A Glycol-targeting Hollow MnO₂ Drug Delivery System With An Ultrahigh Loading Capacity For Tumor Phototherapy

Nano drug delivery systems which integrate the tumor-targeting ability,ultrahigh drug loading capacity,photothermal therapy（PTT）,and photodynamic therapy（PDT）have great potential to improve the efficacy,safety,and accuracy of cancer treatment.However,in view of integrating targeting specificity and biocompatibility of nanosystems,there remains a huge challenge for the construction of multifunctional nanosystems for highly efficient cancer therapy.Therefore,glucosamine pillar[5]arene（NP5）modified hollow manganese dioxide（HM）was prepared to load aza-BODIPY derivative（Bod）with photothermal and photodynamic properties for precise and efficient phototherapy.HM can not only be applied as nanocarrier,but also consume GSH in cancer cells,reducing the reduction of reactive oxygen species（ROS）to enhance the therapeutic effect of PDT.The main research contents are as follows:（1）Synthesis of compounds and self-aggregation behavior of Bod:NP5 was synthesized via click reaction between azido group and alkyne functional group.Through the modification for hydrophobic photosensitizer BODIPY,the water soluble small molecule（Bod）possessing photodynamic and photothermal properties was synthesized.In addition,the self-aggregation behavior of Bod in water was observed,and the particle size,zeta potential,and morphology of Bod aggregate（Bod NPs）were characterized by DLS,UV-Vis,and TEM.（2）Preparation and characterization of SHMPB6:Through electrostatic interaction between HM and NP5,the inorganic nanocarrier（HMP）with cancer-targeting ability was constructed,which was then used to load Bod.Three kinds of nanoparticles（MHMPB6,SHMPB6,and SHMPB8）were prepared using different preparation methods and proportions,respectively.SHMPB6 was determined for further experiments.DLS,UV-Vis,and TEM experiments verified the successful construction of SHMPB6 and its ultrahigh drug loading capacity（84.0%）,great ROS generation and photothermal properties at 685 or 808 nm laser irradiation.The experimental results showed that SHMPB6 has the strongest ROS generation and photothermal conversion ability under 685 nm and 808 nm laser irradiation,respectively.（3）Study on anticancer effect:Flow cytometry analysis showed that SHMPB6 could be effectively uptake by Hep G2 cells.Moreover,it had a specific targeting ability towards Hep G2,Hela,and 4T1 cancer cell lines.In addition,confocal laser scanning microscope experiments show that SHMPB6 can generate ROS under 808 nm or 685 nm light source.MTT experiments proved that SHMPB6 had good biocompatibility and phototoxicity.After co-incubated with SHMPB6 for 48 h,the survival rate of cells remained above 95%in dark.Compared with the 808 nm laser irradiation group（Bod:40μg/m L,43.5%）,SHMPB6 showed a better phototoxicity towards Hep G2 cells under 685 nm laser irradiation（IC50,0.41μg/m L）.In this thesis,a novel glycol-targeting hollow Mn O₂ drug delivery system with an ultrahigh loading capacity was constructed for synergistic cancer phototherapy.This work provides a good example of a single NIR-controlled nano drug delivery system with an ultrahigh loading capacity.