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.
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Authors | Xinpeng Ma, Xiumei Huang, Zachary Moore, Gang Huang, Jessica A Kilgore, Yiguang Wang, Suntrea Hammer, Noelle S Williams, David A Boothman, Jinming Gao |
Journal | Journal 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 |
PMID | 25542645
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Copyright © 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
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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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