Metal–Organic Framework Nanoparticles for Ameliorating Breast Cancer-Associated Osteolysis

Abstract

Breast cancer metastases to bone poses a significant challenge for the administration of treatment strategies. The bone microenvironment, metastatic tumor cells, osteoclasts, and tumor-associated macrophages (TAMs) all play crucial and synergistic roles in creating a favorable environment for the proliferation, progression, and survival of the metastatic tumor, which in turn induces osteoclast-mediated bone destruction. In this study, we functionalized immunostimulatory cytosine–phosphate–guanosine (CpG)-loaded metal–organic framework (MOF) nanoparticles with bone targeting capabilities by surface modification with FDA approved antiresorptive bisphosphonate, zoledronic acid (ZOL). The functionalized bone targeting immunostimulatory MOF (BT-isMOF) nanoparticles demonstrates strong binding to calcium phosphate in vitro and exhibits specific targeting and accumulation in bone tissues in vivo. In vitro cellular and biochemical analyses demonstrated that the BT-isMOF nanoparticles could potently inhibit osteoclast formation and concomitantly induce macrophages polarization toward the M1 pro-inflammatory phenotype. Finally, using the intratibial murine model of breast cancer bone metastasis, we showed that the administration of BT-isMOF nanoparticles significantly suppressed osteoclast-mediated bone destruction and enhanced polarization of tumor-resident macrophages to M1 phenotype. Together, our data provides promising evidence for the potential therapeutic application of the BT-isMOF nanoparticles in the treatment of breast cancer bone metastases.

Small extracellular vesicles deliver osteolytic effectors and mediate cancer‐induced osteolysis in bone metastatic niche

“…To explore the role of miR‐152‐3p in intercellular crosstalks in tumour‐bone microenvironment, we established an orthotopic xenograft mouse model by injecting tumour cells into the intramedullary cavity of the tibia in BALB/c nude mice. This mouse model is useful to assess the interaction between implanted cancer cells and host cells in tumour‐bone microenvironment (Pang et al., 2020; Zhang et al., 2020). Bioluminescence imaging (BLI) was performed weekly using a firefly luciferase reporter stably expressed in the cell line to monitor the tumour progression in real time, while microcomputed tomography (micro‐CT) analysis was performed at the week 5 to evaluate the osteolytic destruction of tibias (Figure 5a).…”

Nanocarrier-Based Drug Delivery for Melanoma Therapeutics

“…Nanotechnology also provides strategies for targeted delivery of drugs, genes, and proteins to tumors, thereby reducing their nonspecific accumulation in peripheral tissues [53][54][55]. Currently, the major medical nanomaterials include organic (e.g., liposome, polymeric nanoparticles, and dendrimer) and inorganic (e.g., magnetic nanoparticles, carbon nanoparticles, gold nanoparticles, and silica nanoparticles) nanomaterials [56][57][58], which are used in the diagnosis and treatment of various cancers. Liposomes are amphoteric lipid bilayers with a hydrophilic core and a hydrophobic outer shell [59].…”

Combination of AZD3463 and DZNep Prevents Bone Metastasis of Breast Cancer by Suppressing Akt Signaling

“…Female BALB/c (7 week-old) nude mice were purchased from Jihui Laboratory Animal Care Co., Ltd. (Shanghai, China) and maintained in a specific-pathogen-free animal facility. An intratibial murine model of breast cancer bone metastasis (Pang et al, 2020) was created by harvesting MDA-MB-231 cells and resuspending them in sterile PBS (1 × 10 6 cells/ml) and then injecting 100 μl of the cell suspension into the left tibia plateau of each mouse. After being observed for 1 week, 24 mice in good condition were randomly allocated to four groups (n 6 per group) and then intraperitoneally injected twice per week with PBS, AZD3463 (7.5 mg/kg body weight), DZNep (2 mg/kg body weight), or AZD3463 (7.5 mg/kg body weight) plus DZNep (2 mg/kg body weight).…”