Research On Amphiphilic Aniline Tetramer/Pillar[5]arene Supramolecular Core-Shell Assemblies And Their Photothermal Properties

Photothermal therapy（PTT）is demonstrated to be an effective methodology for cancer treatment.However,the relatively low photothermal conversion efficiency and limited enrichment and penetration of photothermal reagents in tumor sites are still challenging problems hindering its clinical application.Tumor accumulation and tumor penetration of photothermal agents are the two main factors that influence the efficacy of photothermal therapy.It is well known that nanomaterials with relative large size（200 nm）can be efficiently accumulated in the tumor site due to the enhanced permeability and retention（EPR）effect.However,nanomaterials with smaller size are demonstrated to be benefical for their deep penetration into the tumor tissue due to the high interstitial fluid pressure and dense extracellular matrix.Therefore,the dilemma between high tumor accumulation and sufficient tumor penetration remains to be one of the major challenges for PTT.Herein,taking advantage of the host-guest interaction between water-soluble pillar[5]arene（WP5）and polyethylene glycol-modified aniline tetramer（TAPEG）,supramolecular coreshell nanostructures with phase separation feature were developed through multi-micelle aggregation mechanism.Contributed to the proton doping characteristic of TAPEG,the coreshell nanostructures are endowed with size switchable property thanks to the weak acidity characteristic of tumor microenvironment,with the average diameter of 200 nm in the neutral pH and 50 nm in the tumor microenvironment,which facilitates not only tumor accumulation but also tumor penetration.Moreover,the structure switch of WP5（?）TAPEG under acidic microenvironment and the dual mechanism regulated extending of п conjugate,inclusion in the hydrophobic cavity of WP5 and the dense distribution in the core-shell structured assemblies,dramatically enhanced the absorption of WP5（?）TAPEG in the near-infrared-Ⅱregion and,further,the photothermal conversion efficiency.Combining the size switching of WP5（?）TAPEG supramolecular core-shell assemblies in the tumor microenvironment and the enhancement of photothermal conversion efficiency,the photothermal agent achieved complete tumor removal by photothermal therapy in the NIR-Ⅱ region.The main issue addressed in this thesis are summarized as follows:1.TAPEG and WP5 were chosen as host and guest,respectively.Through the host-guest interaction between TAPEG and WP5,supramolecular core-shell assemblies in aqueous solution were developed.The above mentioned host-guest interaction was characterized by 1HNMR spectroscopy and fluorescence titration,and the stoichiometric ratio（1:1）and binding constant（Ka=（2.50±0.43）×105 M-1）between host and guest were calculated.In addition,through TEM and DLS characterization,it was found that the pH-responsive performance endows the supramolecular core-shell assemblies with size switchable property,with an average diameter of 200 nm in the neutral pH and 50 nm in the acidic microenvironment,which facilitates not only tumor accumulation but also tumor penetration.Besides,the NIR absorption characteristics of WP5（?）TAPEG supramolecular core-shell assemblies under different pH conditions were studied,and its potential application in NIR-Ⅱ biological window tumor photothermal therapy was verified.Furthermore,the photothermal performance of WP5（?）TAPEG supramolecular core-shell assemblies in vitro was studied,and the influencing factors of photothermal performance（pH,concentration,laser power density）and the stability of photothermal behavior of the as designed phtothermal agents were investigated.Moreover,the photothermal conversion efficiency was calculated to be as high as 60.2%.2.Based on the high photothermal conversion of WP5（?）TAPEG supramolecular coreshell assemblies,the size switch in response to pH stimulation,and the unique core-shell structure,the related chemo-photothermal synergistic therapy was investigated.Praggregation[J].Macromolecular Rapid Communications,2016,37:998-1004.imarily,the drug loading and release behavior of WP5（?）TAPEG supramolecular core-shell assemblies were investigated taking doxorubicin（DOX）as the model compound.It is proved that the WP5（?）TAPEG supramolecular core-shell nanoparticles exhibit high encapsulation efficiency（91.7%）and drug loading efficiency（13.1%）for DOX.Under 1064 nm laser irradiation,both the release rate and release amount of DOX increased with the decrease of pH value,revealing that the sustained drug release of WP5（?）TAPEG supramolecular core-shell assemblies can be regulated by both pH and NIR-Ⅱ laser.Thirdly,the cellular uptake of WP5（?）TAPEG supramolecular core-shell assemblies was confirmed by CLSM and the controllable intracellular release of DOX was verified.Subsequently,the biocompatibility of WP5（?）TAPEG supramolecular core-shell assemblies was investigated.The results showed that the WP5（?）TAPEG supramolecular core-shell assemblies had good biocompatibility to normal cells,but had specific toxicity to cancer cells.This difference is due to the chemical structure change of TAPEG in the tumor microenvironment.Finally,the antitumor mechanism of WP5（?）TAPEG supramolecular core-shell assemblies was explored.The anti-tumor activity of WP5（?）TAPEG supramolecular core-shell assemblies is demonstrated to be mediated by mitochondrial apoptosis pathway through the decrease of mitochondrial membrane potential and the expression of antibody protein.3.The in vivo chemo-photothermal synergistic tumor therapy of WP5（?）TAPEG supramolecular core-shell assemblies was investigated.Experimental results of the biocompatibility of the WP5（?）TAPEG supramolecular core-shell assemblies in mice suggested low toxicity and negligible side effects.Through pharmacokinetic experiments,the half-life of WP5（?）TAPEG supramolecular assemblies in mice（139.6 min）was measured.The rapid tumor targeting capability of the WP5（?）TAPEG assembly was demonstrated by ex vivo fluorescence imaging.In addition,photothermal therapy in mice was explored,and anticancer experiments in mice were carried out taking advantage of individual chemotherapy,photothermal therapy and chemo-photothermal synergistic therapy,respectively,and remarkable curative effect was achieved.,Moreover,no obvious adverse effect was observed for the mice after various treatments.