Construction Of Supramolecular Photosensitizers Based On Host-guest Chemistry Of Pillararene For Enhanced The Efficiency Of Tumour Photodynamic Therapy

Cancer is one of the major diseases that threateus human health and life.Photodynamic therapy（PDT）has gained more attention due to its unique features such as low systemic toxicity,non-initiation of drug resistance and non-invasiveness.However,it has several factors that significantly affect the efficiency of PDT,such as the dark toxicity of photosensitizers,poor water solubility and targeting ability,low O₂concentration in tumor tissue.Macrocyclic molecules are able to integrate with various guest groups through host-guest interactions to form supramolecular systems without complex synthesis steps and purification processes.In particular,the supramolecular PDT systems constructed by host-guest interactions between macrocyclic hosts and photosensitizers have great potential to overcome the limitations of PDT.Herein,in this thesis,we constructed two different kinds of pillar[5]arene-based supramolecular photosensitizers for enhanced hypoxic-tumor PDT effectiveness.The details are as follows.1.A supramolecular photosensitizer system based on galactose-targeting pillar[5]arene for the combination of PDT and chemotherapy in tumoursModification of Nile Blue（NBS,modified with“S”atoms）into NBSPD capable to be used as the guest molecule of pillararene.A galactose functionalized pillar[5]arene（GP5）with the ability to target liver cancer cells act as host molecule.The amphiphilic supramolecular photosensitizer was constructed through host-guest interactions between GP5 and NBSPD,which self-assembled into nano-vesicles（GP5（?）NBSPD）.Experiment results showed that the binding stoichiometry between GP5 and NBSPD was 1:1.The observation of GP5（?）NBSPD nanoparticles by SEM and TEM revealed that the nanoparticles were hollow vesicles with a mean diameter of ca.220 nm.,which could load anti-cancer drug DOX to preaper DOX@GP5（?）NBSPD nanoparticles（drug loading is 29.8%）.The nanoparticles can achieve cancer cell-targeted delivery and GSH-stimulated release of drugs and photosensitizers in cancer cells.Meanwhile,It can produce O₂￣^·in both normoxic and hypoxic environments,and is further converted into more cytotoxic OH·.Cytotoxicity experiments showed that DOX@GP5（?）NBSPD NPs can effectively kill cancer cells in both normoxic and hypoxic environments,providing an efficient way to enhance the effects of PDT in tumours by co-delivery of photosensitizers and anti-cancer drugs.2.A supramolecular photosensitizer based on L-Arginine-modified pillar[5]arene for the combination of PDT and tumour cell membrane damage in tumoursThe amphiphilic complexes（LAP5（?）NBSPD）was obtained by L-Arginine-modified pillar[5]arene（LAP5）as host molecule and Nile Blue with sulfur atoms derivatives（NBSD）as guest molecule through host-guest interactions,which self-assembled into nanoparticles.Experiment results showed that the binding stoichiometry between LAP5 and NBSPD was1:1.Moreover,the assembled morphology and size of the LAP5（?）NBSPD NPs were characterized by DLS,SEM and TEM,which showed LAP5（?）NBSPD NPs were micelles with a mean diameter of ca.91.3 nm.Flow cytometry results show that LAP5（?）NBSPD NPs can enter cells through clathrin-mediated cystocytosis.CLSM experiments showed that nanoparticles can rapidly escape from endocytic vesicles after entering cells and release LAP5and NBS in response to high concentrations of GSH,which are distributed to organelles such as mitochondria,endoplasmic reticulum,lysosomes,and golgi apparatus.When irradiated with 660 nm light,the NBS produced large amounts of O₂￣^·damage to various organelles through a type I PDT mechanism.Meanwhile,LAP5 synergistically enhances the effects of PDT in a hypoxic environment by binding to organelle membranes or cell membranes to damage cells.MTT results showed LAP5（?）NBSPD NPs could enhance the effect of PDT in a hypoxia environment,providing a new idea for PDT treatment of hypoxia tumour.In summary,two different kinds of pillar[5]arene-based supramolecular photosensitizers have been constructed in this thesis for enhanced tumor PDT effectiveness.It provides a new strategy for the study of tumour therapy and broadens the application of pillararene-based supramolecular photosensitizers in hypoxia-tumour PDT.