Construction Of Responsive Nanotheranostic Platforms And Their Application In Tumor And Brain Diseases

The nanotheranostic platform constructed by nanomaterials has attracted extensive attention in the theranostics of diseases.However,in practical application,most platforms suffer from significant toxic side effects,low treatment efficiency,and poor imaging signal-to-noise ratio.The responsive nanotheranostic platforms can specific responses to internal/exogenous stimuli,especially the pathological characteristics of the disease（endogenous stimuli）.While,activating the diagnostic and therapeutic functions,provides a new idea for personalized and precise theranostics.Herein,this thesis took tumor and Alzheimer’s disease as the research objects and constructed a series of well-designed integrated nanotheranostic platforms that can respond to the pathological characteristics of tumor or Alzheimer’s disease.The preparation method,specific response,and application in the above diseases were studied.A biocompatible H₂O₂self-supplying nanotheranostic platform（CaO₂-Fe₃O4@HA NPs）was constructed that can respond to tumor acidic environment.The hyaluronic acid（HA）stabilized CaO₂was synthesized firstly,then conjugated with ultra-small Fe₃O₄to afford CaO₂-Fe₃O₄@HA NPs.The CaO₂-Fe₃O₄@HA NPs can actively target the tumor and are internalized by CD44overexpressed cancer cells.In the acidic tumor microenvironment,CaO₂-Fe₃O₄@HA NPs gradually decomposes and release a large amount of H₂O₂.Catalyzed by Fe₃O₄NPs,the generated H₂O₂was further converted to highly reactive·OH,thus inducing programmed death of cancer cells.At the same time,the paramagnetic of Fe₃O₄make the treatment process can be real-time monitored by MRI.In vivo and in vitro results demonstrated that CaO₂-Fe₃O₄@HA NPs can effectively improve the chemodynamic therapy efficiency and exhibit good biocompatibility and biosafety,which provides a new idea for the construction of efficient chemodynamic therapy nanoplatform（In Chapter 2）.A nanotheranostic platform that can respond to tumor microenvironment was constructed to realize multimodal diagnosis and treatment（chemodynamic therapy（CDT）,photothermal therapy（PTT）,and photoacoustic imaging）.Specifically,the Zn S quantum dots and ultra-small Cu₂O nanoparticles were encapsulated in ZIF-8through a one-step method to obtain the nanotheranostic platform（Zn S/Cu₂O@ZIF-8@PVP）.In the acidic tumor microenvironment,the nanoplatform was gradually decomposed and released Zn S QDS and Cu⁺,which could initiate the cation exchange reaction and generate Cu₂S.The generated Cu₂S can be used for photothermal therapy（PTT）and photoacoustic（PA）imaging of tumors.The remaining Cu⁺can also catalyze the overexpressed H₂O₂in the tumor microenvironment to strong oxidizing·OH for CDT.In vivo and in vitro results demonstrated that the Zn S/Cu₂O@ZIF-8@PVP nanotheranostics platform can be specifically activated by the tumor microenvironment and realize the PA imaging-guided PTT/CDT synergistic therapy,which provides a new approach for multi-modal precision theranostics of tumors（In Chapter 3）.A copper ion responsive diagnostic platform with potential therapeutic effects for Alzheimer’s disease was designed.The nanoprobe applies the spontaneous cation exchange reaction between ZnSe and copper ions to realize the rapid transformation from ZnSe to Cu Se.There were no obvious photoacoustic signals for ZnSe,while it was strong for Cu Se.The Cu ions can be quantitatively detected according to the PA intensity change before and after the cation exchange reaction.Theoretical calculation and experimental results show that the morphology of ZnSe has a significant influence on the PA performance of Cu Se.Compared to nanodots and nanoparticles,the ultrathin ZnSe nanoplatelets exhibit the highest sensitivity for copper ions.The proposed inorganic nanoprobe provides a new strategy for the design of PA probes（In Chapter 4）.After tethering with a BBB targeting peptide ligand,the ZnSe nanoprobe can efficiently transport across BBB and rapid exchange with endogenous copper ions,enabling activatable boosting PA imaging for dynamically tracking copper levels in the mice brain.In addition,the cation exchange reaction between ultrathin ZnSe nanoplatelets and copper ions can also reduce the oxidative stress level of neurons,and protect neurons from apoptosis.The ZnSe nanoprobe based on in situ cation exchange reactions provides a new paradigm for activatable PA imaging of copper levels in the mice brain（In Chapter 5）.