Preclinical pharmacokinetic, biodistribution, imaging and therapeutic efficacy of ¹⁷⁷Lu-Labeled glycated bombesin analogue for gastrin-releasing peptide receptor-positive prostate tumor targeting

The gastrin-releasing peptide receptor (GRPR) has been shown to be overexpressed in many human tumors, including prostate, colon, gastric, breast, pancreatic, and small cell lung cancers. Because bombesin (BBS) binds to GRPR with high affinity, BBS derivatives have been labeled with various radionuclides and have been demonstrated to be successful candidates for peptide receptor radiotherapy (PRRT). The present study describes the in vitro and in vivo preclinical characteristics of ¹⁷⁷Lu-DOTA-Lys(glucose)-4 aminobenzoic acid-BBS_7-14 (¹⁷⁷Lu-DOTA-gluBBN) to prepare radiolabeled candidates for the treatment of GRPR-expressing prostate tumors. Methods: ¹⁷⁷Lu-DOTA-gluBBN was prepared as previously published [1]. Human prostate PC-3 tumor cells were used to determine the binding (Kd) retention and efflux of ¹⁷⁷Lu-DOTA-gluBBN. Pharmacokinetic, imaging, and radiotherapy studies were performed in PC-3 xenografted mice. Results: The Kd value of ¹⁷⁷Lu-DOTA-gluBBN was 0.63 nM, with a maximum binding capacity (Bmax) of 669.7 fmol/10⁶ cells (4.04 × 10⁵ GRPR/cell). During a 2-hr incubation, 90.1 ± 0.4% of the cell-associated radio-peptide was internalized, and 56.3 ± 7.1% of the internalized radio-peptide was externalized in vitro. High amounts of the radio-peptide were rapidly accumulated in a PC-3 tumor in vivo, and the % ID/g of the tumor was 12.42 ± 2.15 1 hr p.i. The radio-peptide was quickly cleared from the blood, yielding tumor-to-blood ratios of 39.22 ± 17.36 at 1 hr p.i. and 330.67 ± 131.23 at 24 hr p.i. In addition, ¹⁷⁷Lu-DOTA-gluBBN was clearly visualized in PC-3 tumors 1 hr p.i. and significantly inhibited the tumor growth (P < 0.05). Treatment-related toxicity in the pancreas and kidneys was not observed, except for slight glomerulopathy. Conclusions: The pharmacokinetic, imaging, and therapy studies suggest that this ¹⁷⁷Lu-DOTA-gluBBN has promising characteristics for application in nuclear medicine, namely, for the diagnosis and treatment of GRPR-overexpressing prostate tumors