title: Beta-lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells.
abstract: Beta-lapachone (beta-lap) is a novel anticancer agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme overexpressed in a variety of tumors. Despite its therapeutic promise, the poor aqueous solubility of beta-lap hinders its preclinical evaluation and clinical translation. Our objective was to develop beta-lap-containing poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-PLA) polymer micelles for the treatment of NQO1-overexpressing tumors. Several micelle fabrication strategies were examined to maximize drug loading. A film sonication method yielded beta-lap micelles with relatively high loading density (4.7+/-1.0% to 6.5+/-1.0%) and optimal size (29.6+/-1.5 nm). Release studies in phosphate-buffered saline (pH 7.4) showed the time (t(1/2)) for 50% of drug release at 18 h. In vitro cytotoxicity assays were performed in NQO1-overexpressing (NQO1+) and NQO1-null (NQO1-) H596 lung, DU-145 prostate, and MDA-MB-231 breast cancer cells. Cytotoxicity data showed that after a 2 h incubation with beta-lap micelles, a marked increase in toxicity was shown in NQO1+ cells over NQO1- cells, resembling free drug both in efficacy and mechanism of cell death. In summary, these data demonstrate the potential of beta-lap micelles as an effective therapeutic strategy against NQO1-overexpressing tumor cells.
authors.affiliation: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
authors.forename: Elvin
authors.initials: E
authors.lastname: Blanco
authors.forename: Erik A
authors.initials: EA
authors.lastname: Bey
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.forename: Brent D
authors.initials: BD
authors.lastname: Weinberg
authors.forename: Damon M
authors.initials: DM
authors.lastname: Sutton
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D008297:Male; D008823:Micelles; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis*; D053758:Nanoparticles / Q000737:chemistry*; D009285:Naphthoquinones / Q000008:administration & dosage / Q000494:pharmacology; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D009285:Naphthoquinones; D011091:Polyesters; D011092:Polyethylene Glycols; C083464:poly(ethyleneglycol-lactide); C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human