Targeted Photo-chemo Cascading Cancer Therapy Based On The Photosensitizer/Tirapazamine-encapsulated Hyaluronic Acid Nanomicelles

Cancer is still a serious threat to human health and life.Photodynamic therapy(PDT),as a new method of therapy,produces reactive oxygen species(ROS)to kill tumor cells through the photochemical reaction of photosensitizers upon laser irradiation.It has the advantages of high selectivity,minimally invasiveness,controllability and etc.However,the therapeutic effect of PDT greatly depends on the concentration of oxygen.For one hand,the solid tumor is in the state of hypoxia.On the other hand,PDT process consums oxygen.These factors would limit the curative effect of PDT.Reductive pro-drugs are only effective under the reductive conditions,and they may be used to combine with PDT to enhance anti-tumor effects.At the same time,drug delivery system has been attached enormous attention due to the advantages of tumor targeting,prolonged time of drug circulation,controlled drug release and enhanced drug accumulation at tumor site.Based on the above,this thesis fabricated a type of a photosensitizer and bioreductive prodrug(Tirapazamine,TPZ)-loaded hyaluronic acid(HA)nanomicelles(denoted as HA-Ce6/TPZ)with the aim to develop a cascading mode of photo-chemo cancer therapy.HA-Ce6/TPZ was constructed by assembling TPZ in the nanomicells formed by the amphiphilicity HA-Ce6.The nanomicelles showed good dispersibility and stability with the hydrodynamic size of 160 nm.Ce6 and TPZ could release from HA-Ce6/TPZ upon treatment with hyaluronic hyaluronidase.The in vitro results demonstrated the enhanced and targeted endocytosis of HA-Ce6/TPZ by 4T1 cells.Also,the time-dependent intratumor fluorescence intensity suggested that HA-Ce6/TPZ could effectively target the tumor and retained longer for at least 24 h.The photoacoustic imaging and the hypoxia probe fluorescence imaging verified the enhanced hypoxia state of tumor post PDT mediated by HA-Ce6/TPZ,which helped activate TPZ.Compared with the single PDT or chemotherapy of TPZ,HA-Ce6/TPZ exhibited enhanced tumor killing efficiency towards the mouse 4T1 breast cancer,suggesting the cascading anticancer effect of photo-chemotherapy.In conclusion,this study demonstrated great promise of the easily prepared and highly efficient hybrid nano-micelle HA-Ce6/TPZ for the targeted cancer combination therapy as well as tumor imaging.