Beta-lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells

J Control Release. 2007 Oct 8;122(3):365-74. doi: 10.1016/j.jconrel.2007.04.014. Epub 2007 Apr 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents* / administration & dosage
  • Antineoplastic Agents* / 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
  • Naphthoquinones* / pharmacology
  • Particle Size
  • Polyesters / chemistry*
  • Polyethylene Glycols / chemistry*
  • Solubility

Substances

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