Biodistribution and delivery efficiency of unmodified tumor-derived exosomes

Abstract

The use of exosomes as a drug delivery vehicle has gained considerable interest. To establish if exosomes could be utilized effectively for drug delivery, a better understanding of their in vivo fate must be established. Through comparisons to liposomal formulations, which have been studied extensively for the last thirty years, we were able to make some comprehensive conclusions about the fate of unmodified tumor-derived exosomes in vivo. We observed a comparable rapid clearance and minimal tumor accumulation of intravenously-injected exosomes, PC:Chol liposomes, and liposomes formulated with the lipid extract of exosomes, suggesting the unique protein and lipid composition of exosomes does not appreciably impact exosomes’ rate of clearance and biodistribution. This rapid clearance along with minimal tumor accumulation of unmodified exosomes limits their use as an anti-cancer drug delivery vehicle; however, when delivered intratumorally, exosomes remained associated with tumor tissue to a significantly greater extent than PC:Chol liposomes. Furthermore, experiments utilizing mice with impaired adaptive or innate immune systems, revealed the significance of the innate immune system along with the complement protein C5 on exosomes’ rate of clearance.

Evaluation of electroporation-induced adverse effects on adipose-derived stem cell exosomes

“…One of the main issues being addressed in these papers is the way of loading the exosomes with therapeutic cargo and reaching superior therapeutic effects compared to synthetic liposomes (Smyth et al 2015;Fuhrmann et al 2015). As described in Johnsen et al (2014), the method of electroporation has been questioned due to the fact that exosomes as well as siRNA cargo tend to aggregate in the process (Kooijmans et al 2013;Johnsen et al 2014).…”

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

“…However, according to previous studies of their biodistribution, less than 5% of systemically administered nanoparticles reach tumour tissues [154,155]. Remarkably, most exosomes and small-sized microvesicles distribute to the liver, and less than 2% of the injected vesicles were found to accumulate in tumour tissues after systemic administration [156]. A great deal remains unknown regarding the in vivo properties of EVs, including their tissue distribution, half-life, blood levels, and urine clearance.…”

Therapeutic and diagnostic applications of extracellular vesicles

“…As EVs are abundantly present and stable in the blood circulation, it was speculated that EVs could have longer circulation times and mediate drug targeting to extrahepatic and non-lymphoid tissues. However, reports studying the PK of IV injected EVs described short half-lives (~2 minutes [115,116] and ~20 minutes [117]) with predominant uptake by liver, lung, kidney and spleen, thus closely resembling the biodistribution of synthetic liposomes [70,118,119]. The elimination after IV injection occurs via hepatic and renal routes [117] in which MPS-associated macrophages seem to play a key role [118].…”

“…However, reports studying the PK of IV injected EVs described short half-lives (~2 minutes [115,116] and ~20 minutes [117]) with predominant uptake by liver, lung, kidney and spleen, thus closely resembling the biodistribution of synthetic liposomes [70,118,119]. The elimination after IV injection occurs via hepatic and renal routes [117] in which MPS-associated macrophages seem to play a key role [118]. It is conceivable that this recognition is in part mediated by the exposure of PS at the external side of EV (subtypes) [120,121].…”