Abstract
3
Objectives: Radionuclide therapy directed against tumors that express somatostatin receptors (SSTRs) has proven effective for the treatment of advanced, low- to intermediate-grade neuroendocrine tumors in the clinic. In clinical usage, somatostatin peptide-based analogs, labeled with therapeutic radionuclides, provide an overall response rate of about 30%, despite the high cumulative activity injected per patient. We set out to improve the effectiveness of somatostatin radiotherapy by preparing a chemical analog that would clear more slowly through the urinary tract and, concomitantly, have increased blood circulation half-life and higher targeted accumulation in the tumors. Materials and methods: We conjugated a common, clinically-used SST peptide derivative, DOTA-octreotate (TATE), to an Evans blue analog (EB), which reversibly binds to circulating serum albumin. The resulting molecule (EB-TATE) was used to chelate 86Y and 90Y, a diagnostic and a therapeutic radionuclide, respectively. The imaging capabilities and the radiotherapeutic efficacy of the resulting radioligand was evaluated in HCT116/SSTR2, HCT116, and AR42J cell lines that express differing levels of SST2 receptors. Results: The synthesized radiopharmaceutical retained affinity and specificity to SSTR2. The resulting radiolabeled EB-TATE showed significantly longer half-life and higher accumulation in SSTR2-positive tumors, compared with radiolabeled DOTA-TATE. Labeling of our novel EB-TATE with the therapeutic, pure beta emitter, 90Y, resulted in improved tumor response and survival rates of mice bearing SSTR2 xenografts and had long term efficacy when compared to DOTA-TATE itself. Conclusions: The coupling of a targeted peptide, a therapeutic radionuclide, and the EB‑based albumin binding provides for effective treatment of SSTR2-containing tumors.