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This Article Figures Only Full Text Full Text (PDF) Supplemental Data All Versions of this Article: jnumed.109.064444v1 50/12/2017    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Maddalena, M. E. Articles by Lantry, L. E. Search for Related Content PubMed PubMed Citation Articles by Maddalena, M. E. Articles by Lantry, L. E.

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

Ernst Felder Laboratories, Bracco Research USA Inc., Princeton, New Jersey

Correspondence: For correspondence or reprints contact: Mary Ellen Maddalena, Discovery Biology, Ernst Felder Laboratories, Bracco Research USA, 305 College Rd. East, Princeton, NJ 08540-6608. E-mail: maryellen.maddalena{at}bru.bracco.com

¹⁷⁷Lu-DO3A-CH₂CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH₂ (¹⁷⁷Lu-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, ¹⁷⁷Lu-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 x 10⁵/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 x 10³ and 1.2 x 10⁴/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 ¹⁷⁷Lu-AMBA in low GRP-R models of prostate cancer and determine how reduced expression affects ¹⁷⁷Lu-AMBA radiotherapy efficacy. Methods: The LNCaP and DU145 cell lines were used to determine the binding (K_d), retention, and efflux of ¹⁷⁷Lu-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: ¹⁷⁷Lu-AMBA binds to GRP-R in these cell lines with high affinity (K_d of LNCaP, 0.65 ± 0.2 nM; K_d of DU145, 0.53 ± 0.1 nM). The uptake of ¹⁷⁷Lu-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 -images of ¹⁷⁷Lu-AMBA identify tumors in vivo. Despite having lower uptake, ¹⁷⁷Lu-AMBA demonstrated radiotherapeutic efficacy and decreased proliferation in the LNCaP and DU145 xenografts; in the LNCaP model, ¹⁷⁷Lu-AMBA normalized the phenotype of microvasculature, reducing tumoral blood pooling. Conclusion: ¹⁷⁷Lu-AMBA is a single radiolabeled agent that combines targeted radiotherapy after imaging dosimetry with the potential for single-agent or multimodality therapy for prostate cancer.

Key Words: gastrin-releasing peptide • prostate cancer • radiotherapeutics • imaging • ¹⁷⁷Lu

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