UNLABELLED

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 (177)Lu-DOTA-Lys(glucose)-4 aminobenzoic acid-BBS7-14 ((177)Lu-DOTA-gluBBN) to prepare radiolabeled candidates for the treatment of GRPR-expressing prostate tumors.

METHODS

(177)Lu-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 (177)Lu-DOTA-gluBBN. Pharmacokinetic, imaging, and radiotherapy studies were performed in PC-3 xenografted mice.

RESULTS

The Kd value of (177)Lu-DOTA-gluBBN was 0.63 nM, with a maximum binding capacity (Bmax) of 669.7 fmol/10(6) cells (4.04×10(5) 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 24hr p.i. In addition, (177)Lu-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 (177)Lu-DOTA-gluBBN has promising characteristics for application in nuclear medicine, namely, for the diagnosis and treatment of GRPR-overexpressing prostate tumors.