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Intratumoral delivery of beta-lapachone via polymer implants for prostate cancer therapy.

AbstractPURPOSE:
beta-Lapachone (ARQ 501, a formulation of beta-lapachone complexed with hydroxypropyl-beta-cyclodextrin) is a novel anticancer agent with selectivity against prostate cancer cells overexpressing the NAD(P)H:quinone oxidoreductase-1 enzyme. Lack of solubility and an efficient drug delivery strategy limits this compound in clinical applications. In this study, we aimed to develop beta-lapachone-containing polymer implants (millirods) for direct implantation into prostate tumors to test the hypothesis that the combination of a tumor-specific anticancer agent with site-specific release of the agent will lead to significant antitumor efficacy.
EXPERIMENTAL DESIGN:
Survival assays in vitro were used to test the killing effect of beta-lapachone in different prostate cancer cells. beta-Lapachone release kinetics from millirods was determined in vitro and in vivo. PC-3 prostate tumor xenografts in athymic nude mice were used for antitumor efficacy studies in vivo.
RESULTS:
beta-Lapachone killed three different prostate cancer cell lines in an NAD(P)H:quinone oxidoreductase-1-dependent manner. Upon incorporation of solid-state inclusion complexes of beta-lapachone with hydroxypropyl-beta-cyclodextrin into poly(D,L-lactide-co-glycolide) millirods, beta-lapachone release kinetics in vivo showed a burst release of approximately 0.5 mg within 12 hours and a subsequently sustained release of the drug ( approximately 0.4 mg/kg/d) comparable with that observed in vitro. Antitumor efficacy studies showed significant tumor growth inhibition by beta-lapachone millirods compared with controls (P < 0.0001; n = 10 per group). Kaplan-Meier survival curves showed that tumor-bearing mice treated with beta-lapachone millirods survived nearly 2-fold longer than controls, without observable systemic toxicity.
CONCLUSIONS:
Intratumoral delivery of beta-lapachone using polymer millirods showed the promising therapeutic potential for human prostate tumors.
AuthorsYing Dong, Shook-Fong Chin, Elvin Blanco, Erik A Bey, Wareef Kabbani, Xian-Jin Xie, William G Bornmann, David A Boothman, Jinming Gao
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 1 Pg. 131-9 (Jan 1 2009) ISSN: 1078-0432 [Print] United States
PMID19118040 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Drug Carriers
  • Drug Implants
  • Naphthoquinones
  • Polymers
  • beta-lapachone
Topics
  • Animals
  • Antineoplastic Agents (administration & dosage, therapeutic use)
  • Cell Line, Tumor
  • Drug Carriers (administration & dosage)
  • Drug Implants (administration & dosage, therapeutic use)
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Naphthoquinones (administration & dosage, therapeutic use)
  • Polymers (pharmacology)
  • Prostatic Neoplasms (drug therapy, pathology)
  • Xenograft Model Antitumor Assays

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