Whole-Body Imaging of High-Dose Ionizing Irradiation-Induced Tissue Injuries Using 99mTc-Duramycin

Exposure to high-dose ionizing irradiation, such as in radiation therapy or incidental radiation exposure, can cause injuries in susceptible tissues. There is extensive and growing literature on the temporal and spatial characterization of ionizing irradiation–induced tissue injuries. However, current knowledge is based largely on symptomatic interpretations, functional changes, pathologic and histologic analysis, and in vitro cell-based studies. A noninvasive imaging technique would provide a new approach for dynamic, whole-body assessment of radiation-induced pathophysiologic changes. The availability of a noninvasive imaging technique would contribute to our general knowledge on radiation-induced tissue injuries on a system level. Additionally, this technique might help in the early detection of injury, as well as in monitoring progression of tissue damage and the efficacy of interventional treatments. Apoptosis is abundant in susceptible tissues after high-dose ionizing irradiation (1–7). On a cellular level, the primary cause of cellular injury by ionizing irradiation includes DNA damage, in which severely damaged cells commit to apoptosis (6,7). Ionizing irradiation also results in the generation of reactive free-radical species, which attack vital cellular components and can cause cell death (6,7). Given that the peak of the early wave of apoptosis arrives within hours after irradiation, apoptotic cell death is one of the earliest manifestations of tissue injury. Detection of radiation-induced apoptosis, therefore, has significant potential in the characterization of tissue injuries in the acute phase. The externalization of certain phospholipids, such as phosphatidylserine (PS) and phosphatidylethanolamine (PE), is an established molecular marker for apoptosis (8–11). In a typical viable mammalian cell, PS and PE are predominantly distributed in the inner leaflet of the plasma membrane in an energy-dependent manner (9). During apoptosis, the redistribution of these phospholipids across the bilayer is facilitated. As a result, PS and PE become exposed onto the cell surface (8–11). Being major phospholipid components of the plasma membrane, exposed PS and PE provide well-defined molecular targets for detection using phospholipid-targeted imaging agents (12–14). Noninvasive imaging in a whole-body fashion demands that an imaging agent bind avidly to target tissues, with fast systemic clearance and a low general background level. In terms of apoptosis imaging, considerable effort has been invested in developing agents with optimal in vivo binding, biodistribution, and clearance profiles. To this end, 99mTc-labeled duramycin has been shown to have favorable imaging properties, including high-affinity and high-specificity binding to PE, fast blood clearance, and a low general background level (14). These properties of 99mTc-duramycin have been studied in depth with quantitative analysis and shown as advantageous over larger, protein-based imaging agents (14,15). The combination of these characteristics makes it appropriate to test 99mTc-duramycin in a whole-body imaging survey. The goal of the current study was to investigate the feasibility of using 99mTc-duramycin to capture the global dynamics of early cell death induced by high-dose ionizing radiation.