PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin

Abstract

Purpose To develop a new probe for the αvβ6-integrin and assess its potential for PET imaging of carcinomas. Methods Ga-68-Trivehexin was synthesized by trimerization of the optimized αvβ6-integrin selective cyclic nonapeptide Tyr2 (sequence: c[YRGDLAYp(NMe)K]) on the TRAP chelator core, followed by automated labeling with Ga-68. The tracer was characterized by ELISA for activities towards integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1, as well as by cell binding assays on H2009 (αvβ6-positive) and MDA-MB-231 (αvβ6-negative) cells. SCID-mice bearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static (75 min p.i.) µPET imaging, as well as for biodistribution (90 min p.i.). Structure–activity-relationships were established by comparison with the predecessor compound Ga-68-TRAP(AvB6)3. Ga-68-Trivehexin was tested for in-human PET/CT imaging of HNSCC, parotideal adenocarcinoma, and metastatic PDAC. Results Ga-68-Trivehexin showed a high αvβ6-integrin affinity (IC50 = 0.047 nM), selectivity over other subtypes (IC50-based factors: αvβ8, 131; αvβ3, 57; α5β1, 468), blockable uptake in H2009 cells, and negligible uptake in MDA-MB-231 cells. Biodistribution and preclinical PET imaging confirmed a high target-specific uptake in tumor and a low non-specific uptake in other organs and tissues except the excretory organs (kidneys and urinary bladder). Preclinical PET corresponded well to in-human results, showing high and persistent uptake in metastatic PDAC and HNSCC (SUVmax = 10–13) as well as in kidneys/urine. Ga-68-Trivehexin enabled PET/CT imaging of small PDAC metastases and showed high uptake in HNSCC but not in tumor-associated inflammation. Conclusions Ga-68-Trivehexin is a valuable probe for imaging of αvβ6-integrin expression in human cancers.

Therapeutic Efficacy of 177Lu-Labeled A20FMDV2 Peptides Targeting ανβ6

“…We demonstrated good imaging of BXPC-3 tumors with [ 68 Ga]Ga-DOTA-(PEG28) 2 -A20FMDV2 that was specific as evidenced by the reduction in SUV upon administration of the blocking agent. Other 68 Ga studies targeting integrin α v β 6 have shown good tumor uptake compared to blocking and clearance through the kidney, which is consistent with our results [16,35,36,38].…”

“…Several radiolabeled α ν β 6 -targeting ligands have been identified and used in preclinical imaging studies [12][13][14][15][16][17]. Quigley et al introduced a cyclic nonapeptide c[YRGDLAYp(NMe)K] radiolabeled with 68 Ga that showed a high affinity and target-specific uptake in integrin α ν β 6 -positive tumors [16].…”

“…Several radiolabeled α ν β 6 -targeting ligands have been identified and used in preclinical imaging studies [12][13][14][15][16][17]. Quigley et al introduced a cyclic nonapeptide c[YRGDLAYp(NMe)K] radiolabeled with 68 Ga that showed a high affinity and target-specific uptake in integrin α ν β 6 -positive tumors [16]. Kimura et al presented a series of highly stable cystine knot peptides radiolabeled with 64 Cu that showed potent and specific integrin α v β 6 binding in vitro and in vivo studies [17].…”

Integrin-Mediated Tumorigenesis and Its Therapeutic Applications

“…Neil et. al found that Ga-68-Trivehexin is a promising probe for imaging of aVb6integrin expression in human cancers because of its high expression density at the boundary of tumor and healthy tissue (104). Recent studies also show that it may be possible to develop next-generation nanomedicine based on the combined derivatives of resveratrol and tetrac targeting the Integrin avb3 (105).…”

Molecular Targeted Positron Emission Tomography Imaging and Radionuclide Therapy of Pancreatic Ductal Adenocarcinoma

“…A recent small study from Quigley et al showed the first promising results for 68 Ga-labelled trimerized αvβ6-integrin-selective nonapeptide ( 68 Ga-Trivehexin)-enabled PET-CT imaging. One patient, out of a total of four, was included with PDAC, showing a high tracer uptake in the pancreatic tumour, including multiple liver metastases [ 49 ].…”