Targeted in vivo imaging of integrin alphavbeta6 with an improved radiotracer and its relevance in a pancreatic tumor model.
The cell surface receptor alpha(v)beta(6) is epithelial specific, and its expression is tightly regulated; it is low or undetectable in adult tissues but has been shown to be increased in many different cancers, including pancreatic, cervical, lung, and colon cancers. Studies have described alpha(v)beta(6) as a prognostic biomarker linked to poor survival. We have recently shown the feasibility of imaging alpha(v)beta(6) in vivo by positron emission tomography (PET) using the peptide [(18)F]FBA-A20FMDV2. Here, we describe improved alpha(v)beta(6) imaging agents and test their efficacy in a mouse model with endogenous alpha(v)beta(6) expression. The modified compounds maintained high affinity for alpha(v)beta(6) and >1,000-fold selectivity over related integrins (by ELISA) and showed significantly improved alpha(v)beta(6)-dependent binding in cell-based assays (>60% binding versus <10% for [(18)F]FBA-A20FMDV2). In vivo studies using either a melanoma cell line (transduced alpha(v)beta(6) expression) or the BxPC-3 human pancreatic carcinoma cell line (endogenous alpha(v)beta(6) expression) revealed that the modified compounds showed significantly improved tumor retention. This, along with good clearance of nonspecifically bound activity, particularly for the new radiotracer [(18)F]FBA-PEG(28)-A20FMDV2, resulted in improved PET imaging. Tumor/pancreas and tumor/blood biodistribution ratios of >23:1 and >47:1, respectively, were achieved at 4 hours. Significantly, [(18)F]FBA-PEG(28)-A20FMDV2 was superior to 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) in imaging the BxPC-3 tumors. Pancreatic ductal adenocarcinoma is highly metastatic and current preoperative evaluation of resectability using noninvasive imaging has limited success, with most patients having metastases at time of surgery. The fact that these tumors express alpha(v)beta(6) suggests that this probe has significant potential for the in vivo detection of this malignancy, thus having important implications for patient care and therapy.
Hausner
Sven H
SH
Department of Biomedical Engineering, University of California Davis, Davis, California 95616, USA.
Abbey
Craig K
CK
Bold
Richard J
RJ
Gagnon
M Karen
MK
Marik
Jan
J
Marshall
John F
JF
Stanecki
Cathy E
CE
Sutcliffe
Julie L
JL
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis* / Q000378:metabolism; D001565:Benzoates / Q000737:chemistry; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005240:Feasibility Studies; D005434:Flow Cytometry; D005462:Fluorine Radioisotopes; D029544:Foot-and-Mouth Disease Virus / Q000737:chemistry; D006801:Humans; D016023:Integrins / Q000032:analysis* / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism
D000951:Antigens, Neoplasm; D001565:Benzoates; D005462:Fluorine Radioisotopes; D016023:Integrins; D019275:Radiopharmaceuticals; D014764:Viral Proteins; C073878:integrin alphavbeta6; C022893:4-fluorobenzoic acid