Tumor-Homing pH-Sensitive Extracellular Vesicles for Targeting Heterogeneous Tumors

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.

Transferrin-Conjugated pH-Responsive γ-Cyclodextrin Nanoparticles for Antitumoral Topotecan Delivery

“…respectively). These results indicate that the NPs with Tf ligands were efficiently endocytosed to MDA-MB-231 tumor cells [16,[32][33][34][35][36][37], which was also readily apparent in the confocal image results. Figure 5b shows that the apoptotic cell population (Q2 and Q3) [16,30] of MDA-MB-231 cells treated with γCDP-(DMA/PEG-Tf) NPs was 55.7%, but those of MDA-MB-231 cells treated with γCDP-(DMA/PEG) NPs, γCDP-(PEG-Tf) NPs, and γCDP-(PEG) NPs were 27.8%, 41.6%, and 18.2%, respectively.…”

“…The particle size and zeta potential of each NP sample (0.1 mg/mL) was measured using a Zetasizer 3000 instrument (Malvern Instruments, Malvern, UK) after being stabilized in 150 mM PBS (pH 7.4, 6.5, or 6.0) at 25 °C for 4 h. The morphology of each NP sample was confirmed using a field-emission scanning electron microscopy (FE-SEM, Hitach S-400, Fukuoka, Japan) after being stabilized in 150 mM PBS (pH 7.4, 6.5, or 6.0) at 25 °C for 4 h [ 32 , 33 , 34 , 35 , 36 , 37 ].…”

“…In addition, the RBC solution, which was completely lysed using 2% ( w / v ) Triton X-100, was used as a positive control, and the PBS-treated RBC solution was used as a negative control. The endosomolytic activity (%) of NPs was determined from the degree of RBC hemolysis [ 36 , 37 ].…”

“…All data were analyzed using Student’s t -test or analysis of variance (ANOVA) at a significance level of ** p < 0.01 [ 27 , 28 , 29 , 30 , 31 , 32 , 36 , 37 ].…”

Novel Anticancer Strategies

“…Park et al report the use of tumor-homing pH-sensitive EV blends made from tumor-specific EVs, extracted from two different tumor cell types, and pH-sensitive HDEA (3-(diethylamino)propylamine). These EVs were loaded with hyaluronic acid grafted with HDEA and doxorubicin (DOX, as a model antitumor drug) [ 9 ]. HDEA/DOX-anchored EVs were able to target the two different parent tumor cells owing to the EVs’ homing ability.…”