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Intratumoral Delivery of β-Lapachone via Polymer Implants for Prostate Cancer Therapy

Authors' Affiliations: ¹ Simmons Comprehensive Cancer Center, ² Department of Pathology, and ³ Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas; and ⁴ Department of Experimental Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Jinming Gao, ND2.210, 6001 Forrest Park, Dallas, TX 75390-0001. Phone: 214-645-6370; Fax: 214-645-6347; E-mail: jinming.gao{at}utsouthwestern.edu and David A. Boothman, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390. Phone: 214-645-6371; Fax: 214-645-6347; E-mail: david.boothman{at}utsouthwestern.edu.

Purpose: β-Lapachone (ARQ 501, a formulation of β-lapachone complexed with hydroxypropyl-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(D,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 (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.