Detection And Treatment Of Orthotopic Bone Tumor And Lymphatic Metastasis By Protein-biomimetic Nanomedicines

Malignant tumors are diseases that seriously endanger human health.The World Health Organization（WHO）statistics show that its incidence is increasing,and it is predicted that the number of deaths worldwide will reach 13.1 million in 2030.Therefore,tumors have become a serious problem in global human health in the 21st century.How to achieve highly sensitive and high-resolution tumor imaging diagnosis to provide effective information is a major problem in cancer treatment.Due to its unique size and physicochemical properties,nanomaterials have great potential for imaging and treatment of cancer.On the one hand,many nanomaterials have optical,magnetic,acoustic and other physical properties that can be used for biomedical imaging.On the other hand,nanomaterials are widely used as drug carriers to achieve passive targeting and active targeting in tumor areas,increasing local concentration of drugs in tumor sites and reducing distribution in other organs,thereby enhancing chemotherapy efficacy.At the same time,some special physical properties of nanomaterials,such as light absorption,electromagnetic wave absorption and superparamagnetism,can also be used as new cancer therapies platforms,including photothermal therapy,electromagnetic wave therapy,and magnetothermal therapy.These novel theranostics have also shown good application prospects in animal experiments and clinical studies in recent years.This thesis focuses on the efficient and accurate diagnosis and treatment of tumors.We use protein biomimetic mineralization or assembly strategy to construct protein biomimetic nanomedicines,and explore tumor-targeted imaging,lymphatic metastasis monitoring and living body distribution analysis of protein biomimetic nanomedicines.The main contents of this paper are as follows:Part Ⅰ:We developed multimodal imaging of orthotopic bone tumors and their lymphatic metastasis based on ^99mTc and near-infrared dye-labeled serum protein biomimetic Gd₂O₃ nanoprobes.Using chemical covalent coupling and coordination methods,near-infrared Cypate and radioactive ^99mTc were labeled on the surface of albumin-stabilized Gd₂O₃ nanoparticles to construct a set of multimodal nanoprobes with MRI,near-infrared fluorescence and single photon emission computed tomography（SPECT）.For in situ osteosarcoma and metastatic lymph nodes model,multimodal imaging provides accurate localization information of tumors and sentinel lymph nodes.Part Ⅱ:We developed in vivo photoacoustic/single photon emission computed tomography dynamic monitoring method for aggregated enhanced protein biomimetic photothermal nanomedicines.The integrated diagnosis and treatment function of nanoagents has potential application value in the image navigation to achieve accurate treatment.Understanding the dynamic processes of the diagnostic agents,including absorption,distribution,metabolism,and clearance,is important to optimize the design strategy of nanomedicines and treatment plans.The self-assembly strategy of silk fibroin induced by hydrophobic near-infrared fluorescent cypate was used to construct a nanoagent,which significantly improved the chemical stability and biosafety of dyes.After labeling the radionuclide ^99mTc on the surface of the nanoagent,we used SPECT and three-dimensional photoacoustic imaging technology to study the dynamic processes of the absorption,distribution,metabolism and removal of the nanoagent.Due to the highly aggregated state of cypate,its near-infrared fluorescence was quenched,and the nanomedicine exhibits stronger near-infrared light absorption efficiency and higher photothermal conversion efficiency than free dye,and thus has more sensitive photoacoustic imaging performance.This study is instructive for the non-invasive visualization of nanomedicine in vivo distribution and metabolic behavior,tumor targeting performance and treatment planning.