Oxygen Self-Sufficient Multivariate Porphyrinic MOFs For Chemo-photodynamic Synergistic Therapy

Cancer has become one of the most life-threating diseases to human health in the21st century due to its high morbidity,high metastasis and high mortality.Despite the rapid development of medical technology,the current conventional treatment methods are often limited in many aspects and the therapeutic effect cannot meet patient's needs.Lately,photodynamic therapy?PDT?,as an emerging photochemical-based treatment modality,has become a promising anti-cancer treatment.It could destroy cancer cells,through using photosensitize,irradiated with light of appropriate wavelength,followed by the consumption of oxygen molecules to generate cytotoxic singlet oxygen?¹O₂?efficiently.However,the staggering complexity of tumor microenvironment?TME?,such as hypoxia and overexpressed GSH,severely limit the efficiency of PDT.In order to improve the efficiency of cancer treatment,here,we developed a novel multivariate porphyrinic metal-organic frameworks?MOFs?for oxygen self-sufficient chemo-photodynamic synergistic therapy?1?Construction of the multivariate porphyrin MOFs system:the photosensitizer TCPP is integrated as a ligand into Ui O-66,with uniform spherical structure and good dispersion.The diameter is about 65 nm;As a drug delivery system,Porphyrin MOFs was loaded with doxorubicin?DOX?for chemotherapy treatment,coated with a layer of Mn O₂ to control drug release,and modified with polyethylene glycol?PEG?to improve the biocompatibility.A series of characterizations,such as EDX,Zeta potential,XRD,UV-vis spectroscopy and fluorescence spectroscopy,proved that the synthesis of these nanopparticles were successful.?2?In-vitro study of oxygen self-sufficient system:we validated their TME-response and TME-regulation abilities from the three aspects:drug release,oxygen generation capacity and reactive oxygen generation capacity.The results showed that under simulated tumor conditions?p H 5.5,2 m M GSH?,the DOX release of TUDMP NPs was above 75.0%in 0.5 hours,showing a good TME-response ability;With 20m M H₂O₂,the dissolved oxygen in the TUDMP NPs was increased by 9 mg/m L within140 s,and the ¹O₂ generation capacity of photosensitizer was enhanced,further enhancing the efficiency of PDT treatment.It proves that the drug-loading nanosystem can not only effectively relieve tumor hypoxia,but also has the ability of TME-responsive drug release.?3?In vitro anti-tumor activity study of TUDMP NPs:intracellular ROS generation experiments showed that TUDMP NPs have a much stronger ROS production capacity.Confocal laser scanning microscopy?CLSM?and flow cytometry analysis proved that TUDMP NPs can effectively enter into cells and the DOX was gradually accumulated in the nucleus along with the time prolonging.A significant expression rate of apoptosis?98.4±6.1%?was shown after treated with TUDMP NPs under 650 nm laser irradiation.Cytotoxicity assay in vitro showed that the efficiency of chemo-photodynamic synergistic therapy was better than that of any single therapy.For TUDMP NPs group with a laser irradiation,the cytotoxicity presented a concomitant increase of its concentration and the cell viability decreased remarkably to below 15%at a concentration of 100?g/m L?4?In vivo antitumor activity study of TUDMP NPs:Herein,the subcutaneous xenograft colon tumors model was constructed to further evaluate the in vivo treatment efficacy of TUDMP NPs.The most prominent inhibited efficacy of tumor growth has been exhibited in mice of group TUDMP NPs with laser irradiation?the relative inhibition rate is 71.4%?,which was superior to any single treatment.Afterwards,the mice major organs and body weight were in normal ranges throughout the treatment period and the H&E staining images of the main organs showed no marked pathological damage in the TUDMP NPs-laser group,indicating the good biosafety of our prepared NPs.Consequently,the oxygen self-sufficient multivariate porphyrinic MOFs our constructed have excellent promoting applications in the fields of TME regulation and chemo-photodynamic synergistic therapy.