Preparation Of Reduction-responsive Ferrite Nanoassemblies For Triple Negative Breast Cancer Treatment

Tumor cells are vigorously metabolized,and there was higher mitochondrial ROS levels than normal cells.Abnormal ROS will lead to mitochondrial damage,resulting in the death of cancer cells,It is important for development of tools to effectively regulate mitochondrial ROS.But a major challenge is how to achieve regulation of mitochondrial ROS in vivo.Our laboratory was developed 3 nm ultra-small manganese oxide nanoparticles and showed strong catalase-like enzyme activity in the alkaline microenvironment of mitochondria,which is expected to reduce the ROS level of mitochondria.but it's too small size leads to a short blood circulation time.The tumor enrichment is limited,and fewer particles reach the mitochondria.It is difficult to effectively regulate the mitochondrial ROS levels.To solve this problem,we developed an innovative,tumor cell and mitochondria hierarchical-targeting high-efficiency nanosestem?UMFS8-TPP?by conjugation of the triphenylphosphine-modified quasi-paramagnetic manganese ferrite nanoparticles?UMF-TPP?with to eight-arm polyethylene glycol through reduction-responsive disulfide bonds for treatment of triple negative breast cancer.The system can maintain a large size in blood with low glutathione?GSH?concentration and passively target the tumor tissue through the enhanced penetration and retention?EPR?effect of solid tumors.when entering the cytoplasm of tumor cells with high GSH concentration,the system will release the quasi-paramagnetic manganese ferrite nanoparticles targeted by mitochondria,and its small size can enrich mitochondria more efficiently.The experimental results that we have successfully prepared a reduction-responsive ferrite nanoassemblies?UMFS8-TPP?,the hydrodynamic diameter of the product is about 92 nm,and the blood circulation time and makes the half-life time(t_1/2)around 37.39 h,which is nearly enhanced 4-folds in comparison to that of UMF-TPP.the Structured Illumination Microscopy?SIM?to observe the exacted location of UMFS8-TPP in mitochondria,achieving a colocalization between UMFS8-TPP and mitochondria up to 68.8%.In addition,We found that UMFS8-TPP can significantly down-regulation the level of mitochondrial ROS in MDA-MB-231 breast cancer cells by AMF,leading to apoptosis.The above properties allow that nanosystem can orthotopically regulate mitochondrial ROS in vivo.Finally,it can achieve effective suppression of triple negative breast cancer.This work will provide an important reference for the development of mitochondrial targeted tumor treatment methods.