| Cancer,as one of the most significant diseases worldwide,severely threatens human health and social development.Photo-induced imaging and therapy based on photosensitizers have attracted widespread attention in the field of cancer diagnosis and treatment due to their characteristics of remarkable spatiotemporal precision,high efficiency and non-invasiveness.However,most reported photosensitizers are"always on"probes with short-wavelength excitation,making them incapable of achieving deep-seated and specific diagnosis and treatment of tumors.Additionally,individual photosensitizers typically suffer from poor tumor targeting,unsatisfied biocompatibility and severe side effects,which in turn affect their effectiveness in clinical applications.Therefore,this thesis aims to develop a novel near-infrared reversibly activated photosensitizer-based tumor-responsive theranostic nanocapsule for tumor-specific imaging-guided precision photothermal/photodynamic therapy.The main results are as follows:A novel pH reversibly responsive near-infrared fluorescence/photothermal/photodynamic-in-one photosensitizer（BAC808）was designed and synthesized through conjugate regulation.The prepared BAC808 presented a p Ka（5.75）and p H-sensitive range（4.0-7.5）that were well-matched with the acidic tumor microenvironment.Under acidic conditions,the activated BAC808 had the largest absorption peak at 808 nm and exhibited superior near-infrared fluorescence emission,photothermal conversion efficiency（42.68%）and singlet oxygen quantum yield（ΦΔ=0.10）.In contrast,BAC808 did not possess these properties under normal physiological conditions,reducing non-specific damage to normal cells.The p H-reversible activation characteristic of BAC808 laid the foundation for the construction of tumor acidic microenvironment-triggered specific theranostic nanoplatform.The tumor microenvironment p H/glutathione（GSH）-responsive photo-induced theranostic nanoplatform（DMMA@c RGD@BAC808）was constructed by co-precipitation of BAC808 with functionalized polyethylene glycols（DSPE-PEG-S-S-PEG-DMMA and DSPE-PEG-c RGD）modified with charge reversal moiety 2,3-dimethylmaleic anhydride（DMMA）and tumor-targeting ligand cyclic arginine-glycine-aspartic（c RGD）peptide,respectively.The synthesized nanocapsule exhibited a uniform spherical structure with good monodispersity and stability with the particle size of 131.0±8.9 nm.Compared to BAC808,the DMMA@c RGD@BAC808 nanocapsule retained its p H-reversible activation characteristics and desirable optical,photothermal and photodynamic properties.The zeta potential of the nanocapsule was-10.47±0.89 m V under normal physiological conditions,while it changed to2.17±0.44 m V under acidic conditions,successfully achieving the charge reversal.In the presence of GSH overexpressed in the tumor microenvironment,its zeta potential changed to-6.24±0.57 m V and the hydrodynamic size decreased by approximately 21.8 nm,accompanied by the disappearance of the typical infrared stretching vibration bank of DMMA at 1704 cm-1,demonstrating that the disulfide bond of DSPE-PEG-S-S-PEG-DMMA was cleaved in the presence of GSH subsequently leading to the exposure of c RGD.The above results validated that the prepared nanocapsule possessed p H/GSH dual-responsive smart targeting properties of charge reversal and stealth,which provided a basis for subsequent tumor microenvironment-responsive intelligent targeting imaging and efficient photothermal/photodynamic therapy.The tumor-responsive nanocapsule DMMA@c RGD@BAC808 successfully achieved specific near-infrared fluorescence imaging-guided precision photothermal/photodynamic synergistic therapy.Compared to BAC808,the constructed nanocapsule exhibited superior biocompatibility.In vivo imaging results showed that after tail vein injection,the near-infrared fluorescence denoted by the nanocapsule was detected only at the tumor sites and reached the maximum at 10 h.This demonstrated that the nanocapsule possessed both extended circulation time,excellent tumor targeting and prominent specificity.Guided by the precision imaging,the short-term and low-power density of 808 nm laser irradiation(0.6 W cm-2,5 min)was treated and successfully achieved efficient photothermal/photodynamic synergic therapy.The above research presented an innovative strategy and method for developing the clinical theranostic nanomedicines. |
