but higher accumulation in the pancreas and bowel than intravenous administration
of the same EVs [35].
The important technical factor which affects biodistribution is the labeling
method. As lipophilic fluorescent dye itself has long half-life in vivo, it remained in
the tissues even after the degradation of EVs [22]. Reporter system based on surface
proteins or lipid bilayers could show different biodistribution patterns from other
methods. Simultaneous labeling of fluorescence dye and radionuclide
99m Tc-HMPAO revealed that fluorescence signals and radioactivity had different
kinetics patterns [43]. As labeling process may hamper integrity of EVs and cause
composition changes, optimized labeling process under physiologic condition will
again be very important for accurate monitoring of biodistribution. Furthermore,
multimodal imaging using various labeling methods can help understand accurate
biodistribution of administered EVs.
8.2.3 Intrinsic Factors
According to the earlier findings of the in vivo distribution of liposomes, size of
liposomes was already known to be a determinant factor of major uptake sites. The
liposomes were commonly accumulated in the organs of mononuclear phagocyte
system including liver, spleen and the lungs. When they were injected intravenously, they were generally taken up by macrophages in liver or spleen [44, 45].
The size of the nanoparticles including liposomes affected the sites of clearance
among mononuclear phagocytic system organs of liver, spleen and bone marrow.
Very small nanoparticles (<80 nm) tended to be cleared by bone marrow [46].
Around 100 nm sized nanoparticles can penetrate the hepatic sinusoidal endothelium, which results in increased hepatic accumulation [47, 48]. Larger nanoparticles
including liposomes are prone to higher chances of opsonization and accumulate
more in the spleen.
Current reports of in vivo biodistribution study of EVs showed that the major
accumulation of EVs were similar with liposomes. Mostly, EVs were accumulated
in the liver and spleen [43]. This pattern is similar to various nanoparticles
including liposomes. Moreover, a study showed that liposomes with similar size of
EVs and liposomes synthesized by lipid extracts of EVs have very similar
biodistribution patterns [14]. It suggested the distribution of EVs could be mainly
determined by intrinsic physiologic factors such as size.
Nonetheless, the definition of EVs include a broad spectrum of vesicles secreted
by several types of cells [5, 49, 50]. Thus, size of EVs is varied according to the
definition of EVs among different studies. In general, EVs include exosomes and
microvesicles. Exosomes are small (30–100 nm) vesicles derived from the endosomal pathway. The microvesicles relatively larger than exosomes (50–1000 nm)
and they are generated by budding of the plasma membrane [50]. The broad
spectrum of size of EVs could affect various biodistribution results. EVs are not a
single entity and include a group of vesicles which have been called exosomes,
160
H. Choi and D. S. Lee
of the same EVs [35].
The important technical factor which affects biodistribution is the labeling
method. As lipophilic fluorescent dye itself has long half-life in vivo, it remained in
the tissues even after the degradation of EVs [22]. Reporter system based on surface
proteins or lipid bilayers could show different biodistribution patterns from other
methods. Simultaneous labeling of fluorescence dye and radionuclide
99m Tc-HMPAO revealed that fluorescence signals and radioactivity had different
kinetics patterns [43]. As labeling process may hamper integrity of EVs and cause
composition changes, optimized labeling process under physiologic condition will
again be very important for accurate monitoring of biodistribution. Furthermore,
multimodal imaging using various labeling methods can help understand accurate
biodistribution of administered EVs.
8.2.3 Intrinsic Factors
According to the earlier findings of the in vivo distribution of liposomes, size of
liposomes was already known to be a determinant factor of major uptake sites. The
liposomes were commonly accumulated in the organs of mononuclear phagocyte
system including liver, spleen and the lungs. When they were injected intravenously, they were generally taken up by macrophages in liver or spleen [44, 45].
The size of the nanoparticles including liposomes affected the sites of clearance
among mononuclear phagocytic system organs of liver, spleen and bone marrow.
Very small nanoparticles (<80 nm) tended to be cleared by bone marrow [46].
Around 100 nm sized nanoparticles can penetrate the hepatic sinusoidal endothelium, which results in increased hepatic accumulation [47, 48]. Larger nanoparticles
including liposomes are prone to higher chances of opsonization and accumulate
more in the spleen.
Current reports of in vivo biodistribution study of EVs showed that the major
accumulation of EVs were similar with liposomes. Mostly, EVs were accumulated
in the liver and spleen [43]. This pattern is similar to various nanoparticles
including liposomes. Moreover, a study showed that liposomes with similar size of
EVs and liposomes synthesized by lipid extracts of EVs have very similar
biodistribution patterns [14]. It suggested the distribution of EVs could be mainly
determined by intrinsic physiologic factors such as size.
Nonetheless, the definition of EVs include a broad spectrum of vesicles secreted
by several types of cells [5, 49, 50]. Thus, size of EVs is varied according to the
definition of EVs among different studies. In general, EVs include exosomes and
microvesicles. Exosomes are small (30–100 nm) vesicles derived from the endosomal pathway. The microvesicles relatively larger than exosomes (50–1000 nm)
and they are generated by budding of the plasma membrane [50]. The broad
spectrum of size of EVs could affect various biodistribution results. EVs are not a
single entity and include a group of vesicles which have been called exosomes,
160
H. Choi and D. S. Lee