Bombesin antagonist-based radiotherapy of prostate cancer combined with WST-11 vascular targeted photodynamic therapy

Purpose: DOTA-AR, a bombesin-antagonist peptide, has potential clinical application for targeted imaging and therapy in gastrin-releasing peptide receptor (GRPr)–positive malignancies when conjugated with a radioisotope such as ⁹⁰Y. This therapeutic potential is limited by the fast washout of the conjugates from the target tumors. WST-11 (Weizmann STeba-11 drug; a negatively charged water-soluble palladium-bacteriochlorophyll derivative, Tookad Soluble) vascular targeted photodynamic therapy (VTP) is a local ablation approach recently approved for use in early-stage prostate cancer. It generates reactive oxygen/nitrogen species within tumor blood vessels, resulting in their instantaneous destruction followed by rapid tumor necrosis. We hypothesize that the instantaneous arrest of tumor vasculature may provide a means to trap radiopharmaceuticals within the tumor, thereby improving the efficacy of targeted radiotherapy. Experimental Design: GRPr-positive prostate cancer xenografts (PC-3 and VCaP) were treated with ⁹⁰Y-DOTA-AR with or without VTP. The uptake of radioisotopes was monitored by Cherenkov luminescence imaging (CLI). The therapeutic efficacy of the combined VTP and ⁹⁰Y-DOTA-AR in PC-3 xenografts was assessed. Results: CLI of ⁹⁰Y-DOTA-AR demonstrated longer retention of radiotracer within the VTP-treated PC-3 xenografts compared with the non–VTP-treated ones (P < 0.05) at all time points (24–144 hours) after ⁹⁰Y-DOTA-AR injection. A similar pattern of retention was observed in VCaP xenografts. When ⁹⁰Y-DOTA-AR administration was combined with VTP, tumor growth delay was significantly longer than for the control or the monotherapy groups. Conclusions: Tumor vascular arrest by VTP improves ⁹⁰Y-DOTA-AR retention in the tumor microenvironment thereby enhancing therapeutic efficacy.