Abstract
Integrin αvβ6 is expressed at an undetectable level in normal tissues, but is remarkably upregulated during many pathological processes, especially in cancer and fibrosis. Noninvasive imaging of integrin αvβ6 expression using a radiotracer with favorable in vivo pharmacokinetics would facilitate disease diagnosis and therapy monitoring. Through disulfide-cyclized method, we synthesized in this study, a new integrin αvβ6-targeted cyclic peptide (denoted as cHK), and radiolabeled it with 99mTc. The ability of the resulting radiotracer 99mTc–HYNIC–cHK to detect integrin αvβ6 expression in pancreatic cancer xenografts and idiopathic pulmonary fibrosis was evaluated using small-animal single-photon emission computed tomography (SPECT)/computed tomography (CT). 99mTc–HYNIC–cHK showed significantly improved in vivo metabolic stability compared to the linear peptide-based radiotracer 99mTc–HYNIC–HK. 99mTc–HYNIC–cHK exhibited similar biodistribution properties to 99mTc–HYNIC–HK, but the tumor-to-muscle ratio was significantly increased (2.99 ± 0.87 vs. 1.82 ± 0.27, P < 0.05). High-contrast images of integrin αvβ6-positive tumors and bleomycin-induced fibrotic lungs were obtained by SPECT/CT imaging using 99mTc–HYNIC–cHK. Overall, our studies demonstrate that 99mTc–HYNIC–cHK is a promising SPECT radiotracer for the noninvasive imaging of integrin αvβ6 in living subjects.Graphical
Highlights
Integrin avb6, a member of the integrin family, is present at undetectable levels in adult differentiated tissues, but is overexpressed during embryogenesis, tumorigenesis, and tissue injury (Breuss et al 1993; Desgrosellier and Cheresh 2010; Peng et al 2016)
Increased expression of integrin avb6 usually correlates with more aggressive disease and poor prognosis (Bates and Mercurio 2005; Elayadi et al 2007; Lee et al 2006), and the upregulation of integrin avb6 expression in a wide variety of cancers is associated with increased tumor cells migration, invasion, and metastasis (Bates 2005; Bates and Mercurio 2005)
Integrin avb6-mediated transforming growth factor (TGF)-b activation has been implicated in multiple models of lung fibrosis, and the upregulated expression of integrin avb6 has been found in patients with Idiopathic pulmonary fibrosis (IPF) (Horan et al 2008; Xu et al 2009)
Summary
A member of the integrin family, is present at undetectable levels in adult differentiated tissues, but is overexpressed during embryogenesis, tumorigenesis, and tissue injury (Breuss et al 1993; Desgrosellier and Cheresh 2010; Peng et al 2016). To overcome the limitations of 99mTc-labeled HK peptide, in this study, we selected the first seven amino acid residues of the integrin avb6targeting HK peptide and added a lysine residue at C-terminal in order to conjugate the chelator. We cyclized it by adding a cysteine residue at N- and C-terminals, respectively, to generate a new peptide c (CRGDLATLKC, denoted as cHK). The peptide cHK was conjugated with the chelator sodium succinimidyl 6-(2(2-sulfonatobenzaldehyde) hydrazono) nicotinate (HYNIC)-NHS and radiolabeled with 99mTc. The resulting radiotracer 99mTc–HYNIC–cHK was evaluated in vivo as a SPECT radiotracer for imaging of integrin avb expression in both cancer and IPF mouse models
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