Tumor Microenvironment Responsive Porphyrin-Metal Coordination Polymers Nanoparticles: Synthesis And Their Application In Tumor Thersnostics

Cancer is a huge threat to human health and life.The number of deaths due to cancer each year is increasing year by year.Therefore,there is an urgent need to find an efficient and low-cost cancer treatment plan.Some traditional cancer treatment methods,such as chemotherapy,surgical resection,and radiotherapy,have been widely used clinically,but these therapies also have some shortcomings.For example,it is difficult to completely treat metastatic tumors,it is impossible to specifically identify and kill cancer cells.In order to overcome some of the limitations of the above methods,phototherapy and chemodynamic therapy（CDT）have been extensively studied due to their unique advantages over traditional treatment options.Phototherapy methods are divided into PTT and PDT,which are new and effective methods for the treatment of cancer.PDT is a laser-assisted non-invasive treatment that uses light to activate the photosensitive molecules（PS）enriched in the tumor site.Photosensitive molecules convert oxygen into singlet oxygen（¹O2）with high cytotoxicity to trigger apoptosis and necrosis of cancer cells.CDT uses Fe^2+/3+,Cu⁺,Mn²⁺and other metal ions mediated Fenton reaction to induce intracellular oxidative stress and induce cell apoptosis by converting the less reactive H2O2 into the most harmful hydroxyl radicals（·OH）.However,PDT and CDT still have certain limitations.For example,the penetration depth of light is insufficient,and the photosensitizer is easy to aggregate;a single Fenton has low reaction efficiency and a single treatment effect is poor.Coordination polymers are porous hybrids constructed by bridging metal-based nodes（metal ions or clusters）with organic linkers（organic ligands）.It has the characteristics of strong design,high specific surface area,and good stability.It is widely used in the fields of bioimaging and biomedicine.In recent years,in the field of biomedicine,the tumor microenvironment has been extensively studied by scientific researchers due to its high expression of glutathione（GSH）,high concentration of H2O2,low oxygen,and low p H.As a promising carrier,metal-organic nano-coordination polymers can be used for drug loading and slow drug release,optical therapy and chemodynamic therapy,and they have also caused extensive research.In this paper,using photosensitizer-integrated metal organic coordination polymer,using the characteristics of tumor microenvironment（TME）,combined therapy to kill cancer cells,effectively overcoming the shortcomings of single treatment efficiency and tumor hypoxia.Mainly launched the following work:1.In this paper,a one-pot method is used to prepare a metal organic nanoparticle FT@HA based on the integration of photosensitizers.Taking into account the oxidation and contrast effect of Fe element,Fe（III）is selected as the metal node,and it can react with reduced glutathione（GSH）in the cell to generate glutathione disulfide bond（GSSG）.In addition,using coordination interactions,Fe-TCPP nanocomposites are further coated with hyaluronic acid（HA）（called FT@HA）,which greatly improves the biocompatibility,physiological stability and Targeting.FT@HA nanoparticles can respond to the tumor microenvironment,thereby activating Fe（III）-based magnetic resonance imaging（MRI）and TCPP-based optical imaging.Therefore,in vivo and in vitro experimental studies have shown that the combined treatment of GSH-controlled ROS generation and GSH depletion at the tumor site can achieve comprehensive tumor suppression.2.In this paper,calcium ions are doped on the basis of the previous work to stabilize the structure of Fe（III）-TCPP nano coordination polymer and therapeutic agents,and prepare calcium ion-doped metal organic nanoparticles（CFT）.CFT@FA was obtained by modifying PEG-FA on its surface,which enhanced its biocompatibility and targeting ability.In TME,CFT disintegrate and releases TCPP,which produces ¹O2 under the excitation of the light source,thereby causing mitochondrial dysfunction,destroying the Ca²⁺buffering capacity of mitochondrial cells,and activating its imaging ability.The released Ca²⁺can inhibit mitochondrial cell respiration,thereby inhibiting the consumption of oxygen in the cell,alleviating the hypoxic microenvironment,and promoting the enhancement of PDT.At the same time,the production of Ca²⁺can lead to the up-regulation of cytochrome and Caspase-3 and the down-regulation of ATP and Bcl-2,thereby inducing cell apoptosis.In vitro cancer cell toxicity test,the material has a strong killing effect on cancer cells,but has no obvious toxic side effects on normal cells.The research shows that CFT@FA,as a TME-responsive,dual-modal imaging-guided combination therapy strategy that cooperates with Ca²⁺homeostasis imbalance to enhance PDT,shows great potential in tumor treatment.