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

Ying Dong, Shook Fong Chin, Elvin Blanco, Erik A. Bey, Wareef Kabbani, Xian Jin Xie, William G. Bornmann, David A. Boothman, Jinming Gao

Research output: Contribution to journalArticle

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Abstract

Purpose: β-Lapachone (ARQ 501, a formulation of β-lapachone complexed with hydroxy- propyl- β-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 β-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 β-lapachone in different prostate cancer cells. β-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: β-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 β-lapachone with hydroxypropyl-β-cyclodextrin into poly(o,L-lactide-co-glycolide) millirods, β-lapachone release kinetics in vivo showed a burst release of ∼0.5 mg within 12 hours and a subsequently sustained release of the drug (sim; 0.4 mg/kg/d) comparable with that observed in vitro. Antitumor efficacy studies showed significant tumor growth inhibition by β-lapachone millirods compared with controls (P « 0.0001; n = 10 per group). Kaplan-Meier survival curves showed that tumor-bearing mice treated with β-lapachone millirods survived nearly 2-fold longer than controls, without observable systemic toxicity. Conclusions: Intratumoral delivery of β-lapachone using polymer millirods showed the promising therapeutic potential for human prostate tumors.

Original languageEnglish (US)
Pages (from-to)131-139
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2009

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Prostatic Neoplasms
Polymers
Prostate
Neoplasms
Cyclodextrins
Nude Mice
Antineoplastic Agents
NAD
Oxidoreductases
Therapeutics
Kaplan-Meier Estimate
Heterografts
Solubility
Research Design
Cell Line
Survival
Enzymes
Growth
Pharmaceutical Preparations
In Vitro Techniques

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Intratumoral delivery of β-lapachone via polymer implants for prostate cancer therapy. / Dong, Ying; Chin, Shook Fong; Blanco, Elvin; Bey, Erik A.; Kabbani, Wareef; Xie, Xian Jin; Bornmann, William G.; Boothman, David A.; Gao, Jinming.

In: Clinical Cancer Research, Vol. 15, No. 1, 01.01.2009, p. 131-139.

Research output: Contribution to journalArticle

Dong, Y, Chin, SF, Blanco, E, Bey, EA, Kabbani, W, Xie, XJ, Bornmann, WG, Boothman, DA & Gao, J 2009, 'Intratumoral delivery of β-lapachone via polymer implants for prostate cancer therapy', Clinical Cancer Research, vol. 15, no. 1, pp. 131-139. https://doi.org/10.1158/1078-0432.CCR-08-1691
Dong, Ying ; Chin, Shook Fong ; Blanco, Elvin ; Bey, Erik A. ; Kabbani, Wareef ; Xie, Xian Jin ; Bornmann, William G. ; Boothman, David A. ; Gao, Jinming. / Intratumoral delivery of β-lapachone via polymer implants for prostate cancer therapy. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 1. pp. 131-139.
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abstract = "Purpose: β-Lapachone (ARQ 501, a formulation of β-lapachone complexed with hydroxy- propyl- β-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 β-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 β-lapachone in different prostate cancer cells. β-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: β-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 β-lapachone with hydroxypropyl-β-cyclodextrin into poly(o,L-lactide-co-glycolide) millirods, β-lapachone release kinetics in vivo showed a burst release of ∼0.5 mg within 12 hours and a subsequently sustained release of the drug (sim; 0.4 mg/kg/d) comparable with that observed in vitro. Antitumor efficacy studies showed significant tumor growth inhibition by β-lapachone millirods compared with controls (P « 0.0001; n = 10 per group). Kaplan-Meier survival curves showed that tumor-bearing mice treated with β-lapachone millirods survived nearly 2-fold longer than controls, without observable systemic toxicity. Conclusions: Intratumoral delivery of β-lapachone using polymer millirods showed the promising therapeutic potential for human prostate tumors.",
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AU - Chin, Shook Fong

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AU - Kabbani, Wareef

AU - Xie, Xian Jin

AU - Bornmann, William G.

AU - Boothman, David A.

AU - Gao, Jinming

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N2 - Purpose: β-Lapachone (ARQ 501, a formulation of β-lapachone complexed with hydroxy- propyl- β-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 β-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 β-lapachone in different prostate cancer cells. β-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: β-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 β-lapachone with hydroxypropyl-β-cyclodextrin into poly(o,L-lactide-co-glycolide) millirods, β-lapachone release kinetics in vivo showed a burst release of ∼0.5 mg within 12 hours and a subsequently sustained release of the drug (sim; 0.4 mg/kg/d) comparable with that observed in vitro. Antitumor efficacy studies showed significant tumor growth inhibition by β-lapachone millirods compared with controls (P « 0.0001; n = 10 per group). Kaplan-Meier survival curves showed that tumor-bearing mice treated with β-lapachone millirods survived nearly 2-fold longer than controls, without observable systemic toxicity. Conclusions: Intratumoral delivery of β-lapachone using polymer millirods showed the promising therapeutic potential for human prostate tumors.

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