Enhanced effect of autologous EVs delivering paclitaxel in pancreatic cancer

Abstract

We engineered human pancreatic cancer cell (PANC-1)-derived extracellular vesicles (EVs) by conjugating the functional ligand RGD and magnetic nanoparticles (MNPs) onto EV surfaces (rmExo), for pancreatic cancer therapy. Paclitaxel (PTX) loaded into rmExo (rmExo-PTX) was intravenously injected into xenograft mice prepared using PANC-1 cells, which showed a significant reduction in tumor size compared to the free PTX-treated and control groups. The enhanced therapeutic effect was attributed to the modification of the surface of EVs using RGD, which has affinity for αvβ3 that is highly expressed in pancreatic cancer cells. Moreover, autologous EVs seemed to have more benefits in delivering PTX due to an unknown homing property to parent tumor cells, as exemplified by the reduced therapeutic effect of RGD-modified PANC-1 EVs on HT29 xenograft mice and RGD-modified U937 EVs on PANC-1 xenograft mice. The RGD-modified autologous EV vehicles were effective at penetrating and internalizing tumor cells, and eventually regressing the tumors, by mediating spontaneous removal of α-smooth muscle actin and collagen type 1 in the extracellular matrix of xenografts. Our results also identified an important molecule involved in the home-driving properties of PANC-1 EVs, integrin β3, which was expressed both on PANC-1 cells and the EVs derived from them. Additional therapeutic effect by permanent magnet near tumor xenograft was not observed in this study.

Keywords: Autologous extracellular vesicles; Exosomes; Homing effect; Integrin αvβ3; Pancreatic cancer; RGD.