FA-PEG decorated MOF nanoparticles as a targeted drug delivery system for controlled release of an autophagy inhibitor

Abstract

A zeolitic imidazolate framework (ZIF-8) with high loading capacity and pH-responsive properties, an important subclass of metal–organic frameworks (MOFs), has become a promising material for drug delivery. A multifunctional drug delivery system (DDS) was designed in this work for effective targeting delivery of chloroquine diphosphate (CQ) as an autophagy inhibitor. The ZIF-8 nanoparticles encapsulating CQ (CQ@ZIF-8 NPs) were fabricated by a simple one-pot method and were then decorated with methoxy poly(ethylene glycol)-folate (FA-PEG), a special identifier of cancer cells, to form FA-PEG/CQ@ZIF-8. The target identification of FA-PEG/CQ@ZIF-8 NPs, compared with CQ@ZIF-8 NPs, leads to an increasing number of NPs being internalized into HeLa cells, which decreases the loss of drugs and results in high cytotoxicity of CQ for cancer cells. The lower viabilities of HeLa cells (cancer cells) and higher viabilities of HEK293 cells (healthy cells) treated with FA-PEG/CQ@ZIF-8 NPs show that the special target for cancer cells results from the combinations of folic acid and folate receptors on the surface of HeLa cells. The quantitative measurements of autophagy-related proteins and the detection of autophagy flux in HeLa cells suggest that the autophagosome formation and autophagy flux are appreciably blocked after the cells are treated with FA-PEG/CQ@ZIF-8 NPs. The ZIF-8 can disintegrate only under low pH conditions, resulting in fast and full release of CQ. The pH-responsive and tumor-targeted properties of the NPs can control the drug release and enhance the efficiency of autophagy inhibition. It indicates that the FA-PEG/CQ@ZIF-8 NPs combining target identification with controlled drug release can be used as a novel model for discussing targeted cancer therapy and inhibiting the autophagy of cancer cells.