Biodistribution of extracellular vesicles following administration into animals: A systematic review

Abstract

In recent years, attention has turned to examining the biodistribution of EVs in recipient animals to bridge between knowledge of EV function in vitro and in vivo. We undertook a systematic review of the literature to summarize the biodistribution of EVs following administration into animals. There were time‐dependent changes in the biodistribution of small‐EVs which were most abundant in the liver. Detection peaked in the liver and kidney in the first hour after administration, while distribution to the lungs and spleen peaked between 2–12 h. Large‐EVs were most abundant in the lungs with localization peaking in the first hour following administration and decreased between 2–12 h. In contrast, large‐EV localization to the liver increased as the levels in the lungs decreased. There was moderate to low localization of large‐EVs to the kidneys while localization to the spleen was typically low. Regardless of the origin or size of the EVs or the recipient species into which the EVs were administered, the biodistribution of the EVs was largely to the liver, lungs, kidneys, and spleen. There was extreme variability in the methodology between studies and we recommend that guidelines should be developed to promote standardization where possible of future EV biodistribution studies.

Special delEVery: Extracellular Vesicles as Promising Delivery Platform to the Brain

“…IV administration has been the most popular administration route studied up until now and is still gaining interest [ 126 ]. In general, the majority of the IV injected EVs rapidly accumulates in the organs of the reticuloendothelial system (RES), such as liver and spleen, with a rather small proportion of the injected dose reaching the brain after systemic administration [ 85 , 127 , 128 , 129 ]. While more specific differences (e.g., the impact of EV size [ 128 ]) are currently being studied, further detailed study of the EV pharmacokinetics will be important for safe and efficient clinical application.…”

“…In general, the majority of the IV injected EVs rapidly accumulates in the organs of the reticuloendothelial system (RES), such as liver and spleen, with a rather small proportion of the injected dose reaching the brain after systemic administration [ 85 , 127 , 128 , 129 ]. While more specific differences (e.g., the impact of EV size [ 128 ]) are currently being studied, further detailed study of the EV pharmacokinetics will be important for safe and efficient clinical application. Here, we discuss several reports providing evidence for the natural brain barrier crossing capacity or therapeutic efficiency of specific cell type derived EVs.…”

“…This knowledge poses an inherent challenge in comparing results from published studies since they utilize a broad range of available EV isolation techniques (see Table 1 and Table 2 ). Indeed, different EV isolation techniques likely enrich for different EV subpopulations with a varying number of co-isolated contaminants, in turn affecting EV biodistribution and therapeutic capacity [ 128 ]. Furthermore, when aiming to use EVs as therapeutic moieties it will be key to balance two important goals: (1) isolation of a pure EV sample, which will probably require the combination of different EV isolation methods thereby enhancing processing time and implying loss of material in consecutive steps and (2) applying an isolation method that allows processing large sample volumes in a time-efficient manner, probably resulting in a less pure EV sample.…”

“…Additionally, further research will be required to allow extrapolation of dosing and administration from preclinical models to humans [ 188 ]. A general notion that can be observed independent of the EV administration and dosing regimen is the limited EV circulation time whereby the majority of the EVs accumulate in the liver, lungs, kidneys and spleen [ 128 ]. While modifications to enhance brain targeting are discussed in Section 3.3.2 , efforts are also being made to slow down EV clearance from the bloodstream.…”

Synthetic Poly(lactic-co-glycolic Acid) Microvesicles as a Feasible Carbon Monoxide-Releasing Platform for Cancer Treatment

“…The main objective of secreting these EVs is to communicate between individual cells through the signaling genes or proteins delivery, thus regulating cellular processes such as tumor metastasis, gene transport, defense, infection, quorum sensing, and autophagy [6][7][8][9]. Based on this principle, MVs and OMVs have been indicated to have great potential as carriers to transport drugs into specific cancer cells; therefore, many scientists have performed related research on identifying vesicle types, exploring the mechanism of EV secretion, and developing the methodology of vesicle generation [10][11][12]. The generation of MVs and OMVs by biogenesis has shown very low efficiency, and the amount of product produced has been insufficient so far for clinical application.…”