Research On Light-responsive Therapy Based On Polydopamine And Phthalocyanine Photosensitizers To Enhance Anti-tumor Activity

Cancer has become a major disease threat to human health,and it is important to seek safe and effective treatment for cancer.Photo-response therapy has attracted wide attention for its excellent therapeutic effects and low side effects,which mainly includes Photodynamic Therapy?PDT?and Photothermal Therapy?PTT?.The therapeutic mechanism between them is different.PDT results in oxidative damage of cells and tumor micro vessels through Reactive Oxygen Species?ROS?generated by photosensitizers under the light irradiation.On the other hand,PTT mainly cause thermal damage through the photothermal conversion ability of the hyperthermia agent in local area.Combined therapy can improve the therapeutic effect and drug safety,which is a widely used clinical synergistic strategy on account of the difficulty of achieving a complete cure with a single method.We investigate the PTT treatment based on polydopamine?PDA?,PDT based on Zinc Phthalocyanine?Zn Pc?and their combined treatment strategies using nanotechnology according to tumor microenvironment.The PTT/PDT combination therapy realized that disturbing the intracellular reduced/oxidized glutathione?GSH/GSSG?redox equilibrium,controlling and release of Zn Pc,enhancing the damage range of ROS,relieving hypoxia in tumor tissues,and the integration of multi-mode imaging.The main research contents and results are as follows.1.Interfered with intracellular GSH/GSSG redox equilibrium and combined with PDT treatmentGSH/GSSG is an important regulator of intracellular redox equilibrium and closely related to apoptosis.Interference with this redox equilibrium can induce apoptosis.Studies showed that the concentration of GSH in cancer cells is three orders of magnitude higher than that in normal cells,and the reductivity of GSH can weaken the oxidative damage of ROS and reduce the therapeutic effect of PDT.To address this problem,Zn Pc1 was complexed by coordination interaction?T-Hg-T?between thymine?T?and mercury ion(Hg²⁺)to form nanocomposite drug?ZHNP?.The aggregation of Zn Pc1 induced by coordination process significantly reduced the PDT activity.After cellular uptake,the active group?-SH?on GSH will deprive Hg²⁺from ZHNP,resulting in the decrease of GSH concentration,imbalance of GSH/GSSG homeostasis,and release Zn Pc1 to recover its PDT activity.The studies in vitro showed that Hg²⁺could inhibit cell proliferation by interfering with GSH/GSSG balance.Therefore,GSH/GSSG homeostasis imbalance combined with PDT is a very effective treatment strategy.2.2D-PDA with high efficiency load for Zn Pc2 and PTT/PDT combination treatment systemUltra-thin two-dimensional materials have shown great potential in the application of PTT due to their unique properties,such as good stability,high biological safety,large specific surface area and easy combination with anticancer drug molecules or preparations.Studies showed that PDA contains supramolecular structures with planar orientation.Therefore,we attempted to peel off PDA nanospheres by liquid oxidation and successfully prepared ultrathin 2D-PDA.The photothermal conversion efficiency of 2D-PDA is 27.16%.The preparation of 2D-PDA by oxidative stripping is accompanied by the conversion of hydroxyl and carbonyl groups,which can reduce the scavenging ability of oxygen radicals.The formation of carboxyl group effectively improves the dispersion of PDA in water and facilitates its transmission in blood.The high specific surface area of the 2D-PDA allows it to carry 0.495 mg mg^-1 of Zn Pc2?PZNS?.The results of studies in vitro showed that PTT/PDT combined therapy of PZNS had a much better effect on tumor proliferation inhibition than PTT and PDT alone.3.Thermal-response controlled and release of drugs and PTT/PDT combination treatmentTargeted delivery of drug molecules to the lesion tissues through carriers and controlled release can not only improve the utilization rate of drugs and therapeutic effect,but also reduce the toxic and side effects of drugs.The double-stranded structure of DNA is based on special hydrogen bonding in the rules of base complementation.We combined the surface modified adenine?A?polydopamine nanospheres?A-PDA?with the thymine?T?modified phthalocyanine photosensitizer?Zn Pc1?to form stable nanocomposite drugs?PATP?.Under the near-infrared light irradiation,PATP could achieve high temperature in local tumor tissue,and release Zn Pc1.The photothermal conversion efficiency of A-PDA is 38.40%,which is higher than 2D-PDA.The results in vitro indicated that PTT and PDT all showed inhibition of tumor cell proliferation and growth respectively.Results in vivo also showed that PATP?808+665 nm?had a best tumor growth inhibition effect,which was consistent with the results of cell level studies.In addition,the multi-mode imaging?MRI,FI,TI?functions provide strong support for monitoring the distribution of drug tissues and realizing the integration of diagnosis and treatment.4.Preparation of Janus nanomotor for ROS diffusion and PTT/PDT synergistic systemSinglet oxygen?¹O₂?is the most important ROS for photosensitization agents in PDT.However,its half-life in physiological environment is about 40 ns and the diffusion radius are less than 20 nm,which severely limits the efficacy in PDT.Herein,PDA nanobowls were prepared by bubble template and its polymerization mechanism was investigated systematically.Subsequently,PDA nanobowls were loaded with manganese bromide pentacarbonyl?COMn?and Zn Pc3 to form nanomotor?PCZN?,to expand the range of action of ¹O₂ and enhance the therapeutic activity of PDT.After cellular uptake,H₂O₂ could promote COMn decomposition and release CO,providing a driving force for PCZN.In addition,the oxidation product of COMn catalyzed H₂O₂to generate O₂,which can relieve hypoxia in tumor tissues and provide another driving power for PCZN.The PCZN movement was also observed in the cell sections and in the randomized optical reconstruction microimaging experiments.PCZN showed good PDT activity in both normal oxygen and hypoxic conditions,which indicated that PCZN can relieve hypoxic in tumor tissues.The movement of PCZN expanded the damage range of ¹O₂ and enhanced PDT activity.The studies in vivo showed that PCZN?808+665 nm?had the best effect in tumor growth inhibition.PTT/PDT combination therapy was guided by multi-mode imaging?MRI,FI,TI?.