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A free radical polymerization method was adopted for the fabrication of hybrid hydrogel films based on acrylamide and polyethylene glycol dimethacrylate as plasticizing and crosslinking agents, respectively, to be employed as smart skin bandages. Electro-sensitivity, biocompatibility and proteolytic properties were conferred to the final polymer networks by introducing graphene oxide (0.5% w/w), gelatin or trypsin (10% w/w) in the polymerization feed. The physical chemical and mechanical characterization of hybrid materials was performed by means of determination of protein content, Raman spectroscopy, thermogravimetric analysis and measurement of tensile strength. The evaluation of both water affinity and curcumin release profiles (analyzed by suitable mathematical modelling) upon application of an external electric stimulation in the 0–48 voltage range, confirmed the possibility to modulate the release kinetics. Proper proteolytic tests showed that the trypsin enzymatic activity was retained by 80% upon immobilization. Moreover, for all samples, we observed a viability higher than 94% in normal human fibroblast cells (MRC-5), while a reduction of methicillin-resistant Staphylococcus aureus CFU mL −1 (90%) was obtained with curcumin loaded samples. [ABSTRACT FROM AUTHOR]

Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells. [Display omitted] • Complex I is a key regulator of CIP2A, a PP2A inhibitor with protumor activity • Increased mROS mediates the dissociation of CIP2A from PP2A and its degradation • Hypoglycemia and low dosages of mROS inducers can be exploited as cancer therapy Cazzoli et al. show that reactive oxygen species production, under low-glucose conditions in combination with low doses of mitochondrial drug inhibitor, enhances CIP2A degradation. CIP2A is an endogenous PP2A inhibitor with a strong prognostic and therapeutic value; more invasive and lethal tumors show increased levels of CIP2A protein. [ABSTRACT FROM AUTHOR]

Abstract: A new hybrid material made of gelatin, catechin and carbon nanotubes was prepared by the non-covalent incorporation of carbon nanotubes (CNTs) into a gelatin–catechin covalent conjugate. The composite materials was tested by means of determination of the dispersion stability in water and the functionalization degree was assessed by the Folin–Ciocalteu method, finding a 0.9mg of CT/g of protein conjugate. Subsequently, the complete retention of the antioxidant properties of the flavonoid after incorporation into the composite was proved by DPPH and ABTS assays and IC50 values of 5.74mgmL−1 and 0.39mgmL−1 were recorded. The presence of CNT into the materials did not interfere with the scavenging activities of the catechin. Finally, the anticancer activity on HeLa cancer cells was evaluated and a considerable increase in the therapeutic activity of the flavonoid was recorded moving from the free to the conjugated form in the presence of CNT, while in absence of CNT a reduction of the efficiency was observed. [Copyright &y& Elsevier]

Abstract: There are conflicting data concerning the safety and biocompatibility of carbon nanotubes (CNTs). In some reports CNTs have been used for gene delivery without significant toxicity, whereas in others various cytotoxic effects were observed, including induction of intracellular reactive oxygen species (ROS), DNA damage, and apoptosis. Although it is clear that CNT production methods, purity, and functionalization treatments impact on biocompatibility, most of the published reports lack detailed characterization of the CNT samples used. We investigated the effect of various physicochemical features of multiwalled carbon nanotubes (MWCNTs) on toxicity and biocompatibility with cultured human neuroblastoma cells by using MTT, WST-1, Hoechst, and oxidative stress assays. In vitro experiments confirm that after 3 days of incubation with three different types of CNTs dispersed in Pluronic F127 solution, 0.01% cell viability is not affected and apoptosis and ROS are not induced in the SH-SY5Y cells. With prolonged cultures and continued propagation in the presence of MWCNTs, the loss of cell viability was minimal for pure MWCNTs (99% purity), but cell proliferation decreased significantly for 97% purity MWCNTs and acid-treated MWCNTs (97% purity, surface oxidation 8%); no intracellular ROS were detected. When the concentration of CNTs increases, purity and surface oxidation seem to affect cell viability (ED25 is 48, 34.4, and 18.4 μg/mL, respectively, for 99% purity MWCNTs, 97% purity MWCNTs, and acid-treated 97% purity MWCNTs. Our results indicate that concentrations of 5–10 μg/mL MWCNTs seem ideal for studies on the design and development of artificial MWCNT nanovectors for gene and drug therapy against cancer. From the Clinical Editor: With prolonged cultures, loss of cell viability was minimal for preparations with 99% purity, but significant adverse effects were detected with 97% purity and with acid-treated preparations. A concentrations of 5–10 μg/mL of MWCNTs seems ideal for gene and drug therapy against cancer. [Copyright &y& Elsevier]

Abstract: Carbon nanotubes are considered important nanodevices in biomedicine, and several applications in drug and gene delivery in different organs and tissues are presently under investigation. Among them very little attention has been dedicated to white adipose tissue (WAT), despite its wide distribution and endocrine role, which could potentially be used to release therapeutic agents. An important premise to use nanotubes in WAT is to determine their potential for toxicity on adipocytes. Here we show that Pluronic F127 (PF127)–coated multiwalled carbon nanotubes (MWCNTs) can be tolerated by NIH-3T3-L1 pre-adipocytes without affecting their growth. Moreover, the differentiation process of NIH-3T3-L1 pre-adipocytes to adipocytes is not compromised by the presence of 5 μg/mL MWCNTs in the medium. These results suggest that reasonable concentrations of PF127-MWCNTs are not toxic for adipocytes and do not interfere with their differentiation process. From the Clinical Editor: This study established that Pluronic F127 (PF127)–coated multiwalled carbon nanotubes (MWCNTs) are tolerated by NIH-3T3-L1 pre-adipocytes. The differentation of these pre-adipocytes is not compromised by the presence of 5 μg/mL MWCNTs, suggesting that these nanotubes are not toxic for adipocytes. [Copyright &y& Elsevier]

Monodispersed polymersomes based on a hydrophobically-modified protein with dimensional range between 154 and 254 nm were prepared employing a water addition/solvent evaporation method. Gelatin hydrolyzate and PEG 40 -stearate, acting as hydrophilic and hydrophobic blocks, respectively, underwent radical coupling and three materials with different hydrophilic/lipophilic ratio were obtained by varying the amount of PEG 40 -stearate in the reaction feed. Critical aggregation concentrations of each amphiphilic polymer were found ranged from 3.9 to 10.2 μg mL −1 , with lower values recorded for conjugate with lower hydrophilic/lipophilic ratio. Anticancer drug methotrexate was loaded into the vesicular systems with efficiency strictly dependent on the gelatin hydrolyzate content and the in vitro releasing profile assessed and analyzed by suitable mathematical models. To prove the applicability of the proposed delivery vehicle, the biocompatibility properties were assessed in normal human lung fibroblasts cells MRC-5, while the anticancer efficiency was tested on H1299 lung cancer cells, proving that the drug encapsulation into the polymersomes dramatically reduced the cytotoxicity on healthy cells while preserving its efficiency in killing cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: The use of controlled electric fields to facilitate cell permeabilisation for enhanced cellular uptake of molecules is well established. The main limitation to the application of this technology in clinical practice is the requirements of high voltages which cause significant cell death in the target tissue. This paper presents a new modality for cell electro-permeabilisation based on the use of carbon nanotubes (CNTs) and external static electric fields. An explanation of the results based on the dielectric response of multiwall CNTs (MWCNTs) to these electric fields is proposed. The experimental data obtained indicate that this method of CNT-enhanced electro-permeabilisation provides an effective means of lowering the electric field voltage required for repairable cell electro-permeabilisation to below 50V/cm and with an efficiency exceeding 80%. [Copyright &y& Elsevier]

In this contribution, we present a strategy to functionalise three natural carbohydrate polymers (dextran − a neutral polymer, sodium alginate − an anionic polymer and chitosan − a cationic polymer) with catechin with excellent degrees of functionality. In a first step, the carbohydrate polymers were oxidised by sodium periodate to yield aldehyde functionalised carbohydrate polymers. The presence of aldehyde groups was exploited to attach catechin by an acid catalysed nucleophilic reaction. The degree of catechin functionalisation could be easily tuned by varying the acid concentration in the reaction mixture, achieving catechin functionalisation levels of up to 48% for dextran aldehyde catechin, 35% for chitosan-aldehyde-catechin and 22% for sodium alginate aldehyde catechin. 1 H, 1 H- 13 C HSQC and DOSY NMR were performed to elucidate the structural differences between the three aldehyde functionalised polysaccharides and how this affects their reactivity and conjugation behaviour. All three carbohydrate polymer-catechin conjugates showed superior free-radical scavenging activity compared with the non-functionalised polymers. [ABSTRACT FROM AUTHOR]

Phenoxodiol is an isoflavone analogue that possesses potent anticancer properties. However, the poor water solubility of phenoxodiol limits its overall efficacy as an anticancer agent. To overcome this, β-cyclodextrin was used to encapsulate phenoxodiol. The phenoxodiol-β-cyclodextrin complex was prepared via a modified co-evaporation method and characterized by 1 H NMR and X-ray crystallography, revealing a 1:2 stoichiometry. The 2D ROESY NMR spectroscopy suggested the limited motion of phenoxodiol within the cavity of β-cyclodextrin while the X-ray crystal data displays by far the best ‘ship-in-a-bottle’ case of 1:2 inclusion complex. The aqueous solubility of the phenoxodiol in β-cyclodextrin had improved and the in vitro biological evaluation revealed enhanced anti-proliferative activity against three cancer cell lines. Additionally, the toxicity of the complex against normal human cell line was 2.5 times lower. These data indicates that the encapsulation of phenoxodiol into β-cyclodextrin leads to an improvement in its overall water solubility and biological activity. [ABSTRACT FROM AUTHOR]

Phenoxodiol is an isoflavene with potent anti-tumor activity. In this study, a series of novel mono- and di-substituted phenoxodiol-thiosemicarbazone hybrids were synthesized via the condensation reaction between phenoxodiol with thiosemicarbazides. The in vitro anti-proliferative activities of the hybrids were evaluated against the neuroblastoma SKN-BE(2)C, the triple negative breast cancer MDA-MB-231, and the glioblastoma U87 cancer cell lines. The mono-substituted hybrids exhibited potent anti-proliferative activity against all three cancer cell lines, while the di-substituted hybrids were less active. Selected mono-substituted hybrids were further investigated for their cytotoxicity against normal MRC-5 human lung fibroblast cells, which identified two hybrids with superior selectivity for cancer cells over normal cells as compared to phenoxodiol. This suggests that mono-substituted phenoxodiol-thiosemicarbazone hybrids have promising potential for further development as anti-cancer agents. [ABSTRACT FROM AUTHOR]

Electro-responsive hybrid hydrogels were synthesized by free radical polymerization using Gelatin-coated multi-walled carbon nanotubes as electro-conductive component, acrylamide and polyethylene glycol dimethacrylate as plasticizing and crosslinking monomer, respectively. Dynamic light scattering, Raman spectroscopy, scanning electron microscopy, resistivity measurement, cell viability assay, and evaluation of swelling degree upon application of an external voltage at 0, 12, 24, 36, and 48 V were performed as characterization tools. Composite materials were found to be highly versatile in modulating the drug delivery of neutral drugs (e.g. Curcumin) as a function of both nanotube content and voltage magnitude, with drug partition between carrier and releasing media being dependent on the balance between electrostatic attractive and repulsive forces and hydrogel swelling degree. Finally, suitable mathematical modelling were employed for the kinetic characterization of the release mechanism. The results allowed hypothesizing the use of hybrid for different therapeutic needs in wound healing treatment. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading non-communicable diseases with highest mortality rates worldwide. About half of all cancer patients receive radiation treatment in the course of their disease. However, treatment outcome and curative potential of radiotherapy is often impeded by genetically and/or environmentally driven mechanisms of tumor radioresistance and normal tissue radiotoxicity. While nanomedicine-based tools for imaging, dosimetry and treatment are potential keys to the improvement of therapeutic efficacy and reducing side effects, radiotherapy is an established technique to eradicate the tumor cells. In order to progress the introduction of nanoparticles in radiooncology, due to the highly interdisciplinary nature, expertise in chemistry, radiobiology and translational research is needed. In this report recent insights and promising policies to design nanotechnology-based therapeutics for tumor radiosensitization will be discussed. An attempt is made to cover the entire field from preclinical development to clinical studies. Hence, this report illustrates (1) the radio- and tumor-biological rationales for combining nanostructures with radiotherapy, (2) tumor-site targeting strategies and mechanisms of cellular uptake, (3) biological response hypotheses for new nanomaterials of interest, and (4) challenges to translate the research findings into clinical trials. [ABSTRACT FROM AUTHOR]

Phenoxodiol, an analogue of the isoflavone natural product daidzein, is a potent anti-cancer agent that has been investigated for the treatment of hormone dependent cancers. This molecular scaffold was reacted with different primary amines and secondary amines under different Mannich conditions to yield either benzoxazine or aminomethyl substituted analogues. These processes enabled the generation of a diverse range of analogues that were required for structure–activity relationship (SAR) studies. The resulting Mannich bases exhibited prominent anti-proliferative effects against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. Further cytotoxicity studies against MRC-5 normal lung fibroblast cells showed that the isoflavene analogues were selective towards cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: Novel spherical hybrid hydrogels composed of gelatin and multi-walled carbon nanotubes were synthesized by emulsion polymerization in the presence of sodium methacrylate and N,N′-ethylenebisacrylamide, and proposed as drug delivery microspheres for the electro-responsive release of Diclofenac sodium salt. Different amounts of nanotubes (up to 35% by weight) were covalently inserted into the polymeric network in order to determine the percentage conferring the highest electric sensitivity to the composite microspheres. Characterization of hydrogels was performed by electrical, morphological and calorimetric analyses, Raman measurements, biocompatibility assays and evaluation of the swelling behaviors in water (pH 1.0 and pH 7.4) with and without the application of an external electric field. Finally, the release profiles were determined and the diffusion behavior was evaluated by semi-empirical equations. [Copyright &y& Elsevier]