Preclinical Evaluation of Ga- and Lu-Labeled Integrin αβ-Targeting Radiotheranostic Peptides.

The integrin αβ, an epithelium-specific cell surface receptor, is overexpressed on numerous malignancies, including the highly lethal pancreatic ductal adenocarcinomas. Here, we developed and tested a novel αβ-targeting peptide, DOTA-5G () radiolabeled with Ga, for PET/CT imaging and Lu for treatment. With the goal to develop a radiotheranostic, further modifications were made for increased circulation time, renal recycling, and tumor uptake, yielding DOTA-albumin-binding moiety-5G (). Peptides and were synthesized on solid phase, and their affinity for αβ was assessed by enzyme-linked immunosorbent assay. The peptides were radiolabeled with Ga and Lu. In vitro cell binding, internalization, and efflux of Ga- and Lu- were evaluated in αβ-positive BxPC-3 human pancreatic cancer cells. PET/CT imaging of Ga- and Ga- was performed on female nu/nu mice bearing subcutaneous BxPC-3 tumors. Biodistribution was performed for Ga- (1 and 2 h after injection), Ga- (2 and 4 h after injection), and Lu- and Lu- (1, 24, 48, and 72 h after injection). The Lu- biodistribution data were extrapolated for human dosimetry data estimates using OLINDA/EXM 1.1. Therapeutic efficacy of Lu- was evaluated in mice bearing BxPC-3 tumors. Peptides and demonstrated high affinity (<55 nM) for αβ by enzyme-linked immunosorbent assay. Ga-, Ga-, Lu-, and Lu- were synthesized in high radiochemical purity. Rapid in vitro binding and internalization of Ga- and Lu- were observed in BxPC-3 cells. PET/CT imaging and biodistribution studies demonstrated uptake in BxPC-3 tumors. Introduction of the albumin-binding moiety in Lu- resulted in a 5-fold increase in tumor uptake and retention over time. Based on the extended dosimetry data, the dose-limiting organ for Lu- is the kidney. Treatment with Lu- prolonged median survival by 1.5- to 2-fold versus controls. Ga- and Lu- demonstrated high affinity for the integrin αβ both in vitro and in vivo, were rapidly internalized into BxPC-3 cells, and were stable in mouse and human serum. Both radiotracers showed favorable pharmacokinetics in preclinical studies, with predominantly renal excretion and good tumor-to-normal-tissue ratios. Favorable human dosimetry data suggest the potential of Lu- as a treatment for pancreatic ductal adenocarcinoma.