What Is the Role of Nanotechnology in Diagnosis and Treatment of Metastatic Breast Cancer? Promising Scenarios for the Near Future

Metastatic breast cancer represents a diagnostic and therapeutic challenge due to tumor heterogeneity and to various physiological barriers that hinder drug delivery to the metastatic sites. To overcome these limitations, nanoformulated drugs have been developed and tested in preclinical studies, and few of them have been successfully translated into clinical practice. In particular, liposomal anthracyclines and nanoformulated albumin-bound paclitaxel have revealed an improved therapeutic index when compared to conventional chemotherapy, with significant reduction of drugs toxicity. Several strategies for nanoparticles engineering have more recently been explored to increase selectivity for tumor cells and to reach poorly accessible metastatic districts. Targeted nanoparticles, directed toward tumor markers and tissue-specific metastases, may provide effective devices in case of low-vascularized and small-sized metastases, thus paving the way for a real change in the natural history of metastatic disease. A number of targets have been identified and exploited for surface functionalization of different types of nanoparticles, which are currently undergoing preclinical studies. The aim of this review is to provide an overview of current nanotechnology applied to metastatic breast cancer diagnosis and treatment. Promising results encourage an upcoming translation of this research into clinical practice for an effective management of the disease in the near future

Antibacterial, antibiofilm, and antiviral farnesol-containing nanoparticles prevent Staphylococcus aureus from drug resistance development

Multidrug antimicrobial resistance is a constantly growing health care issue associated with increased mortality and morbidity, and huge financial burden. Bacteria frequently form biofilm communities responsible for numerous persistent infections resistant to conventional antibiotics. Herein, novel nanoparticles (NPs) loaded with the natural bactericide farnesol (FSL NPs) are generated using high-intensity ultrasound. The nanoformulation of farnesol improved its antibacterial properties and demonstrated complete eradication of Staphylococcus aureus within less than 3 h, without inducing resistance development, and was able to 100% inhibit the establishment of a drug-resistant S. aureus biofilm. These antibiotic-free nano-antimicrobials also reduced the mature biofilm at a very low concentration of the active agent. In addition to the outstanding antibacterial properties, the engineered nano-entities demonstrated strong antiviral properties and inhibited the spike proteins of SARS-CoV-2 by up to 83%. The novel FSL NPs did not cause skin tissue irritation and did not induce the secretion of anti-inflammatory cytokines in a 3D skin tissue model. These results support the potential of these bio-based nano-actives to replace the existing antibiotics and they may be used for the development of topical pharmaceutic products for controlling microbial skin infections, without inducing resistance development.Peer ReviewedPostprint (published version

Cellular Mechanisms Involved in the Combined Toxic Effects of Diesel Exhaust and Metal Oxide Nanoparticles

Diesel exhaust particles (DEPs) and non-exhaust particles from abrasion are two main representative sources of air pollution to which humans are exposed daily, together with emerging nanomaterials, whose emission is increasing considerably. In the present work, we aimed to investigate whether DEPs, metal oxide nanoparticles (MeO-NPs), and their mixtures could affect alveolar cells. The research was focused on whether NPs induced different types of death in cells, and on their effects on cell motility and migration. Autophagy and cell cycles were investigated via cytofluorimetric analyses, through the quantification of the autophagic biomarker LC3B and PI staining, respectively. Cellular ultrastructures were then observed via TEM. Changes in cell motility and migration were assessed via transwell migration assay, and by the cytofluorimetric analysis of E-cadherin expression. A colony-forming efficiency (CFE) assay was performed in order to investigate the interactions between cells inside the colonies, and to see how these interactions change after exposure to the single particles or their mixtures. The results obtained suggest that NPs can either reduce the toxicity of DEPs (CuO) or enhance it (ZnO), through a mechanism that may involve autophagy as cells’ response to stressors and as a consequence of particles’ cellular uptake. Moreover, NPs can induce modification of E-cadherin expression and, consequentially, of colonies’ phenotypes

What Is the Role of Nanotechnology in Diagnosis and Treatment of Metastatic Breast Cancer? Promising Scenarios for the Near Future

Metastatic breast cancer represents a diagnostic and therapeutic challenge due to tumor heterogeneity and to various physiological barriers that hinder drug delivery to the metastatic sites. To overcome these limitations, nanoformulated drugs have been developed and tested in preclinical studies, and few of them have been successfully translated into clinical practice. In particular, liposomal anthracyclines and nanoformulated albumin-bound paclitaxel have revealed an improved therapeutic index when compared to conventional chemotherapy, with significant reduction of drugs toxicity. Several strategies for nanoparticles engineering have more recently been explored to increase selectivity for tumor cells and to reach poorly accessible metastatic districts. Targeted nanoparticles, directed toward tumor markers and tissue-specific metastases, may provide effective devices in case of lowvascularized and small-sized metastases, thus paving the way for a real change in the natural history of metastatic disease. A number of targets have been identified and exploited for surface functionalization of different types of nanoparticles, which are currently undergoing preclinical studies. The aim of this review is to provide an overview of current nanotechnology applied to metastatic breast cancer diagnosis and treatment. Promising results encourage an upcoming translation of this research into clinical practice for an effective management of the disease in the near future

In Vitro Toxicity of TiO2:SiO2 Nanocomposites with Different Photocatalytic Properties

The enormous technological relevance of titanium dioxide (TiO2) nanoparticles (NPs) and the consequent concerns regarding potentially hazardous effects that exposure during production, use, and disposal can generate, encourage material scientists to develop and validate intrinsically safe design solution (safe-by-design). Under this perspective, the encapsulation in a silica dioxide (SiO2) matrix could be an effective strategy to improve TiO2 NPs safety, preserving photocatalytic and antibacterial properties. In this work, A549 cells were used to investigate the toxic effects of silica-encapsulated TiO2 having different ratios of TiO2 and SiO2 (1:1, 1:3, and 3:1). NPs were characterized by electron microscopy and dynamic light scattering, and cell viability, oxidative stress, morphological changes, and cell cycle alteration were evaluated. Resulting data demonstrated that NPs with lower content of SiO2 are able to induce cytotoxic effects, triggered by oxidative stress and resulting in cell necrosis and cell cycle alteration. The physicochemical properties of NPs are responsible for their toxicity. Particles with small size and high stability interact with pulmonary cells more effectively, and the different ratio among silica and titania plays a crucial role in the induced cytotoxicity. These results strengthen the need to take into account a safe(r)-by-design approach in the development of new nanomaterials for research and manufacturing

Safety Assessment of Polypyrrole Nanoparticles and Spray-Coated Textiles

Polypyrrole (PPy) nanoparticles (NPs) are used for the coating of materials, such as textiles, with biomedical applications, including wound care and tissue engineering, but they are also promising antibacterial agents. In this work, PPy NPs were used for the spray-coating of textiles with antimicrobial properties. The functional properties of the materials were verified, and their safety was evaluated. Two main exposure scenarios for humans were identified: inhalation of PPy NPs during spray (manufacturing) and direct skin contact with NPs-coated fabrics (use). Thus, the toxicity properties of PPy NPs and PPy-coated textiles were assessed by using in vitro models representative of the lung and the skin. The results from the materials’ characterization showed the stability of both the PPy NP suspension and the textile coating, even after washing cycles and extraction in artificial sweat. Data from an in vitro model of the air–blood barrier showed the low toxicity of these NPs, with no alteration of cell viability and functionality observed. The skin toxicity of PPy NPs and the coated textiles was assessed on a reconstructed human epidermis model following OECD 431 and 439 guidelines. PPy NPs proved to be non-corrosive at the tested conditions, as well as non-irritant after extraction in artificial sweat at two different pH conditions. The obtained data suggest that PPy NPs are safe NMs in applications for textile coating

Advanced Cell Culture Models Illuminate the Interplay between Mammary Tumor Cells and Activated Fibroblasts

The interaction between tumor cells and activated fibroblasts determines malignant features of desmoplastic carcinomas such as rapid growth, progression towards a metastatic phenotype, and resistance to chemotherapy. On one hand, tumor cells can activate normal fibroblasts and even reprogram them into CAFs through complex mechanisms that also involve soluble factors. Among them, transforming growth factor beta (TGF-β) and Platelet-Derived Growth Factor (PDGF) have an established role in the acquisition of pro-tumorigenic phenotypes by fibroblasts. On the other hand, activated fibroblasts release Interleukin-6 (IL-6), which increases tumor-cell invasiveness and chemoresistance. However, the interplay between breast cancer cells and fibroblasts, as well as the modes of action of TGF-β, PDGF, and IL-6, are difficult to investigate in vivo. Here, we validated the usage of advanced cell culture models as tools to study the interplay between mammary tumor cells and fibroblasts, taking mouse and human triple-negative tumor cells and fibroblasts as a case study. We employed two different settings, one permitting only paracrine signaling, the other both paracrine and cell-contact-based signaling. These co-culture systems allowed us to unmask how TGF-β, PDGF and IL-6 mediate the interplay between mammary tumor cells and fibroblasts. We found that the fibroblasts underwent activation induced by the TGF-β and the PDGF produced by the tumor cells, which increased their proliferation and IL-6 secretion. The IL-6 secreted by activated fibroblasts enhanced tumor-cell proliferation and chemoresistance. These results show that these breast cancer avatars possess an unexpected high level of complexity, which resembles that observed in vivo. As such, advanced co-cultures provide a pathologically relevant tractable system to study the role of the TME in breast cancer progression with a reductionist approach

Iron nanoparticle bio-interactions evaluated in Xenopus laevis embryos, a model for studying the safety of ingested nanoparticles

Iron nanoparticles (NPs) have been proposed as a tool in very different fields such as environmental remediation and biomedical applications, including food fortification against iron deficiency, even if there is still concern about their safety. Here, we propose Xenopus laevis embryos as a suitable model to investigate the toxicity and the bio-interactions at the intestinal barrier of Fe3O4 and zerovalent iron (ZVI) NPs compared to Fe(II) and (III) salts in the 5 to 100 mg Fe/L concentration range using the Frog Embryo Teratogenesis Assay in Xenopus (FETAX). Our results demonstrated that, at concentrations at which iron salts induce adverse effects, both iron NPs do not cause acute toxicity or teratogenicity even if they accumulate massively in the embryo gut. Prussian blue staining, confocal and electron microscopy allowed mapping of iron NPs in enterocytes, along the paracellular spaces and at the level of the basement membrane of a well-preserved intestinal epithelium. Furthermore, the high bioaccumulation factor and the increase in embryo length after exposure to iron NPs suggest greater iron intake, an essential element for organisms. Together, these results improve the knowledge on the safety of orally ingested iron NPs and their interaction with the intestinal barrier, useful for defining the potential risks associated with their use in food/feed fortification

Heparin–Superparamagnetic Iron Oxide Nanoparticles for Theranostic Applications

In this study, superparamagnetic iron oxide nanoparticles (SPIONs) were engineered with an organic coating composed of low molecular weight heparin (LMWH) and bovine serum albumin (BSA), providing heparin-based nanoparticle systems (LMWH@SPIONs). The purpose was to merge the properties of the heparin skeleton and an inorganic core to build up a targeted theranostic nanosystem, which was eventually enhanced by loading a chemotherapeutic agent. Iron oxide cores were prepared via the co-precipitation of iron salts in an alkaline environment and oleic acid (OA) capping. Dopamine (DA) was covalently linked to BSA and LMWH by amide linkages via carbodiimide coupling. The following ligand exchange reaction between the DA-BSA/DA-LMWH and OA was conducted in a biphasic system composed of water and hexane, affording LMWH@SPIONs stabilized in water by polystyrene sulfonate (PSS). Their size and morphology were investigated via dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The LMWH@SPIONs’ cytotoxicity was tested, showing marginal or no toxicity for samples prepared with PSS at concentrations of 50 µg/mL. Their inhibitory activity on the heparanase enzyme was measured, showing an effective inhibition at concentrations comparable to G4000 (N-desulfo-N-acetyl heparin, a non-anticoagulant and antiheparanase heparin derivative; Roneparstat). The LMWH@SPION encapsulation of paclitaxel (PTX) enhanced the antitumor effect of this chemotherapeutic on breast cancer cells, likely due to an improved internalization of the nanoformulated drug with respect to the free molecule. Lastly, time-domain NMR (TD-NMR) experiments were conducted on LMWH@SPIONs obtaining relaxivity values within the same order of magnitude as currently used commercial contrast agents