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Abstract

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.  

Author information

Kim K1, Zhang H2, La Rosa S1, Jebiwott S1, Desai P2, Kimm S3, Scherz A4, O'Donoghue JA5, Weber WA6, Coleman JA7.​

1Department of Surgery, Memorial Sloan Kettering Cancer Center, New York.2Radiochemistry and Imaging Sciences Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York.3Urology, Palo Alto Medical Foundation, Stanford, California.4Plant Science, Weizmann Institute of Science, Rehovot, Israel.5Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York.6Molecular Imaging and Therapy Services, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York.7Division of Urology, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York. colemanj@mskcc.org.