Dataset Information

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

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Publications

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

Ma Xinpeng X Huang Xiumei X Moore Zachary Z Huang Gang G Kilgore Jessica A JA Wang Yiguang Y Hammer Suntrea S Williams Noelle S NS Boothman David A DA Gao Jinming J

Journal of controlled release : official journal of the Controlled Release Society 20141224

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 eva ...[more]

PMID: 25542645

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Project description:Rationale: Chemodynamic therapy (CDT) is an emerging tumor-specific therapeutic strategy. However, the anticancer activity of CDT is impeded by the insufficient Fenton catalytic efficiency and the high concentration of glutathione (GSH) in the tumor cells. Also, it is challenging to eliminate tumors with CDT alone. Thus, simple strategies aimed at constructing well-designed nanomedicines that can improve therapeutic efficiency of CDT and simultaneously incorporate extra therapeutic modes as helper are meaningful and highly required. Method: Tailored to specific features of tumor microenvironment (TME), in this study, we developed a biosafe, stable and TME-activated theranostic nanoplatform (P(HSD-Cu-DA)) for photoacoustic imaging (PAI) and self-amplified cooperative therapy. This intelligent nanoplatform was fabricated following a simple one-pot coordination and polymerization strategy by using dopamine and Cu2+ as precursors and redox-responsive hydroxyethyl starch prodrugs (HES-SS-DOX) as stabilizer. Results: Interestingly, the pre-doped Cu2+ in polydopamine (PDA) framework can endow P(HSD-Cu-DA) NPs with tumor-specific CDT ability and remarkably enhance NIR absorption of PDA. PAI and biodistribution tests proved such nanoplatform can effectively accumulate in tumor tissues. Following enrichment, massive amounts of toxic hydroxyl radicals (·OH, for CDT) and free DOX (for chemotherapy) were generated by the stimulation of TME, which was further boosted by local hyperthermia. Concomitantly, in the process of activating these therapeutic functions, GSH depletion triggered by disulfide bond (-SS-) breakage and Cu2+ reduction within tumor cells occurred, further amplifying intratumoral oxidative stress. Importantly, the framework structure dominated by bioinspired polydopamine and clinical-used HES guaranteed the long-term biosafety of in vivo treatment. As a result, the mutual promotion among different components yields a potent tumor suppression outcome and minimized systemic toxicity, with one dosage of drug administration and laser irradiation, respectively. Conclusion: This work provides novel insights into designing efficient and tumor-specific activatable nanotherapeutics with significant clinical translational potential for cancer therapy.

Dataset Information

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

Publications

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

Similar Datasets

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