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 tumorinduced 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 68 Ga-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 68 Ga. 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 68 Ga-DOTA-TMVP1 in vivo. In the clinical study, 5 healthy volunteers and 8 patients with gynecologic cancer underwent whole-body PET/CT after being injected with 68 Ga-DOTA-TMVP1.Results: DOTA-TMVP1 was successfully labeled with 68 Ga. LECs showed higher binding capacity with 68 Ga-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 68 Ga-DOTA-TMVP1 was comparable with that of 18 F-FDG PET/CT.Conclusions: 68 Ga-DOTA-TMVP1 is a potential PET tracer for imaging VEGFR-3 with favorable pharmacokinetics.

A TMVP1-modified near-infrared nanoprobe: molecular imaging for tumor metastasis in sentinel lymph node and targeted enhanced photothermal therapy

“…Finally, VEGFR-3 expression is restricted to the new lymphatic endothelial system in adult tissues [ 73 – 75 ]. Research indicates that vascular remodeling in tumor-metastatic lymph nodes may occur ahead of tumor metastasis [ 4 , 76 ]; therefore, VEGFR-3, as a marker of new lymphatic vessels, is appropriate as a molecular imaging ligand to predict and indicate metastasis [ 37 , 77 ]. This study focused on the expression of VEGFR-3 in tumor-induced new lymphatic vessels.…”

“…TMTP1 targets tumors in situ and metastases by binding to XPNPEP2, whereas TMVP1 is better for lymph node imaging as it binds to vascular endothelial growth factor receptor-3 (VEGFR-3) [ 31 – 36 ]. TMVP1 has a higher affinity and more rapid tumor uptake than other VEGFR-3-targeting agents, such as monoclonal antibodies or peptides [ 37 ].…”

“…TMVP1, a five-amino peptide with the core sequence of LARGR, end-collateral amide bond into a ring, and with one cysteine residues at the end was screened for VEGFR-3 binding using bacterial flagellin library display technology in our laboratory. In our previous study, a new type of VEGFR-3 molecular imaging agent, Ga 68 -DOTA-TMVP1, prepared by coupling TMVP1 with radioactive Ga 68 , was successfully used in preclinical experiments and achieved good imaging results in patients with malignant gynecological tumors [ 37 ]. In this study, we designed and synthesized a TMVP1-modified ICG nanoprobe, TMVP1-ICG-NP, using poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PEG-PLGA), a promising biodegradable polymer.…”

Recent advancement of imaging strategies of the lymphatic system: Answer to the decades old questions

“…This 68Ga‐DOTA‐TMVP1 peptide was intravenously injected in nude mice bearing cervical adenocarcinoma or ovarian adenocarcinoma xenografts as well as in human subjects (patients of recurrent cervical and ovarian carcinoma) followed by PET/CT scan. While mice models showed the specificity of this peptide, the lack of any adverse side effects as well as the fast renal clearing of 68Ga‐DOTA‐TMVP1 (30–60 min post‐injection) calls for further imaging studies using this VEGFR3‐specific peptide 84 . Yet another class of VEGFR‐3‐targeting antibody‐mimetic agents was developed using anticalins which are antigen binding proteins usually derived from human lipocalins and shows potential for in vivo imaging 85 …”

“…While mice models showed the specificity of this peptide, the lack of any adverse side effects as well as the fast renal clearing of 68Ga-DOTA-TMVP1 (30-60 min post-injection) calls for further imaging studies using this VEGFR3-specific peptide. 84 Yet another class of VEGFR-3-targeting antibody-mimetic agents was developed using anticalins which are antigen binding proteins usually derived from human lipocalins and shows potential for in vivo imaging. 18F-FHBG/18F-FEAU.…”