Propranolol-induced autophagic dysfunction combined with a targeted metal-organic framework as a novel strategy for improving antitumor therapeutic efficacy

Abstract

Autophagy is an intracellular biological process that involves capturing and degrading intracellular components to sustain metabolism and homeostasis. Especially in the late stage of tumorigenesis, autophagy contributes to the survival and growth of the tumors and promotes the aggressiveness of the tumors by facilitating metastasis. The overactivation of autophagy is also one of the important reasons for the drug resistance of the tumor. Nanoparticles (NPs) can induce autophagic process via certain components and morphologies, providing a new perspective for establishing tumor therapy strategies. Here, we report the preparation of targeted nanoparticles (NPs) encapsulated with paclitaxel (PTX) and propranolol (PRN) into poly(ethylene glycol) (PEG)-mediated zeolitic imidazolate framework-8 NPs to reverse the adverse effects of autophagy, where PEG improves the stability and dispersity of ZIF-8 NPs. PTX and Zn2+ released from the ZIF-8 NPs induce autophagy which could promote the survival of tumors. Propranolol (PRN), as a novel safe potential chemo-sensitizer, can act like a “valve” to block the fusion of autophagosome and lysosomes, and autolysosome degradation. The combinational application of PRN results in a boost of autophagosomes which directly suppresses the delivery of nutrients for tumor cells and changes the pro-survival mechanism of autophagy which promotes the cell-killing effect. In addition, these nanoparticles could cause an increase in intracellular ROS levels significantly and further induce apoptosis and autophagy of tumor cells. As a result, PTX&PRN@ZIF-8@HA NPs provide a novel potential method for the delivery of multiple therapeutics to convert the pro-survival effect of autophagy into a pro-death effect and offer the possibility of propranolol as a specific autophagy inhibitor for the tumor therapy.