Fabrication Of Tumor Microenvironment-responsive Metal-based Nanosystems Towards Cancer Therapy

Cancer is a serious threat to human health with high morbidity and mortality.Traditional cancer treatment methods,such as surgery,chemotherapy,and radiotherapy,suffer from serious side effects and poor targeting specificity.The development of modern nanotechnology,optics,medicine and biology has provided new ideas for cancer therapy.The rational design of functional materials and their application in tumor treatment mediated by chemodynamic therapy（CDT）,photodynamic therapy（PDT）,photothermal therapy（PTT）,sonodynamic therapy（SDT）,and enzyme catalytic therapy,etc.,will be possible to break through the current barriers to cancer therapy.However,it is still difficult to achieve complete tumor ablation with a single treatment modality.Therefore,the development of synergistic therrapy with two or more treatment modality has become a current research hotspot.Layered double hydroxide（LDH）has been widely studied in the field of biomedicine due to its adjustable host layer metal cation,large specific surface area,and good biosafety.In this paper,Co Fe Ce-LDH（CFC-LDH）was prepared by a“bottom-up”method,and then the photosensitizer indocyanine green（ICG）was loaded on its surface.The therapeutic capacity of ICG/Co Fe Ce-LDH（ICG/CFC-LDH）was explored through performance tests as well as cell experiments.After that,Mg Cu Fe-LDH was also prepared by the“bottom-up”method.After vulcanization by thioacetamide（TAA）the resulting Mg Cu Fe-S（MCFS）possesses NIR-II photothermal therapy capability.To solve the problem of bone defects caused by surgical resection of osteosarcoma,we combined MCFS with a 3D printed bioactive glass（BG）scaffold by impregnation method,and the obtained BG/MCFS scaffold was used for the treatment of osteosarcoma,antibacterial and osteogenesis,which showed good therapeutic effect.The research contents of this paper are as follows:1、Preparation of ICG/Co Fe Ce-LDH with the ability of glutathione（GSH）depletion for CDT/PTT synergistic therapy.We prepared Co Fe Ce-LDH nanosheets（CFC-LDH）by a“bottom-up”method,and further loaded with photosensitizer indocyanine green（ICG）to obtain ICG/CFC-LDH nanoplatform,which can achieve CDT/PTT synergistic therapy and has the following therapeutic advantages:（1）The metal cations in host layer exhibit efficient Fenton/Fenton-like reactivity,and the maximum rate of reaction with hydrogen peroxide（H₂O₂）is V_max=7.41×10^-8 M s^-1,with a low Michaelis–Menten constant K_M=0.341,indicating that LDH has a good affinity for H₂O₂ and a high chemical reaction rate;（2）Fe³⁺and Ce⁴⁺can eliminate overexpressed GSH in tumor cells,reducing the consumption of·OH by GSH;the resulting Fe²⁺and Ce³⁺is beneficial to promote CDT performance;（3）To further enhance CDT performance and tumor treatment effect,taking advantage of the positive charge and large specific surface area ofthe LDH layer,the photosensitizer ICG is combined with CFC-LDH through electrostatic interaction,so that the nanoplatform has a PTT/CDT synergistic therapeutic effect.We further investigated the CDT/PTT synergistic therapeutic effect of the ICG/CFC-LDH nanoplatform by 4T1 cells.2、Preparation of metal sulfide/bioactive glass scaffolds for osteosarcoma treatment and bone repairBased on the adjustable properties of metal elements in LDH layers,we introduced Mg ions that can promote osteogenic differentiation,and Cu/Fe ions into the layer to prepare Mg Cu Fe-LDH.The LDH was further sulfided using thioacetamide（TAA）as a sulfur source to obtain Mg Cu Fe-S（MCFS）.Based on the reduction of the LDH band gap after vulcanization,the resulting MCFS has good absorption and photothermal conversion capabilities in NIR-II.In order to solve the problem of bone defects caused by bone tumor treatment,we rationally integrated the MCFS and 3D printed bioactive glass（BG）scaffolds by impregnation method to construct a BG/MCFS composite scaffold,which can achieve osteosarcoma treatment and antibacterial infection mediated by PTT as well as bone repair.This multifunctional 3D composite scaffold has promising application prospects in anti-tumor and bone repair.In summary,this thesis firstly prepared Co Fe Ce-LDH with abundant Fenton/Fenton-like reactive sites,and further loaded with photosensitizer ICG to achieve efficient CDT/PTT synergistic therapy in response to the tumor microenvironment.In addition,the high-valent metals between the LDH layers can also eliminate the overexpressed GSH in tumor cells and enhance the CDT effect.Afterwards,MCFS with NIR-II photothermal conversion capabilities was prepared and integrated with the 3D printed bioactive glass scaffold（BG）by impregnation method.The prepared BG/MCFS not only possess PTT effect to kill cancer cells and bacteria,but also can promote bone repair due to the presence of Mg ions.These research results have an important guiding role for the construction of nano-drugs for cancer treatment.