Clinical Translation of a⁶⁸Ga-Labeled Integrin α_vβ₆–Targeting Cyclic Radiotracer for PET Imaging of Pancreatic Cancer

Abstract

The overexpression of integrin αvβ6 in pancreatic cancer makes it a promising target for noninvasive positron emission tomography (PET) imaging. However, currently, most integrin αvβ6-targeting radiotracers are based on linear peptides, which are quickly degraded in the serum by proteinases. Herein, we aimed to develop and assess a 68 Galabeled integrin αvβ6-targeting cyclic peptide (68 Ga-cycratide) for PET imaging of pancreatic cancer. Methods: 68 Ga-cycratide was prepared, and its PET imaging profile was compared with that of the linear peptide (68 Ga-linear-pep) in an integrin αvβ6-positive BxPC-3 human pancreatic cancer mouse model. Five healthy volunteers (two women and three men) underwent whole-body PET/CT imaging after injection of 68 Ga-cycratide, and biodistribution and dosimetry calculations were determined. PET/CT imaging of two patients was performed to investigate the potential role of 68 Ga-cycratide in pancreatic cancer diagnosis and treatment monitoring. Results: 68 Ga-cycratide exhibited significantly higher tumor uptake than did 68 Ga-linear-pep in BxPC-3 tumor-bearing mice, owing-at least in part-to markedly improved in vivo stability. 68 Ga-cycratide could sensitively detect the pancreatic cancer lesions in an orthotopic mouse model and was well tolerated in all healthy volunteers. Preliminary PET/CT imaging in patients with pancreatic cancer demonstrated that 68 Ga-cycratide was comparable to 18 F-fludeoxyglucose for diagnostic imaging and post-surgery tumor relapse monitoring. Conclusion: 68 Ga-cycratide is an integrin αvβ6-specific PET radiotracer with favorable pharmacokinetics and dosimetry profile. 68 Ga-cycratide is expected to provide an effective noninvasive PET strategy for pancreatic cancer lesion detection and therapy response monitoring.

SPECT/CT Imaging, Biodistribution and Radiation Dosimetry of a 177Lu-DOTA-Integrin αvβ6 Cystine Knot Peptide in a Pancreatic Cancer Xenograft Model

“…However, due to reduced stability and specificity for the receptor, in vivo results were ambiguous. In a recent study, a cyclic radiotracer specific for integrin αvβ6 ( 68 Ga-cycratide) was used in a pancreatic mouse model for PET imaging ( 32 ). The DOTA-integrin αvβ6 knottin applied here has recently been used in a first-in-human clinical study and has demonstrated a high potential for PDAC targeting ( 24 ).…”

Preliminary study on SPECT/CT imaging of pancreatic cancer xenografts by targeting integrin α5 in pancreatic stellate cells

“…integrin α v β 6, tissue factor, neurotensin receptor 1) or neo-vascularendothelial cells (e.g. integrin α v β 3 ), but few researches focus on the CAFs or PSCs 8 , 14 - 16 . However, given that cancer cells constitute a minority but with a high heterogeneity in pancreatic cancer, targeting CAFs or the activated PSCs has its unique advantages and has become one of the research hotspots 17 , 18 .…”

“…Therefore, the development of new molecular probes, which can target pancreatic cancer specifically and overcome the limitations of 18 F-FDG to some extent, are urgently needed and have great clinical significance. For example, integrin α v β 6 is specifically overexpressed in pancreatic cancer, and its targeting peptide has been radiolabeled with 99m Tc or 68 Ga for the SPECT or PET imaging of pancreatic cancer respectively 7 , 8 .…”

SPECT/CT imaging, biodistribution and radiation dosimetry of a177Lu-DOTA-integrin αvβ6 cystine knot peptide in a pancreatic cancer xenograft model

“…However, due to reduced stability and specificity for the receptor, in vivo results were ambiguous. In a recent study, a cyclic radiotracer specific for integrin αvβ6 ( 68 Ga-cycratide) was used in a pancreatic mouse model for PET imaging ( 32 ). The integrin αvβ6 knottin applied here has recently been used in a first-in-human clinical study and has demonstrated a high potential for PDAC targeting ( 24 ).…”