68Ga-duramycin PET/CT imaging of anthracycline-induced cell death in patients with lymphoma

Introduction: Anthracycline-based chemotherapeutic drugs induce cell death in both target malignant and non-target normal cells. The major concern resulting from non-target cell killing is anthracycline-induced cardiotoxicity (AIC). The molecular imaging of cell death in tumor and healthy tissues may be helpful in the early assessment of chemotherapy response evaluation and AIC. During cell death, the membrane phosphatidylethanolamine (PE) molecule gets externalized to the extracellular layer of the plasma membrane. Duramycin binds with the externalized PE molecules with high specificity. In this prospective study, the diagnostic efficacy of ⁶⁸Ga-duramycin PET/CT for cell death imaging has been explored in patients with lymphoma.

Methods: The in-house synthesized ⁶⁸Ga-duramycin was first assessed as a molecular cell death marker in animal models with doxorubicin-induced toxicity. The rat models were developed using a multiple-dose regimen of 2.5 mg/kg/week doxorubicin dose for six weeks. The different sections of the myocardium were examined for change in ⁶⁸Ga-duramycin uptake (before and after doxorubicin administration) with histopathological correlation. The diagnostic potential of ⁶⁸Ga-duramycin PET/CT for early detection of AIC was assessed in lymphoma patients (n=10) undergoing chemotherapy and the outcomes were compared with other diagnostic modalities such as MUGA (Multi-gated Acquisition), STE (Speckle Tracking Echocardiography), cardiac biochemical markers, and the ¹⁸F-FDG PET/CT (with modified diet). The malignant lesions were also imaged before and in between chemotherapy cycles to evaluate the diagnostic utility of ⁶⁸Ga-duramycin PET/CT in response evaluation. Additionally, the interim ⁶⁸Ga-duramycin PET/CT studies were performed at four different time points (1, 3, 7, and 21 days) after chemotherapeutic dose administration to establish the optimal imaging time for cell death.

Results: Pre-clinically, the uptake pattern of ⁶⁸Ga-duramycin in the myocardium of treated rats showed the promising application of developed radiotracer for AIC. However, in lymphoma patients, the abnormal tracer uptake in highly perfused myocardium was not discernible due to persistent high blood pool retention up to 4 hours post-injection. Whereas, ¹⁸F-FDG PET/CT showed an increase in myocardial uptake in post-therapy images as compared to the baseline images with a change in SUV_max of 2.8. Though, the results from STE, MUGA, Troponin T, and proBNP did not show any significant sign of cardiotoxicity. The possibility may be attributed to a lower incidence rate of cardiotoxicity (3-4%) and small sample size. In terms of response evaluation, the diagnostic efficacy of ⁶⁸Ga-duramycin was evident from an increase in radiotracer uptake (>50%) in the malignant lesions on PET/CT images acquired during interim assessment (after two chemotherapy cycles). This increase in radiotracer uptake was observed in the PET/CT images acquired at 24 h after chemotherapeutic agent administration. Whereas, negligible uptake was noted in malignant lesions when imaging was done on the 3^rd, 7^th, and 21^st days after chemotherapy administration. The decreased uptake with delay in imaging could be attributed to the gradual replacement of apoptotic cells with fibrotic cells as evident in the histopathological findings of the animal model study. The results, therefore, provided pertinent information for the optimum time to image apoptosis after its stimulation.

Conclusions: ⁶⁸Ga-duramycin is shown to be a potential cell death bio-imaging marker, but further research especially to decrease blood pool retention is warranted.

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