Design Of Responsive Multifunctional Nanoparticles And Their Application In Biomedical Diagnosis And Treatment

In the last few decades,nanotechnology is an emerging scientific field,and the achieved results have strongly promoted the innovative design and synthesis of nanoparticles.By changing the structure,scale,shape and composition of nanoparticles,they can be endowed with abundant specific properties.In practical applications,researchers have combined stimulus-response factors with nanoparticles to prepare a variety of intelligent responsive nanoparticles.The relevant internal microenvironmental stimuli and external stimuli are also diverse.According to the type of stimulus,it can be divided into p H,temperature,light,electric field,magnetic fiel,sound,REDOX,enzyme and other biomolecular,gas and other responsive nanoparticles.Smart nanoparticles that respond specifically to various physical and chemical stimuli have a wide range of applications in catalysis,optoelectronic devices,marker detection,environmental protection,energy generation/storage,biomedicine,etc.Especially in biomedicine,the nanoscale size makes responsive nanoparticles penetrable and diffusible,which is conducive to non-invasive uptake in the body.Multifunctional groups make them easy to modify and functionalize with arrestability,responsiveness and specificity.Advanced research results have been achieved in the diagnosis and detection of diseases,drug delivery systems,new biological medicine and other specific applications.In response to changes in the microenvironment of diseases in vivo,the introduction of new,multiple and personalized responsive nanoparticles to internal signals will help play a more intelligent and significant role,which has important significance and application prospects.In this paper,the design and preparation of responsive multifunctional nanoparticles are the main line,and the functions of biomedical imaging,detection and treatment are the targets.According to the treatment needs of different diseases and the application environment in vivo,intelligent responsive nanoparticles are designed to study their practical application potential and scientific significance in solving important medical problems such as tumor diagnosis and treatment.Firstly,gold nanocluster probe Au-GSH with photo-responsive fluorescence imaging was prepared for high stability geoneural imaging.Au-GSH prepared by electrochemical etching has uniform size and advanced fluorescent photophysical properties,meeting several stringent criteria for fluorescent probes in the field of neuroscience,including good water solubility,significant signal background ratio,photobleaching resistance and high biocompatibility.Compared with other probes such as traditional fluorescent proteins,quantum dots and organic fluorescent dyes,Au-GSH is more suitable for long-term in vivo responsive fluorescence imaging and tracing of nerve tissue.The gold nanocluster exhibits bright red fluorescence,avoiding the interference blue fluorescence of autologous tissue,while label and trace the nerve as well as brain tissues fluorescently in vivo,visualizing the location of the nerve,and avoiding nerve damage during surgery.Secondly,an antigen-responsive gold nanocluster-antibody probe Au-TTF-1 was designed for targeted recognition,multimodal imaging and integrated diagnosis as well as treatment of lung adenocarcinoma.Lung adenocarcinoma is the cancer with the highest mortality and morbidity,so early detection and treatment is of great significance.The antigen-responsive probe was constructed by gold nanoclusters coupling with TTF-1,a specific recognition antibody for lung adenocarcinoma.The probe has excellent fluorescence properties,and the target properties of lung adenocarcinoma reaches70.1%,which is 3 times that of normal cells.Machine learning software was further used to design an image analysis system for the auxiliary detection of lung adenocarcinoma.After deep learning,lung adenocarcinoma cells could be intelligently distinguished from normal cells.In vivo experimental results showed that Au-TTF-1not only illuminated tumor boundaries within 0.5 h by fluorescence visualization targeting lung adenocarcinoma,but also guided and implemented subsequent noninvasive photothermal therapy through multi-mode imaging,and locally ablated tumors in vivo.This probe Au-TTF-1 actively target lung adenocarcinoma through antigenresponsive imaging and treatment,and has important application value in the integration of tumor diagnosis and treatment.Thirdly,we designed and prepared near-infrared light NIR/ p H-responsive gold nanocluster hydrogel composite by functional modification of surface groups,so as to realize the synergistic treatment of chemotherapy and photothermal for osteosarcoma.In order to solve the problem that conventional treatments against osteosarcoma usually cause bone matrix damage,inspired by lotus seedpod,we constructed a gold cluster-hydrogel composite material,and injected it into the lesion of osteosarcoma to achieve local responsive drug release,which obtain the synergistic therapeutic effect of chemotherapy and photothermal therapy.On the one hand,as the lotus see,the gold nanocluster provides enhanced,durable and reproducible photothermal therapeutic ability and fluorescence/CT multi-mode imaging function.On the other hand,the modified gold nanoclusters form injectable hydrogel composites with natural polymer segments through dynamic covalent bonds.The obtained flexible scaffold structure similar to lotus seedpod,which can intelligently load and release the chemotherapy drug doxorubicin.The acidic p H microenvironment of osteosarcoma promotes the degradation of dynamic covalent bonds to release doxorubicin,and the temperature rise caused by photothermal accelerated the continuous release of doxorubicin.This kind of gold nanocluster hydrogel composite material not only significantly reduces the systemic toxicity of chemotherapy drugs,but also effectively ablates osteosarcoma,opening up a new way of deep tumor treatment.Finally,X-ray responsive diselenium-linked mesoporous silica nanoparticles(MSN)containing photosensitizer acridine orange(AO)were designed and prepared for radiodynamic therapy against cervical cancer.Radiation resistance is easy to be caused by radiotherapy for in-depth tumors such as cervical cancer,in view of the medical problem,MSN were designed and constructe to loadedradiotherapy photosensitizer acridine orange(AO).Due to the high specific surface area and pore space of MSN,a high AO coating rate of 83.2% was obtained.Under the condition of X-ray radiation and high hydrogen peroxide concentration in the tumor microenvironment,the diselenide bond fracture caused the degradation of MSN microspheres and released AO in the tumor site,with a release rate of 85%.In particular,the photosensitizer AO can be activated under the action of low dose X-ray,which exerts the characteristics of radiotherapy sensitization and radiotherapy dynamic therapy.By producing ROS,MSN reduces the proliferative activity of cervical cancer cells,inhibit DNA damage repair,damage mitochondria and promote apoptosis of cancer cells.The results show that the tumor can be ablated at a lower radiation dose,and the problem of radiation resistance of cervical cancer can be solved.On the one hand,the design of MSN@AO solves the problems of rapid drug clearance,poor distribution and side effects caused by AO.On the other hand,the advantages of X-ray are fully utilized to achieve the purpose of tumor ablation by intelligently responsive drug release,radiotherapy sensitization and radiotherapy dynamic therapy at low radiation dose.This multifunctional nanoparticle will have excellent application prospects in the treatment of in-depth cancer tissues such as cervical cancer.