Assessing Doxorubicin-Induced Cardiomyopathy by 99mTc-3PRGD2 Scintigraphy Targeting Integrin αvβ3 in a Rat Model

The present study evaluated interstitial alterations in doxorubicin-induced cardiomyopathy using a radiolabeled RGD peptide ^99mTc-3PRGD2 specific for integrin αvβ3 that targets myofibroblasts.Cardiomyopathy was induced in 20 Sprague-Dawley rats by intraperitoneal doxorubicin injections (2.5 mg/kg/week) for up to six weeks. ^99mTc-3PRGD2 scintigraphy was performed in control rats (n = 6) at baseline and three, six, and nine weeks after first doxorubicin administration (n = 6, 6, and 5 for each time point). For another three rats of 6-week modeling, cold c(RGDyK) was co-injected with ^99mTc-3PRGD2 to evaluate specific radiotracer binding. Semi-quantitative parameters were acquired to compare radiotracer uptake among all groups. The biodistribution of ^99mTc-3PRGD2 was evaluated by a γ-counter after scintigraphy. Haematoxylin and eosin, and Masson's staining were used to evaluate myocardial injury and fibrosis, while western blotting and immunofluorescence co-localization were used to analyze integrin αvβ3 expression in the myocardium.The ^99mTc-3PRGD2 half-life in the cardiac region (Heartt _1/2) of the 9-week model and heart radioactivity percentage (%Heart_20 min, %Heart_40 min and %Heart_60 min) of the 6 and 9-week models were significantly increased compared to the control. Heart-to-background ratio (HBR_20 min, HBR_40 min and HBR_60 min) increase began in the third week, continued until the sixth week, and was reversed in the ninth week, which paralleled the changing trend of cardiac integrin αvβ3 expression. The myocardial biodistribution of ^99mTc-3PRGD2 was significantly correlated with integrin β3 expression.The ^99mTc-3PRGD2 scintigraphy allows for non-invasive visualization of interstitial alterations during doxorubicin-induced cardiomyopathy.