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 200 Pg. 201-11 (Feb 28 2015) ISSN: 1873-4995 [Electronic] Netherlands
PMID25542645 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2014 Elsevier B.V. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Lactates
  • Micelles
  • Naphthoquinones
  • Prodrugs
  • poly(lactic acid-ethylene glycol)
  • Polyethylene Glycols
  • beta-lapachone
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Nqo1 protein, mouse
  • Esterases
Topics
  • Animals
  • Antineoplastic Agents (administration & dosage, chemistry, pharmacology, therapeutic use)
  • Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
  • Cell Line, Tumor
  • Comet Assay
  • Erythrocytes (drug effects)
  • Esterases (metabolism)
  • Female
  • Hemolysis (drug effects)
  • Humans
  • Lactates (chemistry)
  • Lung Neoplasms (drug therapy, metabolism, pathology)
  • Mice, SCID
  • Micelles
  • NAD(P)H Dehydrogenase (Quinone) (metabolism)
  • Nanoparticles (administration & dosage, chemistry, therapeutic use)
  • Naphthoquinones (administration & dosage, chemistry, pharmacology, therapeutic use)
  • Polyethylene Glycols (chemistry)
  • Prodrugs (administration & dosage, chemistry, pharmacology, therapeutic use)
  • Tumor Burden (drug effects)

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