7.3.3 Multifunctional Radionuclide Labeling Methods
Using Click Chemistry
Radiolabeling using a chelator combined with radionuclide under physiologic
conditions was also suggested [44]. The method was based on click chemistry [45,
46]. As EVs have surface proteins, there are free amine groups presented on their
surface. This functional amine moiety can be taken advantage of simple clickable
radiolabeling of EVs under mild physiologic condition. To label bifunctional
chelator which can react easily with corresponding radionuclide, EVs were
treated with N-hydroxysuccinimide-azadibenzocyclooctyne (NHS-ADIBO).
N3-introduced chelators including NOTA(1,4,7-triazacyclononane-1,4,7-triacetic
acid), DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or TETA
(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid) can react with
ADIBO-conjugated EVs based on cycloaddition reaction of click chemistry. The
important advantages of this method is that we are able to use various chelators and
positron emitting radionuclides such as
68 Ga,
64 Cu, and
89 Zr. The appropriate
radionuclides can be simply selected according to the research purposes. For
instance, to monitor long-term biodistribution, radionuclides with longer half-life
such as
111 In can be chosen for radiolabeling. In addition, therapeutic radionuclides
such as
67 Cu,
177
Lu,
90 Y and
188 Re can be labeled on the EVs. Labeling of these
therapeutic radionuclides will enable therapeutic usage of EVs in cancer treatment.
The only problem is that most of the EVs systemically administered localized in the
liver and the spleen and only a small amount of EVs seemed to localize at the target
sites. However, this problem of EVs, endogenous radionanomedicines, is not worse
than the problem with other exogenous radionanomedicines, either inorganic or
organic.
Recent studies revealed that EVs could play a role as drug carrier and some
showed effects on tumor suppression by transferring microRNAs or therapeutic
drugs [47–49]. Based on these pioneering proof-of-concept studies, we could just
hope that EVs would play a role in cancer treatment by combining radionuclide
therapy and drug carriers carrying therapeutic drugs as cargos while monitoring by
radionuclide imaging. We still don’t know that this wish is volatile or solid and the
follow-up studies will be very much enlightening. Radiolabeling of EVs are the
prerequisites to understand and predict the future of clinically usable EVs as a
multifunctional multiplex platform.
7.4 Conclusion
Radionuclide imaging of EVs was recently introduced. Since in vivo monitoring of
EVs is crucial to understand in vivo fate of EVs as well as to apply EVs to possible
clinical therapeutics. So far, even though various studies using optical imaging
system reported in vivo biodistribution of systemically administered EVs, it has
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H. Choi and D. W. Hwang
Using Click Chemistry
Radiolabeling using a chelator combined with radionuclide under physiologic
conditions was also suggested [44]. The method was based on click chemistry [45,
46]. As EVs have surface proteins, there are free amine groups presented on their
surface. This functional amine moiety can be taken advantage of simple clickable
radiolabeling of EVs under mild physiologic condition. To label bifunctional
chelator which can react easily with corresponding radionuclide, EVs were
treated with N-hydroxysuccinimide-azadibenzocyclooctyne (NHS-ADIBO).
N3-introduced chelators including NOTA(1,4,7-triazacyclononane-1,4,7-triacetic
acid), DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or TETA
(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid) can react with
ADIBO-conjugated EVs based on cycloaddition reaction of click chemistry. The
important advantages of this method is that we are able to use various chelators and
positron emitting radionuclides such as
68 Ga,
64 Cu, and
89 Zr. The appropriate
radionuclides can be simply selected according to the research purposes. For
instance, to monitor long-term biodistribution, radionuclides with longer half-life
such as
111 In can be chosen for radiolabeling. In addition, therapeutic radionuclides
such as
67 Cu,
177
Lu,
90 Y and
188 Re can be labeled on the EVs. Labeling of these
therapeutic radionuclides will enable therapeutic usage of EVs in cancer treatment.
The only problem is that most of the EVs systemically administered localized in the
liver and the spleen and only a small amount of EVs seemed to localize at the target
sites. However, this problem of EVs, endogenous radionanomedicines, is not worse
than the problem with other exogenous radionanomedicines, either inorganic or
organic.
Recent studies revealed that EVs could play a role as drug carrier and some
showed effects on tumor suppression by transferring microRNAs or therapeutic
drugs [47–49]. Based on these pioneering proof-of-concept studies, we could just
hope that EVs would play a role in cancer treatment by combining radionuclide
therapy and drug carriers carrying therapeutic drugs as cargos while monitoring by
radionuclide imaging. We still don’t know that this wish is volatile or solid and the
follow-up studies will be very much enlightening. Radiolabeling of EVs are the
prerequisites to understand and predict the future of clinically usable EVs as a
multifunctional multiplex platform.
7.4 Conclusion
Radionuclide imaging of EVs was recently introduced. Since in vivo monitoring of
EVs is crucial to understand in vivo fate of EVs as well as to apply EVs to possible
clinical therapeutics. So far, even though various studies using optical imaging
system reported in vivo biodistribution of systemically administered EVs, it has
148
H. Choi and D. W. Hwang