Desialylated Mesenchymal Stem Cells-Derived Extracellular Vesicles Loaded with Doxorubicin for Targeted Inhibition of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the dominating causes of cancer-related death throughout the world. Treatment options for patients with HCC vary, however, the lack of effective targeted drugs is the major reason for death in advanced HCC patients. In this study, a delivery system based on mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) loaded with doxorubicin (Dox) was developed. In this system, we initially erased terminal linked α2–3 and α2–6 sialic acids on the surface of EVs by neuraminidase. The exhibition of galactose (Gal) and N-acetylgalactosamine (GalNAc) residues in treated MSC-EVs can specifically be recognized by asialoglycoprotein receptor (ASGPR) of hepatoma cells. Compared to free Dox and Dox-loaded EVs, desialylated EVs loaded with Dox significantly presented the improved cellular uptake, prioritized targeting efficacy, and had a better inhibiting effect in vitro and in vivo. Overall, the results of the present study of the demonstrated delivery system using desialylated MSC-EVs suggest its therapeutic potential for HCC.

Apoptosis Triggering in Breast Cancer Cells with Co-delivery of Melatonin and Doxorubicin Loaded into Human Adipose Mesenchymal Stem Cell Derived Exosomes

“…The drug loading in Exos is in uenced by several factors including the loading method, the source of Exos, and the size and solubility of the drug. Various studies have reported different loading and encapsulation percentages of drugs in EXOs [38,39], while the results of Chunyan Yang et al were almost similar to our work [40]. TEM and DLS were utilized to assess whether sonication or drug transfer had any impact on the structure of EXOs.…”

Frontiers of stem cell engineering for nanotechnology-mediated drug delivery systems

“…In another study, the encapsulation of DOX in these desialylated MSC-derived EVs after sialic acids on the surface of MSC-derived EVs were removed by neuraminidase. The results showed that for targeting hepatocellular carcinoma, DOX-loaded desialylated EVs increased the cellular uptake and targeting efficiency and had better inhibition both in vitro and in vivo [ 55 ].…”

Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Natural Nanocarriers: Concise Review

“…Interestingly, Lou et al described an increase in hepatocellular carcinoma (HCC) cell sensitivity to EVs containing doxorubicin, in comparison to free drugs [ 123 ]. Moreover, Yang et al demonstrated interesting achievements in targeted therapy mediated by encapsulating doxorubicin in desialylated MSC-derived EVs on HCC cell lines [ 124 ]. Tumour growth inhibition induced by the apoptotic pathway can also be initiated by exosomes derived from TNFα plasmid-transfected MSCs [ 125 ].…”

“…In orthotopic mouse models of hepatocellular carcinoma (HCC), the IV injection of EVs-miR-199a loaded by the lentivirus transfection of adipose-tissue derived MSCs improved HCC chemosensitivity to doxorubicin via mTOR pathway targeting [ 123 ]. Yang et al showed enhanced cytotoxicity efficiency using Doxo-loaded desialylated MSC-derived EVs for better targeting efficiency in Balb/c nude mice injected with HCC cells [ 124 ]. TNF-α and TRAIL protein can also be transfected using a plasmid in MSCs before EV isolation to obtain better drug delivery with increased antitumour activity, and less toxicity, in a melanoma mouse model [ 125 ].…”