Primary Preclinical and Clinical Evaluation of ⁶⁸Ga-DOTA-TMVP1 as a Novel VEGFR-3 PET Imaging Radiotracer in Gynecological Cancer.

Abstract

Tumor periphery and lymph nodes of tumor-induced lymphangiogenesis often abundantly express VEGFR-3. In our previous study, we identified a 5-amino acid peptide named TMVP1, which binds specifically to VEGFR-3. The objective of this study was to develop a novel ⁶⁸Ga-labeled TMVP1 for VEGFR-3 PET imaging and to investigate its safety, biodistribution, and tumor-localizing efficacy in xenograft tumor models and a small cohort of patients with recurrent ovarian and cervical cancer. The DOTA-conjugated TMVP1 peptide was labeled with radionuclide ⁶⁸Ga. SPR and saturation binding assays were used for the receptor-binding studies. Gynecologic xenograft tumors were employed for small-animal PET imaging and biodistribution of ⁶⁸Ga-DOTA-TMVP1 <i>in vivo</i>. In the clinical study, 5 healthy volunteers and 8 patients with gynecologic cancer underwent whole-body PET/CT after being injected with ⁶⁸Ga-DOTA-TMVP1. DOTA-TMVP1 was successfully labeled with ⁶⁸Ga. LECs showed higher binding capacity with ⁶⁸Ga-DOTA-TMVP1 than LEC(shVEGFR-3) and human umbilical vein endothelial cells. In mice with subcutaneous C33-A and SKOV-3 xenografts, the tracer was rapidly eliminated through the kidney to the bladder, and the small-animal PET/CT helped to clearly visualize the tumors. In patients with recurrent ovarian cancer and cervical cancer, tracer accumulation well above the background level was demonstrated in most identified sites of disease; especially with recurrent endodermal sinus tumors, the diagnostic value of ⁶⁸Ga-DOTA-TMVP1 was comparable with that of ¹⁸F-FDG PET/CT. ⁶⁸Ga-DOTA-TMVP1 is a potential PET tracer for imaging VEGFR-3 with favorable pharmacokinetics.