Fullerene-hyaluronic Acid Nanogels With AIEgen Feature As Targeted Delivery Of TPZ For Combined Photodynamic And Hypoxia-activated Therapy

As a new type of cancer treatment,photodynamic therapy（PDT）has the advantages of small trauma,high selectivity and low toxicity.However,the hydrophobicity of photosensitizer and tumor hypoxia limit its development.In order to optimize the therapeutic effect of PDT.It’s significant to develop novel multifunctional nano drug-loading systems with target,stimulus response,and real-time tracking functions to improve the water solubility of photosensitizer,then break through the limitations of tumor hypoxia by combining the treatment of hypoxia-activated bioreductive therapy（BRT）with PDT,acheive the high-efficiency PDT treatment.The research of multifunctional nano drug-loading systems will promote the development and clinical application of chemotherapy.Based on this,this paper aims to design a multi-functional nanogel drug delivery system to deliver hypoxia-activated prodrug（TPZ）and achieve efficient treatment.Firstly,the hydrophobic photosensitizer fullerene（C60）was modified by targeting molecule HA to construct a photodynamic skeleton with good water solubility targeting HA-C60.Then,the aggregation-induced emission（AIE）molecule TPENH₂with terminal free amino group was modified on the HA-C60 skeleton to form the HA-C60/TPENH₂amphiphilic complex by forming an amide bond.Furthermore,the TPZ and HA-C60/TPENH₂complex was self-assembled by ultrasound in an aqueous solution to form the drug-loaded HA-C60/TPENH₂nanohydrogel.For the first time,the nanogel loaded a hypoxia-activated prodrug（TPZ）onto HA-C60/TPENH₂nanocarrier to acheive high-efficiency treatment by real-time tracking,targeted recognition of PDT and hypoxia-activated bioreduction combined.The main research contents are as follows:1.Preparation and characterization of HA-C60/TPENH₂compound.HA-C60/TPENH₂nanogels were characterized and analyzed by SEM,TEM and DLS,and the results showed that they were spherical particles with a particle size of about 100 nm,with good dispersion and uniform particle size in aqueous solution.2.The drug loading rateand and drug release behavior under different p H stimulation of TPZ-loaded HA-C60/TPENH₂nanogel were studied.Studies have shown that the drug loading rate of nanogel is about 29.1%.At p H=5.6,the drug release rate is higher than that at p H=7.Nanogels have good drug loading capacity and can stimulate the release of drugs in the acidic tumor microenvironment.3.The cytotoxicity of HA-C60/TPENH₂nanogels was studied by MTT colorimetry.Research shows that nanogels have low material toxicity and dark toxicity.The TPZ-loaded HA-C60/TPENH₂nanogels under laser conditions have obvious cytotoxicity,and the effective treatment is realized due to the synergistic effect of PDT and hypoxia-activated BRT.4.HA-C60/TPENH₂nanogels without any staining under fluorescence microscope have bright fluorescence,realizing the real-time imaging tracking of HA-C60/TPENH₂nanogels.In summary,we have constructed a stimulation-responsive fluorescent nanogel drug delivery system,HA-C60/TPENH₂,which targeted delivery the hypoxia-activated predrug TPZ for the collaborative treatment of PDT and BRT,and is expected to be applied in the treatment of tumor cells.