Fe²⁺/Fe³⁺ Ions Chelated With Ultrasmall Polydopamine Nanoparticles Inducing Ferroptosis For Cancer Therapy

In recent years,the incidence of malignant tumors in China has shown a significant upward trend.As the main treatment of malignant tumors,radiotherapy and chemotherapy currently only play a very low therapeutic effect,but accompanied by high toxicity and side effects,which makes the cancer cure rate maintained at a very low level.It is very necessary to break through the existing thinking and develop a new treatment method to greatly improve the cure rate of malignant tumors.Recent researchers have been developing a variety of cancer treatments by studying the mechanism of cell death.Recent studies have shown that a new way of cell death has been found,in which iron-rich cells are used to induce non-apoptotic cell death through lipid peroxidation,which is defined as Ferroptpsis.Ferroptpsis is a new pathway of cell death.It is different from apoptosis,necrosis and autophagy in morphology,biochemistry and genetics.This new mechanism can be used to explore a new method of cancer treatment.Nowadays,with the rapid development of nanotechnology,nanomaterials are widely used in cancer treatment.The research on the mechanism of cell death is also in-depth.Designing tumor-targeting particles with precise physical and chemical properties can improve the therapeutic effect and obtain pharmacological targets.Polydopamine(PDA)is a safe and non-toxic material,which is widely used in the field of biomedicine because of its multifunction.Polydopamine has good biocompatibility,hydrophilicity and stability,and can chelate with metal ions.It can be chemically reacted with amino or carboxyl groups to obtain organic molecules,and further modified to obtain better biomaterials.In this paper,we will design a kind of nano-material based on PDA,modified the surface with polyethylene glycol to improve its stability and provide a secondary reaction platform to chelate iron ions,and play an important role in prolonging the circulation time in vivo.The ultrasmall treatment leaded to bigger specific surface area,which could support more reactive sites to chelating a large number of iron ions,which benefited to explore detail mechanism of ferroptosis-induced tumor cell death by iron ions.And the iron ions release with pH-responsible can reach to approximately 70%at pH=5.0,which take advantage of applying in tumor microenvironment.The in vitro tests showed that the as-prepared NPs exhibit effective anticancer effect towards tumor cells including 4T1 and U87MG cells,yet,ferric ions show stronger ability of killing cancer cells than ferrous ions.Differences between ferrous ions and ferric ions in the ferroptosis pathway were monitored by the change of marker including ROS,GPx-4 and LPO,as well as the promoter and inhibiter of ferroptosis pathway.UPDA-PEG@Fee+nanoparticles induce ferroptosis more depended on ROS,however,more LPO dependent ferroptosis was induced by UPDA-PEG@Fe3+ nanoparticles.Additionally,the in vivo studies using tumor-bearing balb/c mice demonstrated that the as-prepared NPs could significantly inhibit tumor progression,have good biocompatibility and hardly cause damage to the main organs and tissues of mice.