Targeted cancer therapy using engineered exosome as a natural drug delivery vehicle

Abstract

PurposeExosomes are small 30–100 nm vesicles secreted by various cell types. They are released by most cell types, indicating their important role in physiological and pathological processes, including signaling pathways, cell-to-cell communication, tumor progression, and molecule transferring. As natural nanovesicles, exosomes can be a good candidate for drug delivery due to low immunogenicity and ability to enter tissues and even cross the blood–brain barrier. In an effort to improve the efficiency of exosomes for targeted drug delivery with minimal effect on normal cells, we expressed ligands against HER2+ cells.MethodsTo purify exosomes, transduced mesenchymal stromal cells were cultured to reach 80% confluency. Next, the cells were cultured in serum-free media for 48 hours and the supernatant was harvested to purify exosomes. These exosomes were then labeled with PKH67 and added to BT-474, SKBR3 (HER2+), and MDA-MB231 (HER2−), cell lines and their binding to HER2+ was evaluated by flow cytometry. Exosomes were loaded with doxorubicin and quantified using intrinsic fluorescence of doxorubicin at 594 nm.ResultsTargeted exosomes were preferably uptaken by HER2+ cells. Therefore, untargeted exosomes showed lower binding to HER2+ cells compared to their targeted counterparts. MTT assay was performed to analyze cytotoxic effect of exo-DOX (exosome encapsulated with doxorubicin). Efficiency of exo-DOX and free DOX (doxorubicin) delivery with different concentrations, to the BT-474 cell line, was compared, and no significant difference was observed.ConclusionOur results imply that targeted exosomes are preferentially uptaken by HER2+ cells relative to HER2− cells and have the potential to be used as an efficient drug delivery system.

Tumor microenvironment complexity and therapeutic implications at a glance

“…More recently, exosomes have also been targeted to deliver DOX to HER2+ cancer cells to evaluate the anticancer effects of DOX-loaded targeted exosomes in a murine tumor model. The results of this study indicate that targeted exosomes are favorably uptaken by HER2+ cells compared with HER2− cells and have the potential to be used as a competent drug delivery system [191].…”

Biology and therapeutic potential of mesenchymal stem cell‐derived exosomes

“…MSC‐derived exosomes have been engineered as an efficient delivery system reported to exert higher anti–tumor efficacy and reduced toxicity 108,109 . For instance, BMSC‐derived exosomes encapsulated with doxorubicin are preferentially taken up by human epidermal growth factor receptor 2+ (HER2+) cells in vitro, leading to an inhibitory effect in a breast tumor model 110 . It was observed that paclitaxel‐treated BMSC mediated obvious anti–tumor activity because of their capacity to take up the drug inside exosomes, which results in an obvious inhibition of cell growth and proliferation in pancreatic cancer cells 105 .…”

A Comprehensive Picture of Extracellular Vesicles and Their Contents. Molecular Transfer to Cancer Cells

“…Exosomes originating from autologous cancer cells caused minimal toxicity during transport to target cells, reach parental cancer cells through endocytosis, increase the cytotoxicity of these cells [207], and can be less immunogenic than artificial delivery vehicles [206]. Different drugs, such as doxorubicin, paclitaxel, docetaxel, or polyphenols like curcumin, were encapsulated in exosomes [208][209][210]. Both in vitro and in vivo studies have shown antitumor activity in the case of the doxorubicin delivery platform using exosomes [211].…”