A Dual Effect Based On A Magnetically Mechano-chemotherapeutic To Overcome Tumor Drug-resistance

For chemotherapy,the ability of tumor cells to develop drug resistance over time currently represents one of the major constraints of such therapeutic strategies.Currently widely used chemotherapy methods are administered by oral or intravenous injection,the chemotherapeutic drugs spread throughout the body with blood circulation and can’t release drugs actively.Therefore,we sought a way to actively release drugs and overcome drug-resistant tumor cells.Previous studies have shown that magnetic nanoparticles can convert magnetic energy into mechanical kinetic energy,and the mechanical forces generated can rupture cell membranes and organelles membranes to cause apoptosis and necrosis.This non-invasive,precisely remotely controllable treatment has great potential to be combined with other therapeutic strategies.The motion of magnetic nanoparticles when exposed to a magnetic field can be association with controllably drug release,creating a new therapeutic mode of mechano-chemotherapy.In order to verify the feasibility of this solution,we synthesize the composite nanomaterials with poly（lactic-co-glycolic acid）（PLGA）shell and co-loaded with Zn_0.2Fe_2.8O₄ superparamagnetic nanoparticles and chemotherapy drug Doxorubicin（DOX）into a uniform particle size,high drug loading and excellent magnetic response.With the stimulation of a rotating magnetic field（45 m T,2000 rpm）,mechanical force generated and controllably drug release at the same time,which enhanced the chemotherapy effect and combined with mechanical force to kill the drug-resistant tumor cells.In this study,we found that the synthesized composite nanomaterials with the characteristics of high drug loading and excellent magnetic response.Stimulated by a remote rotating magnetic field,it can control the drug release behavior and generate magnetic force to kill tumor cells（regardless of whether the tumor cells are drug-resistant）.Through a series of characterizations,it was found that composite nanomaterials can induce apoptosis and necrosis of tumor cells by rupturing the cell membrane and lysosomal membrane.After 2 h rotating magnetic field stimulation,a killing rate of 63%was achieved in common tumor cells MCF-7,and a killing rate of20%was achieved in drug-resistant tumor cells MCF-7/ADR.We also prove that our synthetic nanomaterials have good biological safety through H&E staining of major organs and biodistribution of nanomaterials in major organs experiments,which promotes it can be used in subsequent biomedical applications.In summary,our results show that our synthesized composite nanomaterials can overcome drug-resistant tumor cells with enhanced chemotherapy effect combined with magnetic mechanical killing when exposed to a rotating magnetic field.