Stimulus-responsive Nanodrug Loaded With Azo Initiator AIPH For Tumor Therapy

Nowadays,with the intensification of global aging and the rise of mortality,cancer has become one of the major diseases that threaten human health.At present,the main clinical treatments for cancer are surgical resection,chemotherapy and radiotherapy,which not only cause serious damage to normal tissues and cells,but also have poor targeting and specificity,and the prognostic effect is unsatisfactory.Meanwhile,with the rapid development of nanotechnology,nanomaterials mainfest great advantages in tumor diagnosis and treatment,including the ability to retain in the tumor area for a long time by virtue of the high permeability and retention effect（EPR effect）of the solid tumor,the precise control and release of drugs at the tumor site,and the ability to catalyze highly expressed markers（such as hydrogen peroxide and glutathione）with larger specific surface area to change the hypoxic tumor microenvironment（TME）of the tumor.Based on these advantages,sonodynamic therapy（SDT）,photodynamic therapy（PDT）,chemical dynamic therapy（CDT）and thermodynamics therapy（TDT）represented by the production of reactive oxygen species（ROS）,and photothermal therapy（PTT）through using external light energy to convert heat energy have received great attentions,and gradually become the treatment methods that can be carried out in the future.However,a single treatment method can not completely elimate tumor cells,so it has become a research hotspot to develop multifunctional nanoplatforms for combined therapy of SDT,PTT,TDT,CDT and PDT by designing nanomaterials loaded with drugs.The research mainly focused on the inorganic nanomaterials loaded with the thermal decomposition azo initiator AIPH,and constructs the following two multifunctional nanoplatforms.Firstly,a multifunctional nanoplatform based on mesoporous bismuth selenide nanoparticles（Nano-Bi₂Se₃）was designed and constructed for tumor diagnosis and treatment.In short,AIPH was loaded into Nano-Bi₂Se₃ through mesoporous and mineralized manganese-doped calcium phosphide shell（MnCaP）to form BAM（Bi₂Se₃/AIPH@MnCaP）NPs to achieve CDT,PTT,TDT and immunogenic stimulation of tumor therapy.On the one hand,the nanocomposite achieved accurate and specific drug release through acid response,and the photothermal effect could decompose AIPH into alkyl free radicals（·R）.On the other hand,the Fenton-like reaction rate of Mn²⁺caused by acid response was accelerated under photothermal action,which uses highly expressed hydrogen peroxide（H₂O₂）to produce ROS and induce apoptosis.More importantly,tumor cell apoptosis activated anti-tumor immunity through ICD.In addition,the location of the complex could be tracked by computed tomography（CT）,magnetic resonance（MR）,photoacoustic（PA）and infrared imaging（IR）for further treatment.Finally,as a multifunctional nanoplatform,BAM had high biological safety,and the results in vivo and in vitro suggested that the nanocomposite can significantly improve the tumor inhibitory effect.Next,in order to further improve the depth of tumor penetration and therapeutic effect,a nanoplatform based on oxygen-deficient sonosensitizer agent nano-zirconia(ZrO_2-x)was proposed and constructed for tumor diagnosis and treatment.Specifically,ZrO_2-x was synthesized from zirconia（ZrO₂）by reduction method.And nano-Pt was grown on the surface in situ and AIPH was adsorbed by electrostatic force to form Schottky semiconductor nanocomposite ZPA(ZrO_2-x@Pt@BSA/AIPH)NPs to achieve SDT,TDT and immunogenicity-stimulated tumor therapy.The nanocomposite was enriched to the tumor region through the EPR effect.On the one hand,local heating under ultrasound（US）could decompose AIPH and produce·R to cause apoptosis.On the other hand,the loading of nano-Pt could not only decompose the highly expressed H₂O₂ in the tumor site to produceO₂ to alleviate hypoxia TME,but also shorten the electron lifetime and reduce the width of ZrO_2-x band gap to improve effect of SDT and TDT under US to produce a large amount of ROS and induce tumor cell apoptosis.More importantly,apoptosis also activated systemic immune response,and bilateral tumor and lung metastasis experiments had proved that ZPA had a good ability to resist metastasis.Finally,the nanoplatform could not only achieve tumor ablation,but also lay a foundation for future clinical application with high biosafety.