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Meier S.,Albert Ludwigs University of Freiburg | Putz G.,University Hospital Freiburg | Massing U.,Tumor Biology Center Freiburg | Massing U.,Andreas Hettich GmbH and Co KG | And 10 more authors.
Biomaterials | Year: 2015

To detect unstable atherosclerotic plaques early and noninvasively would be of great clinical interest. Activated platelets are an interesting molecular target for detecting early lesions or unstable plaques. We therefore developed an MRI contrast agent consisting of magnetoliposomes (ML) linked to an antibody (anti-LIBS) specifically targeting the ligand-induced binding site of the activated GPIIb/IIIa receptor of platelets. ML were prepared by dual centrifugation (DC). ML pegylation up to a total PEG content of 7.5mol% positively influenced the stability and amount of entrapped SPIOs, and also reduced SPIO-membrane interactions, while higher PEG contents destabilized PEG-ML. Stable anti-LIBS-ML with high amounts of entrapped SPIOs (~86%, ~0.22mol Fe/mol liposomal lipid) and high MRI sensitivity (relaxivity r2=422s-1mM-1 and r2*=452s-1mM-1) were obtained by coupling anti-LIBS to ML in a two-step post-insertion technique. We confirmed specific binding to the GPIIb/IIIa receptor's activated conformation on activated human platelets and cell lines expressing activated GPIIb/IIIa receptor exvivo. The immuno-ML obtained in this study constitute an important step towards developing a potentially human-compatible MRI contrast agent for the timely detection of plaque rupture by targeting activated platelets. © 2015 Elsevier Ltd. Source

Ardipradja K.,Vascular Biotechnology Laboratory | Ardipradja K.,Atherothrombosis and Vascular Biology Laboratory | Ardipradja K.,University of Melbourne | Yeoh S.D.,Austin Hospital | And 15 more authors.
Nuclear Medicine and Biology | Year: 2014

Introduction: Activated platelets are key players in thrombosis and inflammation. We previously generated single-chain antibodies (scFv) against ligand-induced binding sites (LIBS) on the highly abundant platelet glycoprotein integrin receptor IIb/IIIa. The aim of this study was the construction and characterisation of a novel 18F PET radiotracer based on this antibody. Methods: ScFvanti-LIBS and control antibody mut-scFv were reacted with N-succinimidyl-4-[18F]fluorobenzoate (S[18F]FB). Radiolabeled scFv was incubated with in vitro formed platelet clots and injected into mice with FeCl3 induced thrombus in the left carotid artery. Clots were imaged in the PET scanner and amount of radioactivity measured using an ionization chamber and image analysis. Assessment of vessel injury as well as the biodistribution of the radiolabeled scFv was studied. Results: After incubation with increasing concentrations of 18F-scFvanti-LIBS clots had retained significantly higher amounts of radioactivity compared to clots incubated with radiolabeled 18F-mut-scFv (13.3±3.8 vs. 3.6±1 KBq, p<0.05, n=9, decay corrected). In the in vivo experiments we found an high uptake of the tracer in the injured vessel compared with the non-injured vessel, with 12.6±4.7% injected dose per gram (ID/g) uptake in the injured vessel and 3.7±0.9% ID/g in the non-injured vessel 5minutes after injection (p<0.05, n=6). Conclusions: Our results show that the novel antibody radiotracer 18F-scFvanti-LIBS is useful for the sensitive detection of activated platelets and thrombosis. Advances in knowledge and implications for patient care: We describe the first 18F variant of a scFvanti-LIBS against activated platelets. This diagnostic agent could provide a powerful tool for the assessment of acute thrombosis and inflammation in patients in the future. © 2014 Elsevier Inc. Source

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