Surface modification of ZIF-8 nanoparticles by hyaluronic acid for enhanced targeted delivery of quercetin*

Quercetin (QT) is a natural pharmaceutical substance with anti-inflammatory, antibacterial, and anti-cancer features. Nevertheless, it has low bioavailability, zeolitic-imidazolate framework-8 (ZIF-8) nanoparticles (NPs) with merits like very high surface area and porous nature are increasingly employed in the biomedical field as drug delivery system (DDS). Hyaluronic acid (HA) is a polymer that can be a smart "switch" and tumor-targeted "guider", extending blood circulation, and improving the tumor-specific accumulation of DDS through CD44mediated pathway. Herein, we have successfully synthesized HA-modified ZIF-8 NPs (ZIF-8/HA) for targeted delivery of QT. After characterization of synthesized materials by different advanced techniques, the QT loading capacity of ZIF-8 was investigated through different factors like initial QT concentration, solvent type, loading time and loading temperature. The release of QT in vitro was studied at pH values of 7.4 and 5.5 and ZIF-8 NPs decreased the release of QT at pH 7.4, demonstrating their ability to reduce QT loss during its distribution in blood. Also, HA-modified ZIF-8 resulted in enhanced compatibility, a decrease in toxicity to normal cells and an increase in targeted delivery of QT. Furthermore, the cytotoxicity of QT-loaded ZIF-8/HA on fibroblast cell lines (L929) as well as breast cancer cell lines (MCF-7) were evaluated. It was found that QT-loaded ZIF-8/HA not only led to a decrease in the toxicity of ZIF-8 and QT to normal cells in the body but also increased the toxicity of QT to cancer cells.