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

Abstract Purpose: h-Lapachone (ARQ 501, a formulation of h-lapachone complexed with hydroxypropyl-h-cyclodextrin) is a novel anticancer agent with selectivity against prostate cancer cells overexpressing the NAD(P)H:quinone oxidoreductase-1enzyme. Lack of solubility and an efficient drug delivery strategy limits this compound in clinical applications. In this study, we aimed to develop h-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 h-lapachone in different prostate cancer cells. h-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: h-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 h-lapachone with hydroxypropyl-h-cyclodextrin into poly(D,L-lactide-co-glycolide) millirods, h-lapachone release kinetics in vivo showed a burst release of f0.5 mg within 12 hours and a subsequently sustained release of the drug (f0.4 mg/kg/d) comparable with that observed in vitro. Antitumor efficacy studies showed significant tumor growth inhibition by h-lapachone millirods compared with controls (P < 0.0001; n = 10 per group). Kaplan-Meier survival curves showed that tumor-bearing mice treated with h-lapachone millirods survived nearly 2-fold longer than controls, without observable systemic toxicity. Conclusions: Intratumoral delivery of h-lapachone using polymer millirods showed the promising therapeutic potential for human prostate tumors