good candidate for regenerative therapy [16]. Radiolabeled EVs derived from stem
cells will visualize clearly the localization and duration of stay at the target site and
the consequent reparative effect even at, for example, neurodegenerative lesion of
the brain.
For this future application and new therapeutic development, understanding the
physiology of administered EVs is crucial. EVs are originated from cells and thus
they have much less concerns of toxicity compared with other organic and inorganic exogenous nanomaterials. Using any visualization or imaging methods, EVs’
biological action, metabolism and excretion is to be understood. These in vivo
physiological studies will be initially in small animals, and human-specific physiology is beyond reach again as there are definitive difference between species. To
facilitate achieving this final goal of clinical translation, clinically applicable
imaging methods are desired. Radionuclide imaging is one of the most widely used
functional imaging techniques in the clinical setting, and it enables to investigate
kinetics to elucidate in vivo fate of EVs. We will review the advantages and
expectations of imaging of radiolabeled EVs in vivo and introduce currently
reported radiolabeled EVs.
7.2 Facilitating Clinical Use of EVs: Radionuclide
Imaging of EVs
To realize promises of clinical application of EVs, a better understanding of
biodistribution and systemic feature of administered EVs is needed [25]. Recently,
several methods have been introduced to reveal the physiology of EVs. One of the
most commonly used methods is direct labeling using lipophilic fluorescence dye
intercalated in lipid bilayers [26–29]. The overview of imaging methods including
optical imaging is described in another chapter. However, fluorescence imaging has
substantial limitation in light penetration depth. Thus, it is hard to visualize
biodistribution in deep organs as well as to accurately quantify the distribution of
specific organs. Most fluorescence imaging methods are not free from toxicity
issues. In terms of translation into clinical trials, another noninvasive imaging
technique would be needed to overcome these shortcomings.
A feasible method for human imaging for EVs is to image the radionuclidelabeled EVs and MR imaging. Among them, by virtue of its superb sensitivity,
radiolabeling requires very low dose of EVs for image acquisition, which could be a
definitive advantage in facilitating clinical imaging. The usage of trace amount of
EVs for imaging is important also regarding safety issues. Even though cellular
originated EVs are relatively free from toxicity mediated by innate immune
response which produces reactive oxygen species [30], biocompatible nanomaterials such as liposomes also have concerns of cellular toxicity due to surface ligands
and/or the accompanying phagocytosis and degradation [31]. Degraded products
from EVs, though not intact EVs themselves, might become the target recognized
7 Endogenous Radionanomedicine: Radiolabeling
143
cells will visualize clearly the localization and duration of stay at the target site and
the consequent reparative effect even at, for example, neurodegenerative lesion of
the brain.
For this future application and new therapeutic development, understanding the
physiology of administered EVs is crucial. EVs are originated from cells and thus
they have much less concerns of toxicity compared with other organic and inorganic exogenous nanomaterials. Using any visualization or imaging methods, EVs’
biological action, metabolism and excretion is to be understood. These in vivo
physiological studies will be initially in small animals, and human-specific physiology is beyond reach again as there are definitive difference between species. To
facilitate achieving this final goal of clinical translation, clinically applicable
imaging methods are desired. Radionuclide imaging is one of the most widely used
functional imaging techniques in the clinical setting, and it enables to investigate
kinetics to elucidate in vivo fate of EVs. We will review the advantages and
expectations of imaging of radiolabeled EVs in vivo and introduce currently
reported radiolabeled EVs.
7.2 Facilitating Clinical Use of EVs: Radionuclide
Imaging of EVs
To realize promises of clinical application of EVs, a better understanding of
biodistribution and systemic feature of administered EVs is needed [25]. Recently,
several methods have been introduced to reveal the physiology of EVs. One of the
most commonly used methods is direct labeling using lipophilic fluorescence dye
intercalated in lipid bilayers [26–29]. The overview of imaging methods including
optical imaging is described in another chapter. However, fluorescence imaging has
substantial limitation in light penetration depth. Thus, it is hard to visualize
biodistribution in deep organs as well as to accurately quantify the distribution of
specific organs. Most fluorescence imaging methods are not free from toxicity
issues. In terms of translation into clinical trials, another noninvasive imaging
technique would be needed to overcome these shortcomings.
A feasible method for human imaging for EVs is to image the radionuclidelabeled EVs and MR imaging. Among them, by virtue of its superb sensitivity,
radiolabeling requires very low dose of EVs for image acquisition, which could be a
definitive advantage in facilitating clinical imaging. The usage of trace amount of
EVs for imaging is important also regarding safety issues. Even though cellular
originated EVs are relatively free from toxicity mediated by innate immune
response which produces reactive oxygen species [30], biocompatible nanomaterials such as liposomes also have concerns of cellular toxicity due to surface ligands
and/or the accompanying phagocytosis and degradation [31]. Degraded products
from EVs, though not intact EVs themselves, might become the target recognized
7 Endogenous Radionanomedicine: Radiolabeling
143