Mannose-coated Superparamagnetic Iron Oxide Nanoparticles For Alleviation Of Chemotherapy-induced Peripheral Neuropathic Pain

Background:Chemotherapy-induced peripheral neuropathic pain is a painful progressive peripheral neuropathy affecting approximately 30%of patients receiving chemotherapy.However,there is currently no effective treatment for this pathological pain.Abnormally produced reactive oxygen species in macrophages near the peripheral nerves play a dominant role in CIPNP.However,traditional ROS scavengers,such as catalase and superoxide dismutase,are difficult to deliver to macrophages in vivo and keep their activity.Thus it is difficult to remove abnormally produced ROS in macrophages near the peripheral nerves.Superparamagnetic iron oxide nanoparticles can reduce ROS by catalyzing the decomposition of H₂O₂by their catalase-like activity.Additionly,the mannose-coated superparamagnetic iron oxide nanoparticles can specifically bind the mannose receptors on the surface of macrophages and achieve the purpose of targeting macrophages.Whether mSPION can alleviate vincristine-induced CIPNP by targeting macrophages to clear aberrantly produced ROS in macrophages on peripheral nerves remains to be investigatedated.Methods:In this study,we synthesized mannose-coated superparamagnetic iron oxide nanoparticles.In animal experiments,8-week-old C57/6 male mice were selected for the pain model of vincristine chemotherapy,and the mouse mononuclear macrophage cell line J774A.1 cells were used in cell experiments.Animal experiments and cell experiments were divided into four groups:control group,mannose-coated superparamagnetic iron oxide nanoparticles group,vincristine group,mannose-coated superparamagnetic iron oxide nanoparticles+vincristine group.Peroxy orange-1 and DCFH-DA were used to detect H₂O₂ and ROS,respectively.The pexpression levels of HIF1α/NF-κB signaling pathway related proteins HIF1α,p65 and p-p65 were detected by western blotting and enzyme-linked immunosorbent assay.Mechanical pain in mice was measured with a Von Frey electronic pain meter.Results:In this study,we successfully synthesized mSPION of uniform size verified by fourier transform infrared spectroscopy with a hydrodynamic diameter of about 20nm.And we found that mSPION significantly reduced VCR-induced ROS levels on the sciatic nerve in J774A.1 cells and mice.In addition,administration of mSPION also reduced the levels of IL-6 and TNF-αin J774A.1 cells and sciatic nerve macrophages,and significantly alleviated VCR-induced peripheral neuropathic pain.mSPION inhibited the expression of HIF1αand p-p65 in J774A.1 cells induced by VCR,so we speculated that the HIF1α/NF-κB signaling pathway may be involved in the expression of ROS and inflammatory factors induced by VCR.Conclusion:mSPION can remove H₂O₂ from macrophages and down-regulate ROS,and inhibit peripheral nerve inflammation caused by VCR,thus alleviating CIPNP induced by VCR.HIF1α/NF-κB signaling may be involved in the anti-inflammatory effect of mSPION.This study provides a new strategy for the treatment of CIPIN.