Near-infrared Synergistic Phototherapy Nanoplatform Based On Aza-Boron-Dipyrromethene Derivatives: Design,Preparation And Biological Applications

Phototherapy,which is a non-invasive and light-excited tumor therapy method,has attracted more and more attention.Both photothermal therapy(PTT)and photodynamic therapy(PDT)were studied adequately.Synergistic therapy(SPT),which exhibited both PTT and PDT effects,could reinforce each other.SPT exhibited not only the advantages but also their disadvantages of PTT and PDT.It is very important to design,prepare and apply excellent SPT agents to promote their clinical applications.However,the previously reported SPT only pursued the reactive oxygen species generation yield or photothermal conversion efficiency,resulting in the lag in the development of SPT.Hypoxia,postoperative rehabilitation and other problems encountered during SPT process need to be solved urgently.Among various synergistic therapy agents,aza-BODIPY derivatives have attracted wide research interest.Therefore,we chose aza-BODIPY derivatives as the SPT agents and developed a series of nanoplatforms to solve the above problems.Finally,our SPT nanoplatforms overcame the hypoxia problem in tumors and prevented bacterial prevention at the PTT-induced wound for ablating the tumor and promoting the wound recovery.The main contents of this thesis are shown as below:1.Halogenated aza-BODIPY for imaging-guided synergistic photodynamic and photothermal tumor therapyThe heavy atom effect is often used to improve the photodynamic therapy effect,but its specific influence on photothermal and photodynamic therapy of aza-BODIPY still need to be further exploited.In order to clarify the positive heavy atom effects on the photodynamic and photothermal efficiencies of phototherapy agents,a series of chlorine-,bromine-,or iodine-substituted aza-BODIPYs(B2,B3 and B4,respectively)are designed and synthesized.And the aza-BODIPY without halogen substitute was also synthesized as a control synergistic photothetray agent.The comparison results of their photophysical properties,photodynamic and photothermal efficiencies demonstrated that B4 is the most ideal synergistic phototherapy agent among three agents.The nanoparticles IABN which could disperse well in water were obtained by coating iodine-substituted aza-BODIPY with amphiphilic polymer DSPE-m PEG₅₀₀₀.Based on in vitro experiments of its fluorescence imaging,photodynamic and photothermal effect,IABN was proved to have the potential to achieve fluorescence imaging-guided synergistic therapy.In vivo experiments of IABN proved that it can realize imaging-guided tumor ablation.This work provided a detailed investigation for the development of phototherapy agents and also offered a guiding suggestion for the future design of synergistic agents.2.Facile phototherapy nanoplatform by integrating a multifunctional polymer and MnO₂ for enhancing tumor synergistic therapyThe hypoxic environment in tumors seriously limits the therapeutic effect of oxygen-dependent PDT,leading to the domination of PTT in the SPT process.Therefore,it is urgent to develop a novel SPT platform for overcoming hypoxia in tumors and improving the therapeutic effect of both PTT and PDT.In this work,a novel phototherapeutic platform based on a nanocomposite of aza-BODIPY/manganese dioxide(Mn O₂)is developed via simple electrostatic self-assembly.In this design,Mn O₂ nanosheets,which could produce heat and catalyze endogenous hydrogen peroxide(H₂O₂)to generate oxygen,are prepared as a nanocarrier.After being coated with the as-prepared water-soluble aza-BODIPY-based polymer(PPAIB),the obtained Mn O₂@PPAIB performs as a smart phototherapeutic agent for enhancing the effciency of both PTT and PDT.More importantly,compared to PPAIB,Mn O₂@PPAIB generates more heat and reactive oxygen species to realize the enhanced therapy effects of PTT and PDT.Hence,this work provides a new method to enhance the therapeutic effcacy of SPT by using a polymer/Mn O₂ nanoplatform to improve the oxygen concentration and produce more heat.3.A photothermally-induced HCl O-releasing nanoplatform for imaging-guided tumor ablation and bacterial preventionThe shortcoming of photothermal therapy(PTT)lies in the fact that excessive heat is most likely to lead to thermal injury at the epidermis of the tumor region and even the area of the surrounding tissue.As a consequence,the exposure of the thermally-induced wound would result in the increased risk of bacterial infection.To date,few PTT platforms have exhibited potential of the prevention of bacterial infection at the photothermally-induced wound.Herein,we reported a thermally-sensitive liposome nanosystem(Lipo-B-TCCA)containing aza-BODIPY and trichloroisocyanuric acid,which is conductive for the PTT of tumor and the prevention of bacteria.It is observed that the designed nanoplatform could exhibit remarkable stability,high photothermal conversion efficiency(31.4%),and efficient HCl O-releasing ability in vitro and in vivo.Moreover,Lipo-B-TCCA is able to eliminate tumor efficiently via near infrared fluorescence and photothermal imaging guidance with low side effects.Most importantly,Lipo-B-TCCA could prevent the growth of S.aureus in the thermal wound during the process of PTT.The imaging-guided photothermally-induced HCl O-releasing PTT nanoplatform for tumor ablation and bacterial prevention shows excellent performance and great potential for biomedical applications.