Whole-body Imaging of Cell Death Provides a Systemic, Minimally Invasive, Dynamic, and Near-real Time Indicator for Chemotherapeutic Drug Toxicity

Abstract

Purpose: Response to toxicity in chemotherapies varies considerably from tissue to tissue and from patient to patient. An ability to monitor the tissue damage done by chemotherapy may have a profound impact on treatment and prognosis allowing for a proactive management in understanding and mitigating such events. For the first time, we investigated the feasibility of using whole-body imaging to map chemotherapeutic drug-induced toxicity on an individual basis.Experimental Design: In a preclinical proof-of-concept, rats were treated with a single clinical dose of cyclophosphamide, methotrexate, or cisplatin. In vivo whole-body imaging data were acquired using 99m Tc-duramycin, which identifies dead and dying cells as an unambiguous marker for tissue injury in susceptible organs. Imaging results were cross-validated using quantitative ex vivo measurements and histopathology and compared with standard blood and serum panels for toxicology.Results: The in vivo whole-body imaging data detected widespread changes, where spatially heterogeneous toxic effects were identified across different tissues, within substructures of organs, as well as among different individuals. The signal changes were consistent with established toxicity profiles of these chemotherapeutic drugs. Apart from generating a map of susceptible tissues, this in vivo imaging approach was more sensitive compared with conventional blood and serum markers used in toxicology. Also, repeated imaging during the acute period after drug treatment captured different kinetics of tissue injury among susceptible organs in males and females.Conclusions: This novel and highly translational imaging approach shows promise in optimizing therapeutic decisions by detecting and managing drug toxicity on a personalized basis.Toxicity to normal tissues is a significant limitation in chemotherapies. This work demonstrated an in vivo imaging-based approach for characterizing toxicity-induced tissue injury in a systemic, dynamic, and near-real time fashion. This novel approach shows promise in optimizing therapeutic decisions by monitoring drug toxicity on a personalized basis. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

18F-C2Am: a targeted imaging agent for detecting tumor cell death in vivo using positron emission tomography

“…99m Tc-Annexin V, which binds PS, has translated to the clinic; however, it showed poor pharmacokinetics and non-specific binding [ 33 ]. Exposure of PE by dying cells has been exploited in the development of duramycin, a 19 amino acid tetracyclic peptide (~ 2 kDa), as a cell death imaging agent [ 37 , 38 ]. However, despite its smaller size the clearance profile and contrast generated by 99m Tc-duramycin was similar to that observed here with 18 F-C2Am.…”

Assessment of chemotherapy-induced organ damage with 68Ga-labeled duramycin

“…Recently, Johnson et al [9] provided a proof of concept that 99m Tc-labeled duramycin is a suitable tracer to detect chemotherapy induced cell death by SPECT. In this study, whole body toxic profiles of cyclophosphamide, methotrexate and cisplatin were characterized on a single time point in rats.…”

“…Here we face the same situation as for doxorubicin, where an enhanced unspecific uptake makes the detection of small changes difficult. As statistical significances are depending on many factors such as number of animals per group, number of tests (multiple testing) and heterogeneity within the group, in some unclear cases it might be favorable to use each animal as its own control to detect alterations [9].…”

“…In previous studies, derivatives of duramycin have been used successfully in the detection of therapy-induced tumor cell death, in the assessment of pulmonary injury and cardiac or cerebral ischemia-reperfusion in different animal models using single-photon emission computed tomography (SPECT) [8]. Recently, Johnson et al provided a first proof-of-concept for the suitability of 99m Tc-labeled duramycin to systemically characterize chemotherapy induced cell death in rats [9]. Compared to SPECT, PET provides a higher sensitivity [10].…”

Imaging Cell Death: Focus on Early Evaluation of Tumor Response to Therapy

“…The externalization of PE to cell surface during apoptosis makes PE an alternative target for apoptosis imaging. ,− Moreover, the greater abundance of PE in plasma membrane relative to PS offers more available binding targets, which potentially improves the imaging performance . Duramycin, a low molecular weight peptide capable of specifically binding to PE ( K d ≈ 5 nM), has been the most promising candidate for PE imaging. , 99m Tc-labeled duramycin ( 99m Tc-duramycin) was initially developed as a PE-specific molecular probe, and was demonstrated to be capable of noninvasively detecting apoptosis in different animal models with cerebral and myocardial ischemic/reperfusion injury, − irradiation/chemotherapy-induced tissue injury, − hyperoxia-induced lung injury, tumor necrosis factor-induced systemic inflammatory response syndrome, atherosclerosis, , and aortic aneurysm …”