RT Journal Article
SR Electronic
T1 Comparison of the RGD Motif–Containing α<sub>v</sub>β<sub>6</sub> Integrin–Binding Peptides SFLAP3 and SFITGv6 for Diagnostic Application in HNSCC
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1679
OP 1685
DO 10.2967/jnumed.118.210013
VO 59
IS 11
A1 Roesch, Saskia
A1 Lindner, Thomas
A1 Sauter, Max
A1 Loktev, Anastasia
A1 Flechsig, Paul
A1 Müller, Martin
A1 Mier, Walter
A1 Warta, Rolf
A1 Dyckhoff, Gerhard
A1 Herold-Mende, Christel
A1 Haberkorn, Uwe
A1 Altmann, Annette
YR 2018
UL http://jnm.snmjournals.org/content/59/11/1679.abstract
AB αvβ6 integrin is overexpressed by several carcinomas and thus considered a target for diagnostic imaging and anticancer therapies. Recently, we presented the αvβ6 integrin-binding peptide SFITGv6 as a novel potential tracer for imaging and targeted therapy of αvβ6 integrin–positive carcinomas. Here, we analyzed the affinity and specificity of 5 native αvβ6 integrin–specific binders in comparison to SFITGv6. Methods: Sunflower trypsin inhibitor 1 (SFTI1)–based peptides containing arginine-glycine-aspartic acid (RGD) motif-spanning octamers of fibronectin (SFFN1), tenascin C (SFTNC), vitronectin (SFVTN), and latency-associated peptides (LAP) 1 (SFLAP1) and 3 (SFLAP3) were synthesized, and their binding potential to αvβ6 integrin–expressing head and neck squamous cell carcinoma (HNSCC) cell lines was evaluated. Subsequently, stability, affinity, and specificity were assessed in vitro using radio–high-pressure liquid chromatography, surface plasmon resonance assay, and binding experiments including competition, kinetics, internalization, and efflux. αvβ6 integrin binding specificity was further evaluated by peptide histochemistry. Finally, in vivo binding properties were assessed using small-animal PET imaging and biodistribution experiments in HNSCC-bearing mice, and 68Ga-DOTA-SFLAP3 was applied for diagnostic PET/CT of an HNSCC patient. Results: When the newly designed peptides were compared, significant binding (&gt;20%) to several HNSCC cell lines (HNO97, HNO399, and HNO223) and a fast internalization of up to 60% and 70% were observed for SFLAP3 (GRGDLGRL) and SFITGv6 (FRGDLMQL). In contrast, the other peptides displayed binding that was moderate (SFLAP1, 4.1%–12.1%) to marginal (SFFN1, SFTNC, and SFVTN, &lt;1%) and were therefore excluded from further analysis. Notably, SFLAP3 exhibited improved affinity for αvβ6 integrin (mean half-maximal inhibitory concentration, 3.5 nM; dissociation constant, 7.4). Moreover, small-animal PET imaging and biodistribution studies of HNSCC xenograft mice revealed an increased tumor-specific accumulation 30–60 min after injection of 68Ga-labeled or 177Lu-labeled DOTA-SFLAP3. Peptide staining further demonstrated binding specificity for SFLAP3 to HNSCC tumor cells. Finally, PET/CT scanning of an HNSCC patient showed specific SFLAP3 accumulation in the primary tumor lesion (SUVmax, 5.1) and in corresponding lymph node metastases (SUVmax, 4.1). Conclusion: SFLAP3 represents a promising tracer for prognostic assessment, diagnostic imaging, and possibly targeted therapy of αvβ6 integrin–expressing tumors.