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: Elvin Blanco, Erik A Bey, Ying Dong, Brent D Weinberg, Damon M Sutton, David A Boothman, Jinming Gao
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 122 Issue 3 Pg. 365-74 (Oct 08 2007) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 17574288 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Micelles
• Naphthoquinones
• Polyesters
• Polyethylene Glycols
• poly(ethyleneglycol-lactide)
• beta-lapachone
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human

Topics

• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• DNA Damage
• Drug Carriers (chemistry)
• Female
• Humans
• Male
• Micelles
• NAD(P)H Dehydrogenase (Quinone) (biosynthesis)
• Nanoparticles (chemistry)
• Naphthoquinones (administration & dosage, pharmacology)
• Particle Size
• Polyesters (chemistry)
• Polyethylene Glycols (chemistry)
• Solubility