Tropism of Extracellular Vesicles and Cell-Derived Nanovesicles to Normal and Cancer Cells: New Perspectives in Tumor-Targeted Nucleic Acid Delivery.

Anastasiya Oshchepkova,Valentin Vlassov,Lyudmila Artemyeva,Vera Matveeva,Oleg Markov,Elena Kiseleva,Evgeniy Evtushenko,Ksenia Morozova,Marina Zenkova,Alexander Chernonosov

doi:10.3390/pharmaceutics13111911

Abstract

The main advantage of extracellular vesicles (EVs) as a drug carrier system is their low immunogenicity and internalization by mammalian cells. EVs are often considered a cell-specific delivery system, but the production of preparative amounts of EVs for therapeutic applications is challenging due to their laborious isolation and purification procedures. Alternatively, mimetic vesicles prepared from the cellular plasma membrane can be used in the same way as natural EVs. For example, a cytoskeleton-destabilizing agent, such as cytochalasin B, allows the preparation of membrane vesicles by a series of centrifugations. Here, we prepared cytochalasin-B-inducible nanovesicles (CINVs) of various cellular origins and studied their tropism in different mammalian cells. We observed that CINVs derived from human endometrial mesenchymal stem cells exhibited an enhanced affinity to epithelial cancer cells compared to myeloid, lymphoid or neuroblastoma cancer cells. The dendritic cell-derived CINVs were taken up by all studied cell lines with a similar efficiency that differed from the behavior of DC-derived EVs. The ability of cancer cells to internalize CINVs was mainly determined by the properties of recipient cells, and the cellular origin of CINVs was less important. In addition, receptor-mediated interactions were shown to be necessary for the efficient uptake of CINVs. We found that CINVs, derived from late apoptotic/necrotic cells (aCINVs) are internalized by in myelogenous (K562) 10-fold more efficiently than CINVs, and interact much less efficiently with melanocytic (B16) or epithelial (KB-3-1) cancer cells. Finally, we found that CINVs caused a temporal and reversible drop of the rate of cell division, which restored to the level of control cells with a 24 h delay.

Highlights

We suggest that the origin of cytochalasin-B-inducible nanovesicles (CINVs) only slightly influences the preference of cells to interact with them, it cannot be completely ruled out that the endometrial mesenchymal stem cells (MSCs) may be favorable for targeting to epithelial cancers
Many highly efficient delivery systems still suffer from disadvantages, such as the development of chronic or acute inflammation, instability or rapid elimination from the blood, high toxicity to the liver and kidneys, and the inability to overcome complex biological barriers
The extracellular vesicles (EVs)-based drug delivery system is of great interest due to the possible application of EV’s natural ways of internalization for targeted delivery

Summary

Introduction

Extracellular vesicles (EVs) are known to participate in cancer development [1]; in the spread of bacterial, viral, prion, and other infections [2]; and in neurodegenerative and mental disorders [3], cardiovascular diseases [4], and others. They have found application in diagnostics and in therapeutic design. The ability of EVs to carry various cargos provides a possibility to design EV-based drug delivery systems [5,6]. There are some difficulties in their practical therapeutic use. There are different ways of EV internalization by recipient cells [7–9], and current knowledge is insufficient to predict

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