68Ga-Galmydar PET Tracer for Noninvasive Early Detection of Taxane Induced Cardiotoxicity

Introduction: ⁶⁸Ga-Galmydar PET Tracer for Noninvasive Early Detection of Taxane Induced Cardiotoxicity

Objectives: Cancer patients undergoing chemotherapeutic treatment are susceptible to acute and chronic cardiac pathologies, including arrhythmias, ventricular dysfunction, and heart failure. To stratify patients at high risk for chemotherapy-related heart failure (CHF), diagnostic techniques have been sought. While echocardiography is used for monitoring LVEF, LV volumes, and in some cases myocardial strain due to its wide-availability and cost-efficiency, it may not identify the early stages of chemocardiotoxicity. PET tracers have the potential to provide noninvasive assessment of early and potentially reversible metabolic changes of the myocardium. ⁶⁸Ga-Galmydar is a PET radiotracer that localizes to the mitochondria of heart cells, and is a versatile molecular imaging probe of mitochondrial function. Herein, we report a preliminary investigation of the potential of ⁶⁸Ga-Galmydar to monitor chemotherapy-induced impairment of mitochondrial function in rat cardiomyoblasts using live cell fluorescence imaging and the induction of caspase, a marker of mitochondrial dysfuncton and subsequent cell death. Materials and Methods: Galmydar was obtained through a ligand exchange reaction. ⁶⁸Ga-Galmydar was purified on Phenomenex Strata-X-C cartridge and analysed using radio-HPLC. MicroPET/CT imaging was performed 12 days post treatment with either docetaxel (DTX), (3 x 5.55 mg/kg / 48h or saline as a control in preclinical models of intratibial PyMT-BO1 xenografts in C57BL/6 mice. Images were co-registered for anatomical reference using CT. The effects of DTX on xenografts and the heart were quantified. In cellulo (H9c2, BO1, and 4T1), dose and time dependent paclitaxel (PTX) treatments were also studied using live cell optical imaging. To demonstrate cell death, caspase-3 activation was measured using flow cytometry.

Results: ⁶⁸Ga-Galmydar, micro-PET dynamic scan (60 min post tail-vein administration) demonstrated 1.17-fold lower uptake in hearts of DTX-treated C57 Bl6 mice (implanted with intratibial PyMT-BO1 xenografts) compared with their saline control treated counterparts. Employing the moderate fluorescent traits of Galmydar, live cell optical imaging showed a gradual decrease in uptake and retention of Galmydar within mitochondria of H9c2, BO1, and 4T1 cells following PTX-treatment, while also demonstrating a dose-dependent pharmacological response and time-dependent uptake profiles. Furthermore, the decreased uptake in H9c2 cells correlated with caspase-3 expression, a marker of DTX-induced cell death. Combined data suggest that ⁶⁸Ga-Galmydar has the potential as a sensitive PET imaging biomarker of drug-induced cardiotoxicity through its direct assessment of myocyte mitochondrial function. ⁶⁸Ga-Galmydar could also enable interrogation of therapeutic efficacy of DTX.

Conclusions: This study shows that ⁶⁸Ga-Galmydar has the potential to provide noninvasive and early assessment of chemotherapy-related myocardial metabolic changes, and lays the foundation for further assessment of ⁶⁸Ga-Galmydar in large animal models of chemocardiotoxicity and translation in to human subjects. References: Sivapackiam, J., et al., PlosOne., 2019,14, e0215579. Funding: NIH R01 HL142297, R01 HL111163