received great attention. Increasing evidences demonstrated that EVs can be as a
drug-carrier used in cancer therapy [4, 5] as well as biomolecules-carrier in
regenerative medicine for diseases accompanied by tissue loss [6]. Furthermore,
they transport genetic materials such as microRNAs and proteins for therapeutic
purposes [4, 7, 8]. Although these promising therapeutic effects reported in earlier
proof-of-concept studies [4], most studies did not fully demonstrate the systemic
properties of EVs after in vivo administration [9, 10]. Limited knowledge on this
biodistribution of EVs is one of the obstacles in clinical translation of EVs as carrier
of targeted delivery.
Noninvasive imaging can provide valuable information on in vivo distribution
and kinetics of administered EVs. After in vivo administration of several types of
nanoparticles, various metabolic and clearance processes take place. This variability
in the processes of biological and physiological actions make clinical translation
more difficult, which mandates extensive studies of EVs’ biodistribution and
kinetics in a diverse situations. While the knowledge about physiology of EVs is
fundamental to successful therapeutic application, in vitro results do not always
reflect biological/physiological fates of administered EVs in vivo. For example, as
an essential and elementary study to predict the fate of in vivo administered
nanoparticles, serum stability test is usually performed in vitro. However, the
in vitro observations cannot be directly translated into the in vivo ones, i.e. stability
is vicarious. That is because clearance of nanoparticles in vivo mainly depends
upon the status of biological milieu at the time of injection as well as the milieu
difference between in vitro and in vivo [11, 12]. Understanding biodistribution of
EVs based on in vivo imaging of EVs is more than welcome to predict the role of
EVs as a novel drug-carrier [13–15].
In addition to bioapplication of EVs as drug carriers, stem cell-derived EVs have
attracted considerable attention as promising alternatives to stem cells considering
that EVs contain many biomolecules involved in tissue regeneration. EVs derived
from mesenchymal stem cells (MSC) or hematopoietic stem cells have facilitated
translational researches overcoming previous limitations of stem cell researches
[16]. Initial pioneering studies of stem cell transplantation showed regenerative
effects of transplanted stem cells for disease-associated extensive cell death such as
myocardial infarct [17–19]. Stem cell therapy was supposed to be due to the
plausible phenomena that stem cells differentiate into specific cell types in the
infarcted tissue for successful regeneration. However, despite this initial wishful
speculation, several following studies revealed that the therapeutic effects on
regeneration were mediated not by direct cellular trans-differentiation and regeneration but by paracrine effects of the transplanted cells [20–23]. Paracrine effects
are mediated by various factors secreted by stem cells, including cytokines,
chemokines, growth factors, and various biomolecules such as proteins and nucleic
acids [23]. EVs recently joined this group of factors or molecules. Even though a
variety of factors related to paracrine effects of stem cells have been elucidated, it is
not yet known which factors are essential and others are not; whether a factor affects
critically the tissue regeneration [24]. In tissue regeneration, EVs are also known to
affect cellular differentiation and modulation, and thus EVs are considered to be a
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H. Choi and D. W. Hwang
drug-carrier used in cancer therapy [4, 5] as well as biomolecules-carrier in
regenerative medicine for diseases accompanied by tissue loss [6]. Furthermore,
they transport genetic materials such as microRNAs and proteins for therapeutic
purposes [4, 7, 8]. Although these promising therapeutic effects reported in earlier
proof-of-concept studies [4], most studies did not fully demonstrate the systemic
properties of EVs after in vivo administration [9, 10]. Limited knowledge on this
biodistribution of EVs is one of the obstacles in clinical translation of EVs as carrier
of targeted delivery.
Noninvasive imaging can provide valuable information on in vivo distribution
and kinetics of administered EVs. After in vivo administration of several types of
nanoparticles, various metabolic and clearance processes take place. This variability
in the processes of biological and physiological actions make clinical translation
more difficult, which mandates extensive studies of EVs’ biodistribution and
kinetics in a diverse situations. While the knowledge about physiology of EVs is
fundamental to successful therapeutic application, in vitro results do not always
reflect biological/physiological fates of administered EVs in vivo. For example, as
an essential and elementary study to predict the fate of in vivo administered
nanoparticles, serum stability test is usually performed in vitro. However, the
in vitro observations cannot be directly translated into the in vivo ones, i.e. stability
is vicarious. That is because clearance of nanoparticles in vivo mainly depends
upon the status of biological milieu at the time of injection as well as the milieu
difference between in vitro and in vivo [11, 12]. Understanding biodistribution of
EVs based on in vivo imaging of EVs is more than welcome to predict the role of
EVs as a novel drug-carrier [13–15].
In addition to bioapplication of EVs as drug carriers, stem cell-derived EVs have
attracted considerable attention as promising alternatives to stem cells considering
that EVs contain many biomolecules involved in tissue regeneration. EVs derived
from mesenchymal stem cells (MSC) or hematopoietic stem cells have facilitated
translational researches overcoming previous limitations of stem cell researches
[16]. Initial pioneering studies of stem cell transplantation showed regenerative
effects of transplanted stem cells for disease-associated extensive cell death such as
myocardial infarct [17–19]. Stem cell therapy was supposed to be due to the
plausible phenomena that stem cells differentiate into specific cell types in the
infarcted tissue for successful regeneration. However, despite this initial wishful
speculation, several following studies revealed that the therapeutic effects on
regeneration were mediated not by direct cellular trans-differentiation and regeneration but by paracrine effects of the transplanted cells [20–23]. Paracrine effects
are mediated by various factors secreted by stem cells, including cytokines,
chemokines, growth factors, and various biomolecules such as proteins and nucleic
acids [23]. EVs recently joined this group of factors or molecules. Even though a
variety of factors related to paracrine effects of stem cells have been elucidated, it is
not yet known which factors are essential and others are not; whether a factor affects
critically the tissue regeneration [24]. In tissue regeneration, EVs are also known to
affect cellular differentiation and modulation, and thus EVs are considered to be a
142
H. Choi and D. W. Hwang