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Carbon nanohorns (CNHs), a type of nanocarbon, have been studied for the application of drug delivery systems (DDSs) because they are easily functionalized, support bone regeneration, can be used to perform photohyperthermia, have low toxicity, and are easily phagocytosed by macrophages. To take advantage of these features of CNHs, we developed a DDS for the local treatment of bone metastasis by loading the antibone resorption drug ibandronate (IBN) onto CNHs. The poor adsorption of IBN onto CNHs due to the weak hydrophilic-hydrophobic interaction was overcome by using calcium phosphates (CaPs) as mediators. In the fabrication process, we used oxidized CNH (OxCNH), which is less hydrophobic, onto which IBN was coprecipitated with CaP from a labile supersaturated CaP solution. OxCNH-CaP-IBN composite nanoparticles exerted stronger cell-suppressive effects than OxCNH and IBN in both murine macrophages (RAW264.7 cells) and osteoclasts (differentiated from RAW264.7 cells). OxCNH-CaP-IBN composite nanoparticles were efficiently phagocytosed by macrophage cells, where they specifically accumulated in lysosomes. The stronger cell-suppressive effects were likely due to intracellular delivery of IBN, i.e., the release of IBN from OxCNH-CaP-IBN composite nanoparticles via dissociation of CaP in the acidic environment of lysosomes. Our findings suggest that OxCNH-CaP-IBN composite nanoparticles are potentially useful for the local treatment of metastatic bone destruction.

When cancer metastasizes to bone, the resulting pain and functional disorders due to bone destruction adversely affect the patient's quality of life. We have developed a new cancer metastasis control system consisting of anticancer agents conjugated to carbon fibers (CFs), which are nonbiodegradable, carriers of a wide variety of molecules with extremely high affinity for bone. In the evaluation of cancer suppression effects on Walker 256 cancer cells, cisplatin (CDDP)-conjugated CFs (CF-CDDP) were found to be as effective in cancer suppression as CDDP. In the evaluation of the cancer suppression effects of local injection in the rat model of tibial cancer bone metastasis, similar cancer suppression was noted in the CF-CDDP group and CDDP group; however, blood Pt concentrations were significantly lower in the CF-CDDP group. Experiments with CDDP and CF-CDDP injected into bone actually destroyed by cancer metastases revealed the presence of significantly more newly formed bone tissue with the administration of CF-CDDP. Local administration of CF-CDDP is expected to become the first therapy to suppress cancer growth with low prevalence of adverse reactions, and to repair bone damaged by metastasis.

Purpose Multiwalled carbon nanotubes (MWCNTs) have been known to enter the circulatory system via the lungs from inhalation exposure; however, its carcinogenicity and subsequent accumulation in other organs have not been adequately reported in the literature. Moreover, the safety of MWCNTs as a biomaterial has remained a matter of debate, particularly when the material enters the circulatory system. To address these problems, we used carcinogenic rasH2 transgenic mice to intravenously administer highly dispersed MWCNTs and to evaluate their carcinogenicity and accumulation in the organs. Methods Two types of MWCNTs (thin- and thick-MWCNTs) were intravenously administered at a high dose (approximately 0.7 mg per kg body weight) and low dose (approximately 0.07 mg per kg body weight). Results MWCNTs showed pancreatic accumulation in 3.2% of mice administered with MWCNTs, but there was no accumulation in other organs. In addition, there was no significant difference in the incidence of tumor among the four MWCNTs-administered groups compared to the vehicle group without MWCNTs administration. Blood tests revealed elevated levels in mean red blood cell volume and mean red blood cell hemoglobin level for the MWCNTs-administered group, in addition to an increase in eotaxin. Conclusion The present study demonstrated that the use of current technology to sufficiently disperse MWCNTs resulted in minimal organ accumulation with no evidence of carcinogenicity.

Purpose Although both anti-PD-1 antibody and treatments using anti-PD-L1 antibody are currently in clinical use, their therapeutic effects vary according to cancer type. One of the factors accounting for this variability is the expression level of the immune checkpoint molecule that differs between cancer types; thus, it is important to clarify the relationship between clinical outcomes and immune checkpoint molecules for all types of human cancer. The purpose of this study is to evaluate the clinical outcome of osteosarcoma in relation to PD-L1, PRF, GZMB, and IFNγ expression. Methods Using 19 clinical specimens of osteosarcoma, we examined the expression of PD-L1, PRF, GZMB, and IFNγ in relation to their clinical outcomes. Results PD-L1 expression correlated with early metastatic formation in clinical specimens of osteosarcoma, and the group with highly expressed functional markers for T cells such as PRF and GZMB resulted in a long overall survival time. Conclusion This is the first study to elucidate the clinical outcomes of osteosarcoma in relation to PD-L1, PRF, GZMB, and IFNγ expression. This study provides valuable information regarding the clinical indication and prediction of effect for anti-PD-1 antibody in osteosarcoma.

One of the greatest challenges to overcome in the pursuit of the medical application of carbon nanomaterials (CNMs) is safety. Particularly, when considering the use of CNMs in drug delivery systems (DDSs), evaluation of safety at the accumulation site is an essential step. In this study, we evaluated the toxicity of carbon nanohorns (CNHs), which are potential DDSs, using human lymph node endothelial cells that have been reported to accumulate CNMs, as a comparison to fibrous, multi-walled carbon nanotubes (MWCNTs) and particulate carbon black (CB). The effect of different surface characteristics was also evaluated using two types of CNHs (untreated and oxidized). In the fibrous MWCNT, cell growth suppression, as well as expression of inflammatory cytokine genes was observed, as in previous reports. In contrast, no significant toxicity was observed for particulate CB and CNHs, which was different from the report of CB cytotoxicity in vascular endothelial cells. These results show that (1) lymph endothelial cells need to be tested separately from other endothelial cells for safety evaluation of nanomaterials, and (2) the potential of CNHs as DDSs., Article, NANOMATERIALS. 10(7):1374 (2020)

Many biomaterials have been evaluated using cultured cells. In particular, osteoblast-like cells are often used to evaluate the osteocompatibility, hard-tissue-regeneration, osteoconductive, and osteoinductive characteristics of biomaterials. However, the evaluation of biomaterial osteogenesis-inducing capacity using osteoblast-like cells is not standardized; instead, it is performed under laboratory-specific culture conditions with different culture media. However, the effect of different media conditions on bone formation has not been investigated. Here, we aimed to evaluate the osteogenesis of MC3T3-E1 cells, one of the most commonly used osteoblast-like cell lines for osteogenesis evaluation, and assayed cell proliferation, alkaline phosphatase activity, expression of osteoblast markers, and calcification under varying culture media conditions. Furthermore, the various media conditions were tested in uncoated plates and plates coated with collagen type I and poly-L-lysine, highly biocompatible molecules commonly used as pseudobiomaterials. We found that the type of base medium, the presence or absence of vitamin C, and the freshness of the medium may affect biomaterial regeneration. We posit that an in vitro model that recapitulates in vivo bone formation should be established before evaluating biomaterials., Article, International Journal of Molecular Sciences. 22(14):7752 (2021)