E-selectin targeting cascaded ultrasonic cavitation enables liposomes to deeply penetrate pancreatic cancer.

The insufficient vascular extravasation and dense extracellular matrix in pancreatic cancer jointly resist drug accumulation and penetration into tumor and lead to poor prognosis. The ligand/receptor-mediated nanocarrier has gained widespread recognition as an effective strategy for increasing the tumor targeting accumulation, but which is always impaired by protein corona pollution during circulation, as well as limited intratumor penetration. To address these problems, we have designed an E-selectin targeting cascaded ultrasonic cavitation liposome (GPGLP) that incorporates a gemcitabine prodrug (GOE), perfluoropentane, and an endogenous ligand ganglioside (GM1), which can sequentially overcome the biological barriers of tumor endothelial cells and the extracellular matrix via ligand/receptor-mediated transcytosis and ultrasonic cavitation-induced extracellular matrix loosening. The endogenous GM1 ganglioside can reduce the protein corona formation of liposome and guarantee its capability to recognize the E-selectin receptor on tumor neovascularization, initiating ligand/receptor-mediated transcytosis for efficient tumor accumulation. Upon exposure to ultrasound irradiation, GPGLP liposomes undergo a liquid-to-gas phase transition and self-assemble into smaller liposomes. The in-situ cavitation force following facilitates the extracellular matrix loosening, augmenting GPGLP deep penetration within the tumor parenchyma and releasing active gemcitabine throughout the tumor after intracellular enzymolysis. This process results in potent antitumor efficacy superior to that of clinical chemotherapeutics in pancreatic cancer treatement. This study presents an effective strategy of transcytosis cascaded ultrasonic cavitation to tackle the biological barriers in drug delivery for pancreatic cancer and other solid tumors.