The purpose of coatings on implants is to achieve some or all of the improvements in biocompatibility, bioactivity, and increased protection from the release of harmful or unnecessary metal ions. During the last decade, there has been substantially increased interest in nanomaterials in biomedical science and dentistry. Nanocomposites can be described as a combination of two or more nanomaterials. By this approach, it is possible to manipulate mechanical properties, such as strength and modulus of the composites, to become closer to those of natural bone. This is feasible with the help of secondary substitution phases. Currently, the most common composite materials used for clinical applications are those selected from a handful of available and well-characterized biocompatible ceramics and natural and synthetic polymers. This approach is currently being explored in the development of a new generation of nanocomposite coatings with a wider range of oral and dental applications to promote osseointegration. The aim of this review is to give a brief introduction into the new advances in calcium phosphate nanocoatings and their composites, with a range of materials such as bioglass, carbon nanotubes, silica, ceramic oxide, and other nanoparticles being investigated or used in dentistry.

Current Perspectives Calcium Phosphate Nanocoatings and Nanocomposite Coatings in Dentistry

Activation of autocrine and paracrine signalling by endothelin 1 (ET1) binding to its receptors elicits pleiotropic effects on tumour cells and on the host microenvironment. This activation modulates cell proliferation, apoptosis, migration, epithelial-to-mesenchymal transition, chemoresistance and neovascularization, thus providing a strong rationale for targeting ET1 receptors in cancer. In this Review, we discuss the advances in our understanding of the diverse biological roles of ET1 in cancer and describe the latest preclinical and clinical progress that has been made using small-molecule antagonists of ET1 receptors that inhibit ET1-driven signalling.

Endothelin 1 in cancer: biological implications and therapeutic opportunities.

Systemic sclerosis (SSc) is a multisystem connective tissue disorder featured by vascular injury and fibrosis of the skin and various internal organs with autoimmune background. Although the pathogenesis of SSc still remains elusive, it is generally accepted that initial vascular injury due to autoimmunity and/or environmental factors causes structural and functional abnormalities of vasculature which eventually result in the constitutive activation of fibroblasts in various organs. Structural alterations consist of destructive vasculopathy (loss of small vessels) and proliferative obliterative vasculopathy (occlusion of arterioles and small arteries with fibro-proliferative change) caused by impaired compensatory vasculogenesis and angiogenesis. Impaired function of SSc vasculature includes the altered expression of cell adhesion molecules predominantly inducing Th2 and Th17 cell infiltration, endothelial dysfunction primarily due to the low availability of nitric oxide, the activated endothelial-to-mesenchymal transition leading to fibro-proliferative vascular change and tissue fibrosis, and the impaired coagulation/fibrinolysis system promoting the formation of intravascular fibrin deposits. Recent new insights into the therapeutic mechanisms of intravenous cyclophosphamide pulse and bosentan and the establishment of a new SSc animal model (Klf5 (+/-);Fli1 (+/-) mice) provide us useful clues to further understand the development of vascular alterations characteristic of SSc. This article overviewed the present understanding of the pathogenesis of SSc vasculopathy.

Vasculopathy in scleroderma

Synthetic hydroxyapatite in pharmaceutical applications

Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiac-specific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-alpha content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.

https://cancerres.aacrjournals.org/content/canres/67/21/10428.full.pdf

The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy.

Drug delivery systems offer the advantage of sustained targeted release with minimal side effect. In the present study, the therapeutic efficacy of a porous silica–calcium phosphate nanocomposite (SCPC) as a new delivery system for 5-Fluorouracil (5-FU) was evaluated in vitro and in vivo. In vitro studies showed that two formulations; SCPC50/5-FU and SCPC75/5-FU hybrids were very cytotoxic for 4T1 mammary tumor cells. In contrast, control SCPCs without drug did not show any measurable toxic effect. Release kinetics studies showed that SCPC75/5-FU hybrid provided a burst release of 5-FU in the first 24 h followed by a sustained release of a therapeutic dose (30.7 μg/day) of the drug for up to 32 days. Moreover, subcutaneous implantation of SCPC75/5-FU hybrid disk in an immunocompetent murine model of breast cancer stopped 4T1 tumor growth. Blood analyses showed comparable concentrations of Ca, P and Si in animals implanted with or without SCPC75 disks. These results strongly suggest that SCPC/5-FU hybrids can provide an effective treatment for solid tumors with minimal side effects.

A ceramic-based anticancer drug delivery system to treat breast cancer

We investigated the effects of the endothelin-1 (ET-1) receptor dual antagonist (Bosentan®) on the inflammatory cytokines and the chemoattractant molecules associated with breast cancer growth and the development of tumor infiltration in bone explants. Immunocompetent mice implanted with the murine mammary carcinoma 4T1 cells in a skin-fold chamber and treated with Bosentan® had reduced tumor growth (p < .05). ET-1 promoted the secretion of the anti-inflammatory soluble tumor necrosis factor (TNF) receptor and IL12 p40 in vitro. The Bosentan® treatment in vivo was associated with a local increase of the anti-inflammatory IL-1α cytokine concentration and decrease of the pro-inflammatory TNF-α and IL-17 cytokine concentrations (p < .05).

The Endothelin Axis Stimulates the Expression of Pro-Inflammatory Cytokines and Pro-Migratory Molecules in Breast Cancer

Angiogenic factors including endothelin-1 (ET-1) play a key role in the progression of breast metastases to bone. We investigated the impact of ET-1 on the development of bone metastases in an immunocompetent murine skin-fold chamber model. Murine mammary carcinoma 4T1 was injected in a skin-fold chamber implanted on CB6 mice along with bone explants. Furthermore, mice were treated with or without a dual selective antagonist of both ET-1 receptors. The progression of the vascularization within the chamber was monitored over time by intravital microscopy (IVM). The tumor growth and the development of bone metastases were assessed by cytokeratin-19 gene expression and histological studies. Results indicate that this new model associated with IVM allows for the continuous monitoring of the change in vascularization associated with the development of bone metastases. Additionally, treatment with an antagonist of both ET-1 receptors was associated with the presence of significantly less vessels near the tumor mass compared to control mice. These changes were correlated with smaller tumor masses and reduced bone invasion (P < 0.05). Thus, in an immunocompetent murine model of breast carcinoma metastases to bone, our data support the hypothesis that vascularization plays a role in tumor development and progression and that ET-1 specifically modulates the angiogenesis associated with breast metastases to the bone.

Bosentan ® inhibits tumor vascularization and bone metastasis in an immunocompetent skin-fold chamber model of breast carcinoma cell metastasis

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A ceramic-based anticancer drug delivery system to treat breast cancer

The Endothelin Axis Stimulates the Expression of Pro-Inflammatory Cytokines and Pro-Migratory Molecules in Breast Cancer

Bosentan ® inhibits tumor vascularization and bone metastasis in an immunocompetent skin-fold chamber model of breast carcinoma cell metastasis