Ibandronate-Loaded Carbon Nanohorns Fabricated Using Calcium Phosphates as Mediators and Their Effects on Macrophages and Osteoclasts

Abstract

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.

Bisphosphonate type-dependent cell viability suppressive effects of carbon nanohorn–calcium phosphate–bisphosphonate nanocomposites

“…The resulting OxCNH-CaP-IBN nanocomposites had stronger cell viability suppressive effects than either OxCNH or IBN alone in vitro . 16 Such results in our previous report 16 supported the potential of OxCNH-CaP-IBN nanocomposites as medicines for local treatment of bone metastasis. We hypothesize that hydrophilic BPs other than IBN could also be loaded onto OxCNHs using CaPs as mediators, and that the resulting OxCNH-CaP-BP nanocomposites would have potentially more potent cell viability suppressive effects than OxCNH-CaP-IBN nanocomposites.…”

Current Methods in the Study of Nanomaterials for Bone Regeneration

“…Our group has been developing a DDS with CNHs for the local treatment of metastatic bone destruction. We used calcium phosphate (CaP) as a loading mediator for the bone resorption inhibitor ibandronate (IBN) and observed a significant effect of CNH-CaP-IBN on bone resorption [ 43 ]. We are currently evaluating the efficacy of our DDS in vivo to determine if it not only inhibits bone resorption, but also promotes bone formation in the fractured area by means of CNHs.…”

“…We are currently evaluating the efficacy of our DDS in vivo to determine if it not only inhibits bone resorption, but also promotes bone formation in the fractured area by means of CNHs. As well as CNHs, various NPs have been studied as media for DDS, including liposomes, polylactic acid, poly lactic-co-glycolic acid, PEG, and silica [ 22 , 43 , 44 , 45 , 46 ] ( Table 2 ).…”

Green Approaches to Carbon Nanostructure-Based Biomaterials

“…They are produced by arc-discharge, laser ablation, or joule heating, from graphite [7], although greener alternatives at lower temperatures are continually sought [149]. Similar to the other carbon nanomaterials, they have been proposed for drug delivery [150], sensing [151], theranostics [152], and as components of nanocomposites for phosphoproteomics in cancer diagnosis [153], or for cancer treatment [154], or to yield patches for topical applications on skin [155]. Finally, NDs can be simply used as scaffolds to adsorb other molecular species, as shown for a hydrophobic magnetic-resonance contrast agent that required a mixture of DMSO and water to react with NDs, while the resulting product was water-soluble and could be tested for imaging [131].…”

“…They are produced by arc-discharge, laser ablation, or joule heating, from graphite [7], although greener alternatives at lower temperatures are continually sought [149]. Similar to the other carbon nanomaterials, they have been proposed for drug delivery [150], sensing [151], theranostics [152], and as components of nanocomposites for phosphoproteomics in cancer diagnosis [153], or for cancer treatment [154], or to yield patches for topical applications on skin [155]. Functionalization is required to avoid further aggregation into larger clu ensure homogeneous dispersions in aqueous environments.…”