Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity

The great advances in the studies on metal complexes for the treatment of different cancer forms, starting from the pioneering works on platinum derivatives, have fostered an increasingly growing interest in their properties and biomedical applications. Among the various metal-containing drugs investigated thus far, ruthenium(III) complexes have emerged for their selective cytotoxic activity in vitro and promising anticancer properties in vivo, also leading to a few candidates in advanced clinical trials. Aiming at addressing the solubility, stability and cellular uptake issues of low molecular weight Ru(III)-based compounds, some research groups have proposed the development of suitable drug delivery systems (e.g., taking advantage of nanoparticles, liposomes, etc.) able to enhance their activity compared to the naked drugs. This review highlights the unique role of Ru(III) complexes in the current panorama of anticancer agents, with particular emphasis on Ru-containing nanoformulations based on the incorporation of the Ru(III) complexes into suitable nanocarriers in order to enhance their bioavailability and pharmacokinetic properties. Preclinical evaluation of these nanoaggregates is discussed with a special focus on the investigation of their mechanism of action at a molecular level, highlighting their pharmacological potential in tumour disease models and value for biomedical applications

Crosstalk between oral and general health status in e-smokers

Electronic cigarette (e-cigarette) simulates the act of tobacco smoking by vaporizing a mixture of propylene glycol, nicotine, and flavoring agents. e-cigarette has been proposed as a product able to aid to stop smoking. The aim of the study is to verify the clinical variations of periodontal health induced by e-cigarettes use and, moreover, to investigate about the awareness of the e-smokers about their health variations and about their hypothetical need to turn back to smoke combustible cigarettes.This clinical observational pilot study involved 110 out of 350 smokers, who switched to e-cigarette. Patients were subjected to oral examinations. A questionnaire to self-assess the variations of some parameters of general health, and to self-assess the need to smoke combustible cigarettes, was distributed to such subjects involved in the study.At the end of the study, we registered a progressive improvement in the periodontal indexes, as well as in the general health perception. Finally, many patients reported an interesting reduction in the need to smoke.In the light of this pilot study, the e-cigarette can be considered as a valuable alternative to tobacco cigarettes, but with a positive impact on periodontal and general health status

Micelles by self-assembling peptide-conjugate amphiphile: synthesis and structural characterization.

The solid-phase synthesis of a novel amphiphilic peptide conjugate I, contg. in the same mol. three different functions: N,N-bis[2-[bis(carboxyethyl)amino]ethyl]-L-glutamic acid chelating agent, the CCK8 bioactive peptide, and a hydrophobic moiety contg. four alkyl chains with 18 carbon atoms each, is reported. In water soln. at pH 7.4, I self-assembles in very stable micelles at very low concn. [crit. micellar concn. (cmc) values of 5 10-7 mol kg-1] as confirmed by fluorescence spectroscopy. The structural characterization, obtained with small-angle neutron scattering (SANS) measurements, indicates that the aggregates are substantially represented by ellipsoidal micelles with an aggregation no. of 39 2 and the two micellar axes of about 52 and 26

A negative selection heuristic to predict new transcriptional targets

Background: Supervised machine learning approaches have been recently adopted in the inference of transcriptional targets from high throughput trascriptomic and proteomic data showing major improvements from with respect to the state of the art of reverse gene regulatory network methods. Beside traditional unsupervised techniques, a supervised classifier learns, from known examples, a function that is able to recognize new relationships for new data. In the context of gene regulatory inference a supervised classifier is coerced to learn from positive and unlabeled examples, as the counter negative examples are unavailable or hard to collect. Such a condition could limit the performance of the classifier especially when the amount of training examples is low. Results: In this paper we improve the supervised identification of transcriptional targets by selecting reliable counter negative examples from the unlabeled set. We introduce an heuristic based on the known topology of transcriptional networks that in fact restores the conventional positive/negative training condition and shows a significant improvement of the classification performance. We empirically evaluate the proposed heuristic with the experimental datasets of Escherichia coli and show an example of application in the prediction of BCL6 direct core targets in normal germinal center human B cells obtaining a precision of 60%. Conclusions: The availability of only positive examples in learning transcriptional relationships negatively affects the performance of supervised classifiers. We show that the selection of reliable negative examples, a practice adopted in text mining approaches, improves the performance of such classifiers opening new perspectives in the identification of new transcriptional targets

Bioimpedance detection of Oral Lichen Planus used as preneoplastic model

Introduction: Bioimpedance is a measure of the electrical properties of biological tissues. In the last two decades bioimpedance has been successfully introduced in clinical diagnosis of cancer. It has been demonstrated that tumoral tissues often show lower bioimpedance values than healthy tissues. The aim of this work is to assess the bioimpedentiometric differences between healthy and Oral Lichen Planus (OLP) affected oral mucosa, taking attention to the erosive form which may represent a potential pre-cancerous condition. Methods: 52 patients affected by OLP were recruited for bioimpedance examination of oral mucosa. Four electrical properties, resistance (R), reactance (Xc), phase angle (θ) and impedance (Z) of the tongue and of the intraoral mucosa, were measured. Results: We observed a significant increase of Z and a significant decrease of θ values in correspondence of OLP lesions compared to healthy oral mucosa, and a marked decrease of Z values in correspondence of erosive OLP lesions. Conclusions: These results provide evidence of the usefulness of bioimpedance assay for the characterization of healthy and clinically OLP affected mucosa. Bioimpedance is a valid aid in the early detection and clinical monitoring of the suspicious lesions which could lead to a potentially malignant evolution. The present research article is a valuable addition to the scientific literature of cancer prevention, and our findings can be considered extremely encouraging as they represent the initial step for a more wide clinical study for better define the different cut-off values in the different precancerous conditions occurring in the oral mucosa

Polymerized mixed aggregates containing gadolinium complex and CCK8 peptide.

Two novel amphiphilic unimers contg. an aliph. hydrophobic chain (PDA) with two C C triple bonds and hydrophilic heads presenting the chelating agent DTPAGlu and the CCK8 bioactive peptide, resp., have been prepd. by solid phase synthesis. Aggregates obtained by mixing together PDA-DTPAGlu, or its Gd(III) complex, and PDA-L2-CCK8 in 70/30 molar ratio before and after a polymn. process carried out by UV irradn. have been structurally characterized by means of small angle neutron scattering. The relaxivity properties of aggregates contg. Gadolinium complexes have also been investigated. Elongated mixed micelles have been obsd., in which the relaxivity value r1p for each Gadolinium complex, measured at 20 MHz and 298 K, is around 12 mM-1s-1

perspectives and potential applications of ruthenium based nanocarriers for cancer therapy

Perspectives and Potential Applications of Ruthenium-Based Nanocarriers for Cancer Therapy Rita Santamaria*1 , Carlo Irace1, Gerardino D'Errico 2, Daniela Montesarchio2 and Luigi Paduano2 1Department of Pharmacy, University of Napoli "Federico II", via D. Montesano 49, I-80131, Napoli, Italy 2Department of Chemical Sciences, University of Napoli "Federico II", Complesso Universitario di Monte Sant'Angelo, via Cintia 21, I-80126, Napoli, Italy *Corresponding author: Rita Santamaria, Associate Professor, Department of Pharmacy, University of Napoli "Federico II", via D. Montesano 49, I-80131, Napoli, Italy, Fax: 0039081678403, Tel: 0039 081678421, E-Mail: [email protected] Citation: Rita Santamaria, Carlo Irace, Gerardino D'Errico, Daniela Montesarchio, Luigi Paduano (2013) Perspectives and Potential Applications of Ruthenium-Based Nanocarriers for Cancer Therapy. J Pharm Drug Devel 1(2): e201. doi: 10.15744/2348-9782.1.e201 Received Date: September 30, 2013 Accepted Date: October 15, 2013 Published Date: October 23, 2013 Editorial Open Acces

Physicochemical properties of mixed micellar aggregates containing CCK peptides and Gd complexes designed as tumor specific contrast agents in MRI

New amphiphilic molecules containing a bioactive peptide or a claw moiety have been prepared in order to obtain mixed micelles as target-specific contrast agents in magnetic resonance imaging. The first molecule, C18H37CONH(AdOO)2-G-CCK8 (C18CCK8), contains a C18 hydrophobic moiety bound to the C-terminal cholecystokinin octapeptide amide (CCK 26-33 or CCK8). The second amphiphilic compound, C18H37CONHLys(DTPAGlu)CONH2 (C18DTPAGlu) or its gadolinium complex, (C18DTPAGlu- (Gd)), contains the same C18 hydrophobic moiety bound, through a lysine residue, to the DTPAGlu chelating agent. The mixed aggregates as well as the pure C18DTPAGlu aggregate, in the presence and absence of Gd, have been fully characterized by surface tension measurements, FT-PGSE-NMR, fluorescence quenching, and small-angle neutron scattering measurements. The structural characterization of the mixed aggregates C18DTPAGlu(Gd)-C18CCK8 indicates a spherical arrangement of the micelles with an external shell of 21 Å and an inner core of 20 Å. Both the DTPAGlu(Gd) complexes and the CCK8 peptides point toward the external surface. The measured values for relaxivity in saline medium at 20 MHz proton Larmor frequency and 25 °C are 18.7 mM-1 s-1. These values show a large enhancement in comparison with the isolated DTPAGlu(Gd) complex

Breast cancer chemotherapeutic options: a general overview on the preclinical validation of a multi-target ruthenium(III) complex lodged in nucleolipid nanosystems

In this review we have showcased the preclinical development of original amphiphilic nanomaterials designed for ruthenium‐based anticancer treatments, to be placed within the current metallodrugs approach leading over the past decade to advanced multitarget agents endowed with limited toxicity and resistance. This strategy could allow for new options for breast cancer (BC) interventions, including the triple‐negative subtype (TNBC) with poor therapeutic alternatives. BC is currently the second most widespread cancer and the primary cause of cancer death in women. Hence, the availability of novel chemotherapeutic weapons is a basic requirement to fight BC subtypes. Anticancer drugs based on ruthenium are among the most explored and advanced nextgeneration metallotherapeutics, with NAMI‐A and KP1019 as two iconic ruthenium complexes having undergone clinical trials. In addition, many nanomaterial Ru complexes have been recently conceived and developed into anticancer drugs demonstrating attractive properties. In this field, we focused on the evaluation of a Ru(III) complex—named AziRu—incorporated into a suite of both zwitterionic and cationic nucleolipid nanosystems, which proved to be very effective for the in vivo targeting of breast cancer cells (BBC). Mechanisms of action have been widely explored in the context of preclinical evaluations in vitro, highlighting a multitarget action on cell death pathways which are typically deregulated in neoplasms onset and progression. Moreover, being AziRu inspired by the well‐known NAMI‐A complex, information on non‐nanostructured Ru‐based anticancer agents have been included in a precise manner

The antimicrobial peptide Magainin-2 interacts with BamA impairing folding of E. coli membrane proteins

: Antimicrobial peptides (AMPs) are a unique and diverse group of molecules endowed with a broad spectrum of antibiotics properties that are being considered as new alternative therapeutic agents. Most of these peptides are membrane-active molecules, killing bacteria by membrane disruption. However, recently an increasing number of AMPs was shown to enter bacterial cells and target intracellular processes fundamental for bacterial life. In this paper we investigated the mechanism of action of Maganin-2 (Mag-2), a well-known antimicrobial peptide isolated from the African clawed frog Xenopus laevis, by functional proteomic approaches. Several proteins belonging to E. coli macromolecular membrane complexes were identified as Mag-2 putative interactors. Among these, we focused our attention on BamA a membrane protein belonging to the BAM complex responsible for the folding and insertion of nascent β-barrel Outer Membrane Proteins (OMPs) in the outer membrane. In silico predictions by molecular modelling, in vitro fluorescence binding and Light Scattering experiments carried out using a recombinant form of BamA confirmed the formation of a stable Mag-2/BamA complex and indicated a high affinity of the peptide for BamA. Functional implications of this interactions were investigated by two alternative and complementary approaches. The amount of outer membrane proteins OmpA and OmpF produced in E. coli following Mag-2 incubation were evaluated by both western blot analysis and quantitative tandem mass spectrometry in Multiple Reaction Monitoring scan mode. In both experiments a gradual decrease in outer membrane proteins production with time was observed as a consequence of Mag-2 treatment. These results suggested BamA as a possible good target for the rational design of new antibiotics since this protein is responsible for a crucial biological event of bacterial life and is absent in humans