Abstract
Expression of epithelial-specific integrin ανβ6 is up-regulated in various aggressive cancers and serves as a prognostic marker. Integrin-targeted PET imaging probes have been successfully developed and tested in the clinic. Radiotracers based on the peptide A20FMDV2 derived from foot-and-mouth disease virus represent specific and selective PET ligands for imaging ανβ6-positive cancers. The present study aims to describe the radiolabeling, in vitro and in vivo evaluation of a bi-terminally PEGylated A20FMDV2 conjugated with DOTA or PCTA for 64Cu radiolabeling. Stability studies showed radiolabeled complexes remained stable up to 24 h in PBS and human serum. In vitro cell assays in CaSki cervical cancer cells and BxPC-3 pancreatic cancer cells confirmed that the peptides displayed high affinity for αvβ6 with Kd values of ~50 nM. Biodistribution studies revealed that [64Cu] Cu-PCTA-(PEG28)2-A20FMDV2 exhibited higher tumor uptake (1.63 ± 0.53 %ID/g in CaSki and 3.86 ± 0.58 %ID/g in BxPC-3 at 1 h) when compared to [64Cu]Cu-DOTA-(PEG28)2-A20FMDV2 (0.95 ± 0.29 %ID/g in CaSki and 2.12 ± 0.83 %ID/g in BxPC-3 at 1 h) . However, higher tumor uptake was accompanied by increased radioactive uptake in normal organs. Therefore, both peptides are appropriate for imaging ανβ6-positive lesions although further optimization is needed to improve tumor-to-normal-tissue ratios.
Highlights
Integrins are a class of receptors that play essential roles in mediating cell adhesion, making transmembrane connections to the cytoskeleton, and modulating many intracellular signaling pathways [1, 2]
Increased expression levels of ανβ6 have been shown in various cancers including pancreatic, cervical, non–small cell lung cancer and oral squamous cell carcinoma [10,11,12,13]
Kimura et al demonstrated that highly stable cystine knot peptides have potent and specific integrin ανβ6 binding for cancer detection [15]
Summary
Integrins are a class of receptors that play essential roles in mediating cell adhesion, making transmembrane connections to the cytoskeleton, and modulating many intracellular signaling pathways [1, 2]. Because of their diverse functions, integrins have been studied extensively for decades, leading to the design and development of integrin antagonists in the treatment of multiple types of cancers. Hausner et al used a 20-mer peptide (NAVPNLRGDLQVLAQKVART; A20FMDV2) that showed preferential binding to ανβ6 [14] Another 20mer peptide (RGDLATLRQLAQEDGVVGVR; H2009) isolated from a phage-display peptide library by panning on a lung adenocarcinoma cell line binds to the restrictively expressed integrin ανβ6 [13]. The shared sequence of “RGDLXXL” (X represents unspecified amino acid) in the central binding region is key to high binding affinity and good selectivity www.oncotarget.com
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
