Preparation And Anti-tumor Application Of High-molecular-weight Nano-photosensitive Drugs That Can Overcome Tumor Hypoxi

Cancer is a serious threat to human life and health.At present,chemotherapy,radiotherapy and surgical resection are mainly used to treat cancer.In recent years,photodynamic therapy,as a new technology different from traditional cancer treatment,has shown great application prospects in the field of cancer treatment for its ability to acheive palliative therapy and fulfill minimally invasive or non-invasive treatment with high treatment accuracy and relatively simple operation.Photosensitizer,light and oxygen are the three key elements in the process of photodynamic therapy.The oxygen content in solid tumors is inversely proportional to the distance between blood vessels while even reaching the"anaerobic"state in the deep of tumor.Type II photodynamic process often occurs in traditional photodynamic therapy,which is highly dependent on oxygen.In this paper,we prepared a nanodrug system ATO-IPS@NPs co-loading type I photosensitizer（A_SD_I,IPS）and atovaquone（ATO）which is a mitochondrial oxidative phosphorylation inhibitor at about 30 nm in diameter to fulfill enhanced type I photodynamic therapy both in vitro and in vivo.（1）Nano flash precipitaion was employed as the method to prepare ATO-IPS@NPs with amphiphilic block polymer PEG-b-PCL as carrier.The preparation formula was optimized according to the size,polydispersity index and loading content of nano micelles.The particle size and morphology of micelles were characterized by dynamic light scattering（DLS）and transmission electron microscope（TEM）.Finally,to prepare suitable ATO-IPS@NPs,PEG5k-b-PCL₁₈ was adopted as the carrier and the mass ratio of IPS to ATO was determined as 1:1 while the drug loading percentage was2%.It was verified that the ATO-IPS@NPs micelle solution could produce abundant superoxide anion radicals under light irradiation.（2）At the cellular level,cell uptake experiment,cytotoxicity experiment,intracellular ROS production experiment and intracellular O₂·^-production experiment were carried out to study the accumulation into cells of ATO-IPS@NPs in cells over time and the ability of ATO-IPS@NPs to produce reactive oxygen species under light irradiation to kill tumor cells.The experimental results showed that ATO almost does not affect the photodynamic performance of IPS under normoxic conditions,and successfully improved the photodynamic treatment effect of IPS under hypoxic conditions to nearly 1.4 times.（3）The BALB/c mouse model of breast cancer was constructed to evaluate the photodynamic therapy effect of ATO-IPS@NPs to solid tumor in vivo.The experimental results showed that ATO-IPS@NPs can successfully induce tumor cell death and significantly inhibit tumor growth,indicating a good tumor photodynamic effect.Furthermore,ATO-IPS@NPs exhibited good biosafety for the weight of mice increased normally after drug administration and photodynamic therapy and the H&E staining picture showed no pathological damage to major organs of tumor bearing mice.