Enzyme-triggered transcytosis of drug carrier system for deep penetration into hepatoma tumors

In recent years, nano-drug delivery systems have made considerable progress in the direction of tumor treatment, but the low permeability of drugs has restricted the development of nano drugs. To solve this problem, we constructed a nano-drug delivery system with the dual effects of γ-glutamyltransferase (GGT) reaction and high nuclear targeting in tumor microenvironment to promote the deep penetration of drugs. Over-expression of GGT in tumor cells can specifically recognize γ-glutamyl substrate and release amino group from the hydrolysis reaction, which makes the whole system change from negative or neutral to positive charge system. The conjugated complex with positive charge rapidly endocytosis through electrostatic interaction, enhancing its permeability in tumor parenchyma. At the same time, the cell penetrating TAT contains a large amount of lysine, which can be identified by the nuclear pore complexes (NPCs) on the surface of the nuclear membrane, showing excellent nuclear localization function. The active DOX is released in the nucleus, which inhibits the mitosis of cancer cells and enhances the active transport ability of drugs in tumor cells. Therefore, this drug delivery system actively transports adriamycin into the tumor to achieve deep penetration of drugs through enzyme response and nuclear targeting, showing high anti-tumor activity and can be effectively applied to the treatment of liver cancer.