Graphene-Modified CePO4 Nanorods Effectively Treat Breast Cancer-Induced Bone Metastases and Regulate Macrophage Polarization to Improve Osteo-Inductive Ability

Abstract

Background Breast cancer bone metastasis has become one of the most common complications; however, it may cause cancer recurrence and bone nonunion and local bone defects.Methods Herein, In vitro, we verified the effect of bioscaffold materials on cell proliferation and apoptosis through CCK8 experiment, staining of living dead cells, and flow cytometry. We used immunofluorescence technology and flow cytometry to verified whether bioscaffold materials regulated the polarization of macrophages, and we use ALP staining, alizarin red staining and PCR to verify whether the bioscaffold material promotes bone regeneration. In vivo, we once again studied the effect of bioscaffold materials on tumors by measuring tumor volume in mice, Tunel staining, and caspase-3 immunofluorescence. We also constructed a mouse skull ultimate defect model to verify the effect on bone regeneration.Results Graphene oxide (GO) nanoparticles, hydrated CePO4 nanorods and bioactive chitosan (CS) are combined to form a bioactive multifunctional CePO4/CS/GO scaffolds, which has the following characteristics such as photothermal therapy to kill tumors, macrophage polarization promotes blood vessel formation and induces bone formation. The CePO4/CS/GO scaffold activates the caspase-3 proteasein local tumor cells, thereby lysing DNA between nucleosomes and causing apoptosis. On the one hand, the as-released Ce3+ ions promote the M2 polarization of macrophages, which secretes vascular endothelial growth factor (VEGF) and Arginase-1 (Arg-1), which promotes angiogenesis. On the other hand, the as-released Ce3+ ions also activated BMP-2/Smad signaling pathway that facilitated bone tissue regeneration.Conclusion the multifunctional CePO4/CS/GO scaffolds may become a promising platform for therapy of breast cancer bone metastases.

Application of bioactive metal ions in the treatment of bone defects

“…59 Molecular analysis has shown that Ca 2+ , Zn 2+ , La 3+ , and Cerium ions (Ce 3+ ) play these roles by regulating the TGF-β/Smad signaling pathway, which is the key pathway to osteoblast development. 60,61 TGF-β can bind to its type II receptors and then activate type I receptors. Activated type I receptors lead to the phosphorylation of Smad 2 or Smad 3, which can form a complex with Smad 4 and enter the nucleus.…”

“…However, the specific mechanism of La 3+ promoting angiogenesis has not been thoroughly studied, and the mechanism is not clear. 40,61…”

Multifunctional inorganic nanomaterials for cancer photoimmunotherapy

“…GO can serve as an immunostimulant to activate the host's immune system because they can reduce ROS production in cells, thus changing the repolarization of macrophages and regulating the immune response of the body [78,84]. It has been demonstrated that the earlier shift of macrophage phenotypes to the M2 type and ROS regulation in inflammation-stimulated macrophages play significant roles in M1 macrophage treatment [85,86]. Therefore, Wang et al [87] formulated a hybrid nanocomposite by coating magnetite nanoparticles with reduced graphene oxide (rGO) and followed by PEG-NH 2 modification on their surface.…”

Facile synthesis of flower-like CePO4 with a hierarchical structure for the simultaneous electrochemical detection of dopamine, uric acid and acetaminophen

“…They all belong to Ce 3+ , which means that the as-synthesized F-CePO 4 mainly contains positive trivalent Ce elements. 26,27 The morphology of F-CePO 4 was observed by SEM. As shown in Fig.…”