Page 162 - Read Online

Page 6 of 7 Ioannides et al. J Cancer Metastasis Treat 2020;6:15 I http://dx.doi.org/10.20517/2394-4722.2020.22

dictate whether a targeted or systemic administration will provide the most optimal treatment strategy.
Furthermore, to avoid any possible confounding impact on concurrent cancer treatments, we envision that
such treatments would transpire after the cessation of radiotherapy and/or chemotherapy. This proposition
is also supported by recent evidence demonstrating that irradiation can significantly alter the protein,
lipid, and miRNA cargo of EV derived from cancer and normal cells and circulating EV found within the
plasma [20-22] .

In any case, this targeted study demonstrates the potential feasibility of administering EV through systemic
routes, thereby avoiding the requirement for more invasive surgical procedures. The equivalence found
between administration routes for delivering EV to various subregions of the brain is provocative but not
without caveats. Inherent uncertainties are associated with comparisons of these data, as the different EV
administration routes selected lead to variable (and unavoidable) sample dilution in vivo. Importantly, while
the net amount of EV between each treatment was held constant, each administration route necessitated
different volumes for proper biological distribution. For instance, IC injections cannot accommodate
volumes over 2 µL/site and systemic injections (RO at 50 µL, IN at 25 µL) require larger boluses to facilitate
more homogeneous delivery. Notwithstanding, further work is still required to more rigorously validate
whether systemic administration of EV affords functionally equivalent neuroprotection to the otherwise
compromised or irradiated CNS.

So where does the field of EV therapy stand for the treatment of radiation and other normal tissue
toxicities? Future studies should seek to define optimal cellular sources of EV to delineate the mechanism
of action, to identify bioactive cargo, and to pinpoint efficacious EV dosing regimens. While current data
points to several possible options for delivering EV to the brain, in humans, intravenous routes are likely
to provide the best combination of widespread availability and feasibility for repeated treatment regimens.
Clearly, a more systematic and complete characterization of EV surface markers and the content will be
required to translate these approaches to the clinic and be necessary to evaluate other potential risks. While
the lack of teratoma formation and reduced immunogenic response inherent to EV therapies are clear
benefits, certain safety issues remain to be thoroughly addressed, especially in the area of cancer treatments.
Further work must determine whether such approaches activate “cold” or latent cancers or alter the growth
of recurrent malignancies when administered after the cessation of specific cancer treatments. Despite the
caveats associated with any burgeoning therapy, EV provide a potentially attractive therapeutic avenue
for resolving normal tissue toxicities associated with radiotherapy, injury, disease, and aging. Studies here
provide the proof of principle highlighting the tremendous potential of EV-based therapy and underscore
that such pursuits are warranted.

DECLARATIONS
Author contributions
Performed experiments, analyzed data, wrote paper: Ioannides P
Performed experiments, analyzed data: Giedzinski E
Designed experiments, analyzed data, wrote paper: Limoli CL

Availability of data and materials
Data can be made available upon request. Materials can be provided pending availability.

Financial support and sponsorship
This work was supported by the NINDS grant (R01 NS074388) to Limoli CL.

Conflicts of interest
All authors declared that there are no conflicts of interest.