Nuclear medicine and biology · 2026
Development of angiostatin based radiopharmaceutical as a sensitive tool for detection of ATP synthase during acute vascular damage.
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Das Ankon, Florence Tikum, Rodrigues Carolina Rego, Ambros Barbara, Singh Jaswant, Fonge Humphrey, Aulakh Gurpreet Kaur
Аннотация
BACKGROUND: Angiostatin (ANG) is an endogenously cleaved protein of the plasminogen-plasmin conversion pathway which is activated during tumor angiogenesis and oxidative stress. One of the hallmarks of sub-clinical oxidative stress are persistent aggregation of platelets and neutrophils (and other immune cells) leading to endothelial activation. The goal of the study was to develop and test the specificity of a highly glycosylated form of ANG, derived from neutrophil elastase, as an in vivo radiopharmaceutical marker of oxidative stress and to monitor the progression of vascular and platelet activation.
METHODS: Sequential PET imaging of radiolabeled ANG ([89Zr]Zr-ANG) in a combined ozone and LPS induced murine model of oxidative stress (n = 8 per group) was followed by whole-body, fractionated blood, aortic ring and platelet biodistribution studies. In vitro, platelets were exposed to H2O2 and/or LPS to induce oxidative stress.
RESULTS: Compared with sham mice, the uptake of [89Zr]Zr-ANG in the exposed lungs was 4.8 to 8.5-fold (male mice) and 4.2 to 11.6-fold (female mice) higher over 72 h after ozone and LPS exposure (p < 0.0001). Ex vivo biodistribution and microPET/CT imaging revealed accumulation of [89Zr]Zr-ANG in platelets and multiple organs including lungs highlighting vascular inflammation and platelet activation in response to ozone and LPS. Uptake of ANG in aorta and platelets was confirmed by injecting ozone and LPS exposed mice with fluorescent angiostatin. Lastly, platelets subjected to oxidative stress preferentially bind ANG compared to untreated platelets and split them into ATP-rich ultra-small (0.7-10 nm) vesicles and large (1-10 μm) micro-particles. This binding is dependent upon ATP inhibitory factor, IF1's displacement to bind with ATP synthase subunit β (ATPβ).
CONCLUSIONS: [89Zr]Zr-ANG is a stable, ATP synthase directed endothelial cell and platelet-specific imaging tool for detection of acute murine oxidative stress-induced lung as well as systemic inflammation. Thus, the current study provides evidence towards potential applications of [89Zr]Zr-ANG in understanding the fate of platelets in chronic disease models.
METHODS: Sequential PET imaging of radiolabeled ANG ([89Zr]Zr-ANG) in a combined ozone and LPS induced murine model of oxidative stress (n = 8 per group) was followed by whole-body, fractionated blood, aortic ring and platelet biodistribution studies. In vitro, platelets were exposed to H2O2 and/or LPS to induce oxidative stress.
RESULTS: Compared with sham mice, the uptake of [89Zr]Zr-ANG in the exposed lungs was 4.8 to 8.5-fold (male mice) and 4.2 to 11.6-fold (female mice) higher over 72 h after ozone and LPS exposure (p < 0.0001). Ex vivo biodistribution and microPET/CT imaging revealed accumulation of [89Zr]Zr-ANG in platelets and multiple organs including lungs highlighting vascular inflammation and platelet activation in response to ozone and LPS. Uptake of ANG in aorta and platelets was confirmed by injecting ozone and LPS exposed mice with fluorescent angiostatin. Lastly, platelets subjected to oxidative stress preferentially bind ANG compared to untreated platelets and split them into ATP-rich ultra-small (0.7-10 nm) vesicles and large (1-10 μm) micro-particles. This binding is dependent upon ATP inhibitory factor, IF1's displacement to bind with ATP synthase subunit β (ATPβ).
CONCLUSIONS: [89Zr]Zr-ANG is a stable, ATP synthase directed endothelial cell and platelet-specific imaging tool for detection of acute murine oxidative stress-induced lung as well as systemic inflammation. Thus, the current study provides evidence towards potential applications of [89Zr]Zr-ANG in understanding the fate of platelets in chronic disease models.