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Antonia Mancuso,1 Maria Chiara Cristiano,2 Massimo Fresta,1 Donatella Paolino2 1Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro 88100, Italy; 2Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, Catanzaro 88100, ItalyCorrespondence: Donatella PaolinoUniversity “Magna Græcia” of Catanzaro, Viale Europa, Catanzaro 88100, ItalyTel +39 09613694211Email paolino@unicz.itAbstract: Acne is a common skin disease that affect over 80% of adolescents. It is characterized by inflammation of the hair bulb and the attached sebaceous gland. To date, many strategies have been used to treat acne as a function of the disease severity. However, common treatments for acne seem to show several side effects, from local irritation to more serious collateral effects. The use of topical vesicular carriers able to deliver active compounds is currently considered as an excellent approach in the treatment of different skin diseases. Many results in the literature have proven that drug delivery systems are useful in overcoming the toxicity induced by common drug therapies, while maintaining their therapeutic efficacy. Starting from these assumptions, the authors reviewed drug delivery systems already realized for the topical treatment of acne, with a focus on their limitations and advantages over conventional treatment strategies. Although their exact mechanism of permeation is not often completely clear, deformable vesicles seem to be the best solution for obtaining a specific delivery of drugs into the deeper skin layers, with consequent increased local action and minimized collateral effects.Keywords: targeted therapy, skin, anti-acne drugs, nanocarriers, drug delivery systems

Marianecci C, Rinaldi F, Di Marzio L, et al. Int J Nanomedicine. 2014;9(1):635–651. The Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. Concerns were raised regarding the alleged duplication of TEM images in Figure 1. Specifically, Figure 1A, F1, appears to have been duplicated with the same image for Figure 1C, F3 and Figure 1D, F3AG. The authors did respond to our queries but were unable to explain how the duplication of images occurred, nor were they able to provide the original TEM images from the reported study. The decision was made to retract the article and the authors were notified of this. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Agnese Gagliardi,1 Donatella Paolino,1 Michelangelo Iannone,2 Ernesto Palma,3 Massimo Fresta,3 Donato Cosco3 1Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy; 2CNR, Section of Pharmacology, Institute of Neurological Sciences, Borgia, Italy; 3Department of Health Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy Background: The use of biopolymers is increasing in drug delivery, thanks to the peculiar properties of these compounds such as their biodegradability, availability, and the possibility of modulating their physico-chemical characteristics. In particular, protein-based systems such as albumin are able to interact with many active compounds, modulating their biopharmaceutical properties. Zein is a protein of 20–40 kDa made up of many hydrophobic amino acids, generally regarded as safe (GRAS) and used as a coating material. Methods: In this investigation, zein was combined with various surfactants in order to obtain stable nanosystems by means of the nanoprecipitation technique. Specific parameters, eg, temperature, pH value, Turbiscan Stability Index, serum stability, in vitro cytotoxicity and entrapment efficiency of various model compounds were investigated, in order to identify the nanoformulation most useful for a systemic drug delivery application. Results: The use of non-ionic and ionic surfactants such as Tween 80, poloxamer 188, and sodium deoxycholate allowed us to obtain nanoparticles characterized by a mean diameter of 100–200 nm when a protein concentration of 2 mg/mL was used. The surface charge was modulated by means of the protein concentration and the nature of the stabilizer. The most suitable nanoparticle formulation to be proposed as a colloidal drug delivery system was obtained using sodium deoxycholate (1.25% w/v) because it was characterized by a narrow size distribution, a good storage stability after freeze-drying and significant feature of retaining lipophilic and hydrophilic compounds. Conclusion: The sodium deoxycholate-coated zein nanoparticles are stable biocompatible colloidal carriers to be used as useful drug delivery systems. Keywords: nanoparticles, sodium deoxycholate, stabilizers, zein

Donato Cosco,1,5,* Cinzia Federico,1,2,* Jessica Maiuolo,1 Stefania Bulotta,1 Roberto Molinaro,1,3 Donatella Paolino,1,5 Pierfrancesco Tassone,2,4 Massimo Fresta1Department of Health Sciences, 2Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Catanzaro, Italy; 3Department of NanoMedicine, The Methodist Research Institute, Houston, TX, USA; 4Medical Oncology, Tommaso Campanella Cancer Center, Viale S Venuta, Germaneto, 5Interregional Research Center for Food Safety and Health, University of Catanzaro “Magna Græcia”, Catanzaro, Italy*These authors contributed equally to this paperAbstract: The aim of this study was the evaluation of the effects of two emulsifiers on the physicochemical and technological properties of low molecular weight chitosan/poly (D,L-lactide-co-glycolide) (PLGA) nanoplexes and their transfection efficiency. Nanospheres were prepared using the nanoprecipitation method of the preformed polymer. The mean diameter and surface charge of the nanospheres were investigated by photocorrelation spectroscopy. The degree of binding of the plasmid with the nanoplexes was qualitatively and quantitatively determined. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) testing was performed using HeLa, RPMI8226, and SKMM1 cell lines. Flow cytometry and confocal laser scanning microscopy were used to determine the degree of cellular transfection and internalization of the nanoplexes into cells, respectively. The nanoplexes had a positive zeta potential, and low amounts of PLGA and poloxamer 188 showed a mean colloidal size of ~200 nm with a polydispersity index of ~0.14. The nanoplexes had suitable entrapment efficiency (80%). In vitro experiments showed that the colloidal nanodevices did not induce significant cytotoxicity. The nanoplexes investigated in this study could represent efficient and useful nonviral devices for gene delivery. Use of low amounts of PLGA and poloxamer 188 enabled development of a nanosphere able to transfect cells efficiently. These nanosystems are a helpful platform for delivery of genetic material while preserving therapeutic efficacy.Keywords: nanoplexes, gene delivery, chitosan, poly(D,L-lactide-co-glycolide), poloxamer 188

Carlotta Marianecci,1 Federica Rinaldi,1 Luisa Di Marzio,2 Marica Mastriota,3 Stefano Pieretti,3 Christian Celia,2,4 Donatella Paolino,5 Michelangelo Iannone,6,7 Massimo Fresta,5 Maria Carafa11Department of Drug Chemistry and Technologies, University Sapienza of Rome, Rome, 2Department of Pharmacy, University G d'Annunzio of Chieti of Pescara, Chieti, 3Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy; 4Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX, USA; 5Department of Health Sciences, University Magna Graecia of Catanzaro, University Campus S Venuta, Building of BioSciences, Germaneto, 6ARPA Calabria, Environmental Epidemiology Center, 7CNR, Neuroscience Institute, Pharmacology Section, Complesso "Nini Barbieri", Roccelletta di Borgia, ItalyBackground: Liquorice extracts demonstrate therapeutic efficacy in treating dermatitis, eczema, and psoriasis when compared with corticosteroids. In this work, nonionic surfactant vesicles (niosomes, NSVs) containing polysorbate 20 (Tween 20), cholesterol, and cholesteryl hemisuccinate at different molar concentrations were used to prepare monoammonium glycyrrhizinate (AG)-loaded NSVs. The anti-inflammatory properties of AG-loaded NSVs were investigated in murine models.Methods: The physicochemical properties of the NSVs were characterized using dynamic light scattering. The fluidity of the lipid bilayer was evaluated by measuring the fluorescence intensity of diphenylhexatriene. The drug entrapment efficiency of AG was assessed using high-performance liquid chromatography. The physicochemical stability of the NSVs was evaluated as a function of time using dynamic light scattering combined with Turbiscan Lab® Expert analysis. Serum stability was determined by incubating the NSVs with 10% v/v fetal bovine serum. The cytotoxic effects of the NSVs were investigated in human dermal fibroblasts using the Trypan blue dye exclusion assay (for cell mortality) and an MTT assay (for cell viability). Release profiles for the AG-loaded NSVs were studied in vitro using cellulose membranes. NSVs showing the most desirable physicochemical properties were selected to test for in vivo anti-inflammatory activity in murine models. The anti-inflammatory activity of the NSVs was investigated by measuring edema and nociception in mice stimulated with chemical agents.Results: NSVs showed favorable physicochemical properties for in vitro and in vivo administration. In addition, they demonstrated long-term stability based on Turbiscan Lab Expert analysis. The membrane fluidity of the NSVs was not affected by self-assembling of the surfactants into colloidal structures. Fluorescence anisotropy was found to be independent of the molar ratios of cholesteryl hemisuccinate and/or cholesterol during preparation of the NSVs. The anti-inflammatory AG drug showed no effect on the stability of the NSVs. In vivo experiments demonstrated that AG-loaded NSVs decreased edema and nociceptive responses when compared with AG alone and empty NSVs. In vitro and in vivo results demonstrated that pH sensitive and neutral NSVs show no statistical significant difference.Conclusion: NSVs were nontoxic and showed features favorable for potential administration in vivo. In addition, neutral NSVs showed signs of increased anti-inflammatory and anti-nociceptive responses when compared with AG.Keywords: niosomes, ammonium glycyrrhizinate, pH sensitivity, cytotoxicity, inflammation

Donato Cosco,1 Flavio Rocco,2 Maurizio Ceruti,2 Margherita Vono,1 Massimo Fresta,1,3 Donatella Paolino1,31Department of Health Sciences, University "Magna Græcia", Catanzaro; 2Dipartimento di Scienza e Tecnologia del Farmaco, Torino; 3UOC Farmacia Ospedaliera Fondazione per la Ricerca e la Cura dei Tumori "Tommaso Campanella", Campus Universitario "S Venuta", Catanzaro, ItalyBackground: In this investigation, the antileukemic activity of a new nanomedicine based on the conjugation of 1,1',2-tris-nor-squalenic acid with cytarabine (Ara-C) was evaluated.Methods: Squalenoyl-Ara-C conjugate (Sq-Ara-C) self-assembled nanosystems were obtained by the nanoprecipitation method and characterized in vitro and in vivo.Results: This new nanomedicine, which had a mean diameter of approximately 150 nm, improved the in vitro antitumoral activity of Ara-C in different cancer cell lines (L1210, K562, and MCF-7). Sq-Ara-C nanomedicine allowed reduction of the IC50 value with respect to the free drug and was also active against drug-resistant leukemic cells (L1210R). A noticeable increase in the survival rate of mice with aggressive metastatic L1210R leukemia was observed after treatment with Sq-Ara-C (50 mg/kg) as compared with the free active compound (100 mg/kg). Finally, evaluation of the biodistribution and pharmacokinetic profiles of the drug demonstrated that these nanoaggregates preferentially localized to the liver and spleen, and protected the drug from physiological metabolism.Conclusion: Squalenoylation of cytarabine offers several pharmacological benefits both in vitro and in vivo.Keywords: squalenoyl-cytarabine, self-assembly, antitumoral nanomedicine, leukemia, nanoaggregate, biodistribution