Abstract
In this study, we fabricated tumor-homing pH-sensitive extracellular vesicles for efficient tumor treatment. These vesicles were prepared using extracellular vesicles (EVs; BTEVs extracted from BT-474 tumor cells or SKEVs extracted from SK-N-MC tumor cells), hyaluronic acid grafted with 3-(diethylamino)propylamine (HDEA), and doxorubicin (DOX, as a model antitumor drug). Consequently, HDEA/DOX anchored EVs (HDEA@EVs) can interact with origin tumor cells owing to EVs’ homing ability to origin cells. Therefore, EV blends of HDEA@BTEVs and HDEA@SKEVs demonstrate highly increased cellular uptake in both BT-474 and SK-N-MC cells: HDEA@BTEVs for BT-474 tumor cells and HDEA@SKEVs for SK-N-MC tumor cells. Furthermore, the hydrophobic HDEA present in HDEA@EVs at pH 7.4 can switch to hydrophilic HDEA at pH 6.5 as a result of acidic pH-induced protonation of 3-(diethylamino)propylamine (DEAP) moieties, resulting in an acidic pH-activated EVs’ disruption, accelerated release of encapsulated DOX molecules, and highly increased cell cytotoxicity. However, EV blends containing pH-insensitive HA grafted with deoxycholic acid (HDOC) (HDOC@BTEVs and HDOC@SKEVs) showed less cell cytotoxicity for both BT-474 and SK-N-MC tumor cells, because they did not act on EVs’ disruption and the resulting DOX release. Consequently, the use of these tumor-homing pH-sensitive EV blends may result in effective targeted therapies for various tumor cells.
Highlights
Extracellular vesicles (EVs) are nanosized cellular vesicles released from various types of tumor cells [1,2,3,4,5]
We fabricated tumor-homing pH-sensitive EVs. These EVs were prepared using EVs (BTEVs extracted from BT-474 tumor cells or SKEVs extracted from SK-N-MC tumor cells), hyaluronic acid grafted with 3-(diethylamino)propylamine (HDEA), and doxorubicin (DOX) [3]
HA grafted with deoxycholic acid (HDOC)@BTEVs and HDOC@SKEVs were prepared as pH-insensitive EVs to evaluate the pH-sensitive properties of HDEA@BTEVs and HDEA@SKEVs, respectively
Summary
Extracellular vesicles (EVs) are nanosized cellular vesicles released from various types of tumor cells [1,2,3,4,5]. To achieve quick and extensive intercellular communication between tumor cells, EVs are secreted out of the cells so that they can enter the recipient cells [4,5,6,7] These EVs perform various biological functions, such as the disposal of cellular waste products, release of foreign invaders, control of gene expression, and activation of the immune system [8,9,10]. EVs intrinsically express various membrane proteins, cell adhesion molecules, and tumor specific ligands, thereby enabling the homing of EVs to origin cells [4,11,12,13,14,15,16]. The immunogenicity of these EVs is relatively low; they exhibit excellent body safety for biomedical applications [4,10,19,20]
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