Biodistribution and Pharmacokinectics of Liposomes and Exosomes in a Mouse Model of Sepsis

Abstract

Exosomes have attracted considerable attention as drug delivery vehicles because their biological properties can be utilized for selective delivery of therapeutic cargoes to disease sites. In this context, analysis of the in vivo behaviors of exosomes in a diseased state is required to maximize their therapeutic potential as drug delivery vehicles. In this study, we investigated biodistribution and pharmacokinetics of HEK293T cell-derived exosomes and PEGylated liposomes, their synthetic counterparts, into healthy and sepsis mice. We found that biodistribution and pharmacokinetics of exosomes were significantly affected by pathophysiological conditions of sepsis compared to those of liposomes. In the sepsis mice, a substantial number of exosomes were found in the lung after intravenous injection, and their prolonged blood residence was observed due to the liver dysfunction. However, liposomes did not show such sepsis-specific effects significantly. These results demonstrate that exosome-based therapeutics can be developed to manage sepsis and septic shock by virtue of their sepsis-specific in vivo behaviors.

Keywords: biodistribution; exosome; liposome; near-infrared imaging; pharmacokinetics; sepsis.

Figure 1

Exosome and liposome characterization. (A) Transmission electron microscopy of HEK293T-derived exosomes. (B) Western blot analysis of HEK293T cells and their exosomes for the indicated proteins. (C,D) Representative graphs of nanoparticle tracking analysis demonstrating size distribution and concentration of exosomes (C) and liposomes (D).

Figure 2

Whole-body NIR fluorescence imaging of mice after intravenous injection of HEK293T cell-derived exosomes and PEGylated liposomes. (A,B) NIR fluorescence images of healthy (A) and sepsis mice (B) taken 60, 120, 180, 240, and 480 min after intravenous injection of DiR-labeled liposomes and exosomes.

Figure 3

NIR fluorescence imaging of ex vivo organs after intravenous injection of HEK293T cell-derived exosomes and PEGylated liposomes. (A,B) Fluorescent signal intensity in each organ harvested at different time points after intravenous injection of DiR-labeled exosomes (A) and liposomes (B) into healthy mice. (C,D) Fluorescent signal intensity in each organ harvested at different time points after intravenous injection of DiR-labeled exosomes (C) and liposomes (D) into sepsis mice. The results represent mean ± SD (n = 5).

Figure 4

Blood circulation of HEK293T cell-derived exosomes and PEGylated liposomes after intravenous injection. (A,B) Fluorescent signal intensity of blood sample obtained from healthy (A) and sepsis mice (B) at different time points after intravenous injection of exosomes (closed circle) and liposomes (open triangle). The results represent mean ± SD (n = 5).