sup 177^Lu-AMBA Biodistribution, Radiotherapeutic Efficacy, Imaging, and Autoradiography in Prostate Cancer Models with Low GRP-R Expression

^sup 177^Lu-DO3A-CH^sub 2^CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH^sub 2^ (^sup 177^Lu-AMBA) is a radiolabeled bombesin derivative that is bound and internalized by cells expressing the G-protein-coupled gastrin-releasing peptide receptor (GRP-R) and is currently in phase I clinical trials. In previous radiotherapy studies with PC-3 xenografted mice, ^sup 177^Lu-AMBA treatment significantly increased survival and reduced tumor growth rates. The PC-3 tumor cell line has an elevated expression of GRP-Rs (2.5 × 10^sup 5^/cell), whereas LNCaP-a prostate cancer metastatic cell line representing the early androgen-sensitive stage of prostate cancer-and DU145-an androgen-insensitive metastatic line-express lower receptor numbers (5.9 × 10^sup 3^ and 1.2 × 10^sup 4^/cell, respectively). Because of tumor heterogeneity, the high number of receptors in the PC-3 line may not represent the clinical situation, and little definitive work on the GRP-R status of primary prostate tumors and metastases exists. We sought to evaluate the tumor binding and imaging potential of ^sup 177^Lu-AMBA in low GRP-R models of prostate cancer and determine how reduced expression affects ^sup 177^Lu-AMBA radiotherapy efficacy. Methods: The LNCaP and DU145 cell lines were used to determine the binding (K^sub d^), retention, and efflux of ^sup 177^Lu-AMBA. Biodistribution radiotherapy, imaging, and autoradiography studies were performed in LNCaP, DU145, or PC-3 tumor-bearing male nude mice. Immunohistochemistry was used to determine the proliferative state in LNCaP and DU145 models and the vascular phenotype of LNCaP radiotherapy tumors. Results: ^sup 177^Lu-AMBA binds to GRP-R in these cell lines with high affinity (K^sub d^ of LNCaP, 0.65 ± 0.2 nM; K^sub d^ of DU145, 0.53 ± 0.1 nM). The uptake of ^sup 177^Lu-AMBA is at least 10-fold less in LNCaP and DU145 cell lines than it is in the PC-3 cell line. Autoradiography identifies activity concentrated in areas of viable tumor tissue, and γ-images of ^sup 177^Lu-AMBA identify tumors in vivo. Despite having lower uptake, ^sup 177^Lu-AMBA demonstrated radiotherapeutic efficacy and decreased proliferation in the LNCaP and DU145 xenografts; in the LNCaP model, ^sup 177^Lu-AMBA normalized the phenotype of microvasculature, reducing tumoral blood pooling. Conclusion: ^sup 177^Lu-AMBA is a single radiolabeled agent that combines targeted radiotherapy after imaging dosimetry with the potential for single-agent or multimodality therapy for prostate cance