Integrin α_vβ₆–Targeted SPECT Imaging for Pancreatic Cancer Detection

Abstract

Integrin α v β 6 , a member of the integrin family, is specifically expressed in many malignancies but not in normal organs. Overexpression of integrin α v β 6 is usually correlated with malignant potential and poor prognosis. In this study, we describe the synthesis and evaluation of a 99m Tc-labeled integrin α v β 6 -targeting peptide as a SPECT radiotracer for the in vivo imaging of integrin α v β 6 expression. Methods: An integrin α v β 6 -targeting peptide (denoted as the HK peptide) was conjugated with 6-hydrazinonicotinyl (HYNIC) and radiolabeled with 99m Tc using tricine and TPPTS (trisodium triphenylphosphine-3,3′,3″-trisulfonate) as coligands. The in vitro and in vivo characteristics of 99m Tc-HYNIC(tricine)(TPPTS)-HK ( 99m Tc-HHK) were investigated in BxPC-3 (integrin α v β 6 -positive) and HEK293 (integrin α v β 6 -negative) models. The ability of 99m Tc-HHK to detect liver metastasis of pancreatic cancer was evaluated using small-animal SPECT/CT. Results: 99m Tc-HHK showed high integrin α v β 6 -binding specificity both in vitro and in vivo. 99m Tc-HHK was cleared rapidly from the blood and normal organs except for the kidneys. The highest uptake (0.88 ± 0.12 percentage injected dose per gram) of 99m Tc-HHK in BxPC-3 tumors was observed at 0.5 h after injection. High-contrast images of integrin α v β 6 -positive tumors were obtained using 99m Tc-HHK. The minimum nonspecific activity accumulation in normal liver tissues rendered high-quality SPECT/CT images of metastatic lesions. Conclusion: 99m Tc-HHK is a promising SPECT radiotracer for the noninvasive imaging of integrin α v β 6 expression in vivo. SPECT/ CT with 99m Tc-HHK could provide an effective approach for the noninvasive detection of primary and metastatic lesions of integrin α v β 6 -positive tumors.

In Vivo PET Imaging of the Cancer Integrin αvβ6 Using 68Ga-Labeled Cyclic RGD Nonapeptides

“…Such compounds, for example, the linear peptides A20FMDV2 (sequence: NAVPNLRGDLQVLAQKVART, derived from foot-and-mouth disease virus, FMDV) (21), H2009.1 (sequence: RGDLATLRQL) (22), and cyclic peptide S 0 2 (23) were equipped with radiolabels and applied for in vivo imaging of avb6 expression (24) by SPECT (25)(26)(27) and PET (21,(28)(29)(30)(31)(32). More recently, efforts directed at further downsizing and metabolic stabilization of FMDV peptidederived avb6 integrin ligands led to discovery of the cyclic nonapeptide cyclo(FRGDLAFp(NMe)K) (33), which exhibits high avb6 binding affinity (0.26 nM), remarkable selectivity against other integrins (a v b 3 , 632 nM; a5b1, 73 nM; avb5 and aIIbb3, .1 mM), and full stability in human plasma up to 3 h. In addition, its activity was not compromised by functionalization on the lysine side chain, rendering it an optimal starting point for elaboration of molecular probes.…”

Molecular Imaging of Post-Src Inhibition Tumor Signatures for Guiding Dasatinib Combination Therapy

“…18 F-FDG PET scans and image analysis were performed using a microPET R4 rodent model scanner (Siemens Medical Solutions) as previously described (12,13). Each A549-fLuc tumor-bearing mouse was intravenously injected with 3.7 MBq of 18 F-FDG, and 5-min static PET scans were acquired at 1 h after injection.…”

Development of the Fibronectin–Mimetic Peptide KSSPHSRN(SG)₅RGDSP as a Novel Radioprobe for Molecular Imaging of the Cancer Biomarker α₅β₁ Integrin

“…2C) demonstrated that 18 F-PR_b was relatively stable in mouse blood plasma, but rapidly metabolized in vivo within 30 min post-injection. The rapid blood clearance and relatively low metabolic stability of 18 F-PR_b, which could be attributed to the linear structure of the peptide as observed for other linear peptide-based radiotracers, 40) possibly compromised the efficient accumulation of the probe in the tumor. That is maybe why the differences in tumor uptake between 18 F-PR_b and its control probe were not as large as the differences in cell-and tissue-bound activities between the two probes obtained from in vitro and ex vivo studies.…”