Exosome-like Nanovectors for Drug Delivery in Cancer

Abstract

Cancer treatment still represents a formidable challenge, despite substantial advancements in available therapies being made over the past decade. One major issue is poor therapeutic efficacy due to lack of specificity and low bioavailability. The progress of nanotechnology and the development of a variety of nanoplatforms have had a significant impact in improving the therapeutic outcome of chemotherapeutics. Nanoparticles can overcome various biological barriers and localize at tumor site, while simultaneously protecting a therapeutic cargo and increasing its circulation time. Despite this, due to their synthetic origin, nanoparticles are often detected by the immune system and preferentially sequestered by filtering organs. Exosomes have recently been investigated as suitable substitutes for the shortcomings of nanoparticles due to their biological compatibility and particularly small size (i.e., 30-150 nm). In addition, exosomes have been found to play important roles in cell communication, acting as natural carriers of biological cargoes throughout the body. This review aims to highlight the use of exosomes as drug delivery vehicles for cancer and showcases the various attempts used to exploit exosomes with a focus on the delivery of chemotherapeutics and nucleic acids.

Keywords: Chemotherapy; drug delivery; exosomes; extracellular vesicles; gene therapy; nanoparticles; nanotechnology; surface modifications..

Figure 1.. Exosomes biogenesis.

Schematic representation of the origin and release of exosomes. Exosomes originate by the fusion of intracellular vesicles and early endosomes, heading to the origin of MVBs. MVBs can either fuse with lysosomes or with the membrane ending to the release of their content. There are other types of vesicles that are generated directly from the plasma membrane: microvesicles.

Figure 2.. Exosomes role in chemoresistance.

Schematic representation of exosomes role in drug resistance acquisition. Exosomes can contribute to drug resistance by actively exporting drugs out of the cells transferring drug efflux pumps or delivering molecules (i.e. miRNA and prosurvival proteins) to sensitive recipient cells. Particularly, exosomes released by drug-resistant cells expressed high level of P-gp and are able to transfer P-gp to sensitive cells [37]. Moreover, exosomes containing miRNA expelled from drug-resistant cells can modify chemo-sensitivity in recipient cells by modulating cell cycle distribution and drug-induced apoptosis [37].

Figure 3.. Approaches for synthesis of exosome-like nanovesicles.

A. Schematic of synthesis of leukosomes: synthetic extracellular nanovesicles composed by a lipid bilayer enriched with membrane-associated proteins derived from leukocyte. B. Exosome-like nanovesicles obtained by consecutive extrusion passages of cells through membrane filters with diminishing size, followed by density gradient ultracentrifugation. Adapted with permissions from ref [10] A, and [53] B.

Figure 4.. Evaluation of chemotherapy-loaded exosome nanoparticles.

A. Total particle yield of exosome-mimetic nanovesicles (NV) and exosomes (EXO) derived from 1 × 10⁷ total cells. B. Cryo-transmission electron micrographs depicting NV with and without doxorubicin (DOX). C. Evaluation of TNF-α-activated HUVEC proliferation following treatment with varying doses of DOX-loaded NV. D. Tumor growth following administration of NV and NV containing DOX (2 μg or 10 μg). Reprint with permissions from ref [53].

Figure 5.. EGFR-mediated exosome delivery of miRNA.

A. Electron microscope images depicting the presence of GE11 and EGF on the exosome surface. B. Confocal microscope images depicting PKH67 dye-loaded exosomes (green) internalized within HCC70 human breast cancer cells. C. In vivo imaging comparing normal exosome and GE11-modified exosomes accumulation within a human breast cancer tumor-bearing mouse model. D. Antitumor effect 4 week following post-administration of let7a miRNA-containing exosomes. Reprint with permission from ref [91].