Construction Of Bone-targeting-based ZIF-90-ZOL Drug Delivery System And Study Of Antitumor Activity

Chemotherapeutic agents lack active enrichment of bone tissue, bone metastases result in poor clinical prognosis of cancers.Therefore,how to achieve bone-targeted drug delivery（DDS）is urgent for the treatment of bone metastases.Zoledronic acid,a third-generation bisphosphonate,has excellent osteophytes properties as a bone-targeting ligand.In this study,ZIF-90（Metal-Organic Frameworks）was modified with zoledronic acid to construct bone-targeting-based drug delivery.This DDS was loaded with 5-fluorouracil（5-Fu）and indocyanine green（ICG）to combine chemotherapy and photothermal therapy,achieving the treatment of bone metastases.Chemotherapeutic drugs may cause poor prognosis of tumor resistance,for further search new drugs for safe antitumor,Chlorin e6 was loaded with bone-targeted drug delivery combined with 2-deoxy-D-glucose combined,achieving the treatment of tumor with enhanced photodynamic therapy.The mainly results as following:（1）ZIF-90-ZOL,a bone-targeted drug delivery system,was constructed to be loaded with anticancer drugs 5-fluorouracil（5-Fu）and indocyanine green（ICG）.And ZIF-90 was surface modified with diaminopolyethylene glycol（NH₂-PEG-NH₂）to increase solubility.The carrier（ZIF-90）and the drug loading system（5-Fu/ICG@ZIF-90-PEG-ZOL）were characterized by scanning electron microscopy（SEM）and particle size analyzer（DLS）with homogeneous morphology and good stability.Fourier infrared（FI-IR）,XRD diffractometer,zeta potential analyzer,UV-scanning spectroscopy（UV-VIS）,and nitrogen adsorption were characterized by ZIF-90 and 5-Fu/ICG@ZIF-90-PEG-ZOL to analyze them constructed successfully.The release rate of 5-Fu/ICG@ZIF-90-PEG-ZOL was 36%at p H 7.4 and over 80%at p H 5.5.The bone-targeted ZIF-90-ZOL showed a higher bone adhesion rate than the non-targeted ZIF-90;the drug-loaded system,with good photothermal performance,achieved a photothermal conversion efficiency of 37%.Cytotoxicity,apoptosis,live-dead staining,cell cycle,and cell ultra-thin section,those experiments showed that 5-Fu/ICG@ZIF-90-PEG-ZOL with NIR 808nm irradiation over 70%inhibition of the cell proliferation,the56.69%of apoptosis rate,and the inhibitory on the cell nucleus.Mouse tumor models were to analyze the apoptotic effect under chemotherapy combined with photothermal therapy.5-Fu/ICG@ZIF-90-PEG-ZOL with808nm NIR could inhibit tumor growth in mice.5-Fu/ICG@ZIF-ZOL,a bone-targeted drug delivery system,improved the efficiency of drug delivery to bone and enhanced the inhibition of tumors with chemotherapy-photothermal therapy.This strategy may provide an alternative idea for the treatment of bone metastases.（2）ZIF-90-ZOL was loaded with Ce6 to construct a bone-targeting drug delivery system.ZIF-90 was surface modified with NH2-PEG-NH2 to improve its water solubility and was characterized by SEM,DLS,FT-IR,and UV-VIS.The Ce6@ZIF-PEG-ZOL solution was under660 nm irradiation,it the increased reactive oxygen species（ROS）produced with the duration of irradiation.In vitro cellular assays demonstrated that 2-deoxy-D-glucose（2-DG）combined with Ce6@ZIF-PEG-ZOL inhibited cancer cell proliferation and promoted apoptosis.The cells could produce ROS with the treatment of 2-DG and Ce6@ZIF-PEG-ZOL alone.A combination of 2-DG with Ce6@ZIF-PEG-ZOL was to treat cells that could have more ROS,indicating that 2-DG and Ce6@ZIF-PEG-ZOL mutually promoted the production of ROS.