β-Lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells

Elvin Blanco, Erik A. Bey, Ying Dong, Brent D. Weinberg, Damon M. Sutton, David A. Boothman, Jinming Gao

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

β-Lapachone (β-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 β-lap hinders its preclinical evaluation and clinical translation. Our objective was to develop β-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 β-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 (t1/2) 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 β-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 β-lap micelles as an effective therapeutic strategy against NQO1-overexpressing tumor cells.

Original languageEnglish (US)
Pages (from-to)365-374
Number of pages10
JournalJournal of Controlled Release
Volume122
Issue number3
DOIs
StatePublished - Oct 8 2007

Fingerprint

Micelles
NADP
Oxidoreductases
Polymers
Neoplasms
benzoquinone
monomethoxypolyethyleneglycol-polylactide block copolymer
Sonication
Ethylene Glycol
Pharmaceutical Preparations
Antineoplastic Agents
Solubility
Prostate
Cell Death
Phosphates
Breast Neoplasms
Lung
Enzymes
Therapeutics

Keywords

  • β-Lapachone
  • Cancer nanomedicine
  • Drug delivery
  • Poly(ethylene glycol)-poly(d,l-lactide) (PEG-PLA)
  • Polymer micelles

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

β-Lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells. / Blanco, Elvin; Bey, Erik A.; Dong, Ying; Weinberg, Brent D.; Sutton, Damon M.; Boothman, David A.; Gao, Jinming.

In: Journal of Controlled Release, Vol. 122, No. 3, 08.10.2007, p. 365-374.

Research output: Contribution to journalArticle

Blanco, Elvin ; Bey, Erik A. ; Dong, Ying ; Weinberg, Brent D. ; Sutton, Damon M. ; Boothman, David A. ; Gao, Jinming. / β-Lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells. In: Journal of Controlled Release. 2007 ; Vol. 122, No. 3. pp. 365-374.
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T1 - β-Lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells

AU - Blanco, Elvin

AU - Bey, Erik A.

AU - Dong, Ying

AU - Weinberg, Brent D.

AU - Sutton, Damon M.

AU - Boothman, David A.

AU - Gao, Jinming

PY - 2007/10/8

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N2 - β-Lapachone (β-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 β-lap hinders its preclinical evaluation and clinical translation. Our objective was to develop β-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 β-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 (t1/2) 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 β-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 β-lap micelles as an effective therapeutic strategy against NQO1-overexpressing tumor cells.

AB - β-Lapachone (β-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 β-lap hinders its preclinical evaluation and clinical translation. Our objective was to develop β-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 β-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 (t1/2) 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 β-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 β-lap micelles as an effective therapeutic strategy against NQO1-overexpressing tumor cells.

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