Primary preclinical and clinical Evaluation of 68Ga-DOTA-TMVP1 as a novel VEGFR-3 PET Imaging Radiotracer in Gynecological Cancer

Purpose: Tumor periphery and lymph nodes of tumor-induced lymphangiogenesis often abundantly express vascular endothelial growth factor receptor-3 (VEGFR-3). In our previous study, we identified a 5-amino acid peptide named TMVP1, which binds specifically to VEGFR-3. The objective of the present 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. Experimental Design: The DOTA-conjugated TMVP1 peptide was labeled with radionuclide 68Ga. SPR and saturation binding assays were used for the receptor-binding studies. Gynecological xenograft tumors were employed for small-animal PET imaging and biodistribution of 68Ga-DOTA-TMVP1 in vivo. In the clinical study, five healthy volunteers and eight gynecological cancer patients underwent whole-body PET/CT after being injected with 68Ga-DOTA-TMVP1. Results: DOTA-TMVP1 was successfully labeled with 68Ga. LECs showed higher binding capacity with 68Ga-DOTA-TMVP1 than LEC(shVEGFR-3) and HUVECs. 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 to that of 18F-FDG PET/CT. Conclusions: 68Ga-DOTA-TMVP1 is a potential PET tracer for imaging VEGFR-3 with favorable pharmacokinetics.