Construction Of Multifunctional Gold-based Nanomaterials And The Application In Tumor Diagnosis And Treatment

As one of the most serious public health problems in the world,cancer has greatly threatened the health of people all over the world.Traditional treatments often produce serious side effects and unsatisfactory results.With the development of nanotechnology,metal nanomaterials,as a new type of biomaterials,are being widely studied and applied.Among metal nanomaterials,gold-based nanomaterials have been rapidly developed in the field of biomedicine,especially in the tumor diagnosis and treatment due to their unique morphological structure,excellent physical and chemical properties,biocompatibility and stability.The development of gold-based nanomaterials has broad application prospects and practical significance.In this dissertation,the design and preparation of gold-based nanomaterials are the main line,and the integration diagnosis and treatment of tumors are the targets.According to the diagnosis and treatment needs of different types of tumors,gold-based nanomaterials with different functions are designed to explore their application potential in significant medical problems such as tumor diagnosis and treatment,and finally realize the integrated diagnosis and treatment strategy for tumors.First,to realize real-time image-guided treatment process and improve the radiotherapy（RT）efficacy,the Au/Ag nanodots（Au/Ag NDs）with dual-mode imaging and radiosensitization function were constructed as a"pilot light"to real-time guide surgery,enhanced RT,and brachytherapy of cervical cancer,realizing the treatment strategy of"three birds with one stone".The doping of Ag not only improves the fluorescence（FL）imaging effect but also enhances the RT efficacy.Au/Ag NDs achieve high efficiency radiosensitization by increasing ionizing radiation energy deposition,promoting reactive oxygen species（ROS）generation,reducing mitochondrial membrane potential,inducing cell G₂/M phase arrest,promoting DNA damage,and inhibiting DNA damage repair of tumor cells.In addition,Au/Ag NDs have excellent FL and computed tomography（CT）dual-mode imaging effect,enabling real-time image-guided surgical resection,RT and brachytherapy.It solves the problems caused by the imprecise tumor location,such as positive surgical margins,extended RT target volumes,and radiation damage to healthy tissues.Secondly,target recognition is important for diagnosis and treatment.The multifunctional nano-system（AMNDs-LHRH）with targeted recognition,multi-mode imaging,and photothermal therapy（PTT）functions was constructed for the integration diagnosis and treatment of metastatic prostate cancer（PCa）.To solve the problem of diagnosis and treatment of metastatic PCa,we introduced Mn on the basis of gold nanodots（Au NDs）and synthesized Au/Mn nanodots（AMNDs）by electrochemical exchange method.The AMNDs could not only enable FL/CT imaging,but also have magnetic resonance imaging function.Further,the AMNDs-LHRH nano-system was obtained by linking AMNDs with Luteinizing Hormone-Releasing Hormone（LHRH）,a PCa-specific recognition antibody.The nano-system has great targeting and multi-mode imaging performance,which is expected to achieve accurate detection and real-time intraoperative navigation of PCa and its metastases.In addition,the nano-system has excellent targeted PTT capability and can effectively treat metastatic PCa.The multifunctional nano-system integrating tumor targeting,multi-mode imaging and PTT is expected to provide an effective strategy for the clinical diagnosis and treatment of metastatic PCa.Afterwards,the combination of multiple modes of tumor cell death would improve the therapeutic effect.The multifunctional Au/Cu nanodots（Au/Cu NDs）were constructed for dual-mode imaging,amplifying ROS generation and inducing apoptosis-ferroptosis to sensitize RT of breast cancer.To solve the problems such as imprecise tumor location,insufficient ROS production and poor efficacy during RT,we introduced Cu on the basis of Au NDs to move the wavelength of fluorescence emission from the visible region to the second near-infrared window and to promote ROS production at the same time.A large amount of ROS is derived from three aspects:（1）When Au/Cu NDs are exposed to ionizing radiation,they can effectively absorb photons and emit various electrons,which can interact with H₂O to produce ROS.（2）Au/Cu NDs act as a catalase-like to produce abundant ROS through Fenton-like reaction with hydrogen peroxide overexpressed of tumor cells.（3）Au/Cu NDs deplete overexpressed glutathione,which causes the accumulation of ROS.Large amounts of ROS and ionizing radiation further lead to apoptosis by increasing DNA damage,and ferroptosis by enhancing lipid peroxidation,significantly improving the therapeutic efficiency of RT.Furthermore,Au/Cu NDs serve as an excellent nanoprobe for high-resolution near-infrared FL/CT imaging of tumors.By combining the two imaging modes,it is possible to accurately locate the tumor during treatment,avoid damage to normal tissue,and achieve image-guided precision RT.Finally,immunotherapy is an important breakthrough to improve the cancer treatment.The"in situ nanovaccine"with dual immunomodulatory effects was constructed to enhance immunotherapy of primary and metastatic triple-negative breast cancer（TNBC）.TNBC is highly aggressive and prone to metastasis,resulting in an increasing recurrence and mortality rates.As a“cold tumor”,TNBC exhibits limited responsiveness to current immunotherapy.To enhance the immunogenicity and reverse the immunosuppressive microenvironment of TNBC,the“in situ nanovaccine”（Au/Cu NDs-R848）was prepared to enhance the immunotherapy of TNBC.On the one hand,Au/Cu NDs-R848-mediated PTT and photothermal-enhanced chemodynamic therapy inhibited the progression of primary tumors.Meanwhile,the released antigens and damage-associated molecular patterns（DAMPs）promoted the maturation of dendritic cells（DCs）and facilitated the infiltration of T lymphocytes.Thus,Au/Cu NDs-R848 played a role as an“in situ nanovaccine”to improve the immunogenicity of TNBC by inducing immunogenic cell death（ICD）.On the other hand,the nanovaccine suppressed the myeloid‐derived suppressor cells（MDSCs）,thereby reversing the immunosuppressive microenvironment.Through the dual immunoregulation,“cold tumor”was transformed into a“hot tumor”,not only implementing a“turning foes to friends”therapeutic strategy but also enhancing immunotherapy against primary and metastatic TNBC.Furthermore,Au/Cu NDs-R848 acted as an excellent nanoprobe,enabling high-resolution near-infrared FL/CT imaging for precise visualization of TNBC.This feature offers potential applications in clinical cancer detection and surgical guidance.Collectively,this work provides an effective strategy for enhancing immune response and offers novel insights into the potential clinical applications for tumor immunotherapy.