title: Nanotechnology-enabled delivery of NQO1 bioactivatable drugs.
abstract: Current cancer chemotherapy lacks specificity and is limited by undesirable toxic side-effects, as well as a high rate of recurrence. Nanotechnology has the potential to offer paradigm-shifting solutions to improve the outcome of cancer diagnosis and therapy. β-Lapachone (β-lap) is a novel anticancer agent whose mechanism of action is highly dependent on
  quinone oxidoreductase 1 (NQO1), a phase II detoxifying enzyme overexpressed in solid tumors from a variety of cancer types. However, the poor water solubility of β-lap limits its clinical potential. A series of drug formulations were developed for systemic administration in preclinical evaluations. Encapsulation of β-lap into polymeric micelles showed less side-effects and higher maximum tolerated dose (MTD), prolonged blood circulation time and preferential accumulation in tumors with greatly improved safety and antitumor efficacy. The prodrug strategy of β-lap further decreases the crystallization of β-lap by introducing esterase degradable side chains to the rigid fused ring structure. β-Lap prodrugs considerably increased the stability, drug-loading content and delivery efficiency of nanoparticles. The optimized formulation of β-lap-dC3 prodrug micelles showed excellent antitumor efficacy in treating orthotopic non-small cell lung tumors that overexpress NQO1, with target validation using pharmacodynamic endpoints.
authors.affiliation: a Department of Pharmacology , Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Xinpeng
authors.initials: X
authors.lastname: Ma
authors.affiliation: a Department of Pharmacology , Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Moore
authors.affiliation: a Department of Pharmacology , Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: a Department of Pharmacology , Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Huang
authors.affiliation: a Department of Pharmacology , Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.affiliation: a Department of Pharmacology , Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D020714:Maximum Tolerated Dose; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D053758:Nanoparticles; D036103:Nanotechnology; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D011355:Prodrugs; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: Cancer targeting; NQO1; drug delivery; nanoparticle; prodrug; β-lapachone