Inhibiting Osteolytic Breast Cancer Bone Metastasis by Bone-Targeted Nanoagent via Remodeling the Bone Tumor Microenvironment Combined with NIR-II Photothermal Therapy.

Bone is one of the prone metastatic sites of patients with advanced breast cancer. The "vicious cycle" between osteoclasts and breast cancer cells plays an essential role in osteolytic bone metastasis from breast cancer. In order to inhibit bone metastasis from breast cancer, NIR-II photoresponsive bone-targeting nanosystems (CuP@PPy-ZOL NPs) are designed and synthesized. CuP@PPy-ZOL NPs can trigger the photothermal-enhanced Fenton response and photodynamic effect to enhance the photothermal treatment (PTT) effect and thus achieve synergistic anti-tumor effect. Meanwhile, they exhibit a photothermal enhanced ability to inhibit osteoclast differentiation and promote osteoblast differentiation, which reshaped the bone microenvironment. CuP@PPy-ZOL NPs effectively inhibited the proliferation of tumor cells and bone resorption in the in vitro 3D bone metastases model of breast cancer. In a mouse model of breast cancer bone metastasis, CuP@PPy-ZOL NPs combined with PTT with NIR-II significantly inhibited the tumor growth of breast cancer bone metastases and osteolysis while promoting bone repair to achieve the reversal of osteolytic breast cancer bone metastases. Furthermore, the potential biological mechanisms of synergistic treatment are identified by conditioned culture experiments and mRNA transcriptome analysis. The design of this nanosystem provides a promising strategy for treating osteolytic bone metastases.

External Stimuli-Responsive Strategies for Surface Modification of Orthopedic Implants: Killing Bacteria and Enhancing Osteogenesis.

Bacterial infection and insufficient osteogenic activity are the main causes of orthopedic implant failure. Conventional surface modification methods are difficult to meet the requirements for long-term implant placement. In order to better regulate the function of implant surfaces, especially to improve both the antibacterial and osteogenic activity, external stimuli-responsive (ESR) strategies have been employed for the surface modification of orthopedic implants. External stimuli act as "smart switches" to regulate the surface interactions with bacteria and cells. The balance between antibacterial and osteogenic capabilities of implant surfaces can be achieved through these specific ESR manifestations, including temperature changes, reactive oxygen species production, controlled release of bioactive molecules, controlled release of functional ions, etc. This Review summarizes the recent progress on different ESR strategies (based on light, ultrasound, electric, and magnetic fields) that can effectively balance antibacterial performance and osteogenic capability of orthopedic implants. Furthermore, the current limitations and challenges of ESR strategies for surface modification of orthopedic implants as well as future development direction are also discussed.

Chitosan/NH2-MIL-125 (Ti) scaffold loaded with doxorubicin for postoperative bone tumor clearance and osteogenesis: An in vitro study.

Surgical resection remains the primary treatment modality for bone tumors. However, it is prone to local bone defects and tumor recurrence. Therefore, there is an urgent need for multifunctional biomaterials that combine tumor treatment and bone repair after bone tumor surgery. Herein, a chitosan composite scaffold (CS/DOX@Ti-MOF) was designed for both tumor therapy and bone repair. Among them, the amino-functionalized Ti-based metal-organic framework (NH2-MIL-125 (Ti), Ti-MOF) has a high specific surface area of 1116 m2/g and excellent biocompatibility, and promotes osteogenic differentiation. The doxorubicin (DOX) loading capacity of Ti-MOF was 322 ± 21 mg/g, and DOX@Ti-MOF has perfect antitumor activity. Furthermore, the incorporation of DOX@Ti-MOF improved the physical and mechanical properties of the composite scaffolds, making the scaffold surface rough and favorable for cells to attach. CS/DOX@Ti-MOF retains the unique properties of each component. It responds to the release of DOX in the tumor microenvironment to remove residual tumor cells, followed by providing a site for cell attachment, proliferation, and differentiation. This promotes bone repair and achieves the sequential treatment of postoperative bone tumors. Overall, CS/DOX@Ti-MOF may be a promising substitute for postoperative bone tumor clearance and bone defect repair. It also provides a possible strategy for postoperative bone tumor treatment.