International Journal of Pharmaceutics (v.510, #2)

Noticeboard (IV).

Advanced nano- and bio-materials: A pharmaceutical approach by Alexandru Mihai Grumezescu; Anca Dumitru; Sorin Ion Jinga (407-408).

Control of biofilm-associated infections by signaling molecules and nanoparticles by Alina Maria Holban; Monica Cartelle Gestal; Alexandru Mihai Grumezescu (409-418).
Display OmittedAs the severe infections caused by resistant pathogens and biofilm embedded bacteria continue to emerge, alternative antimicrobial strategies could represent a solution. Recent studies support the development of molecular approaches (through signaling molecules) aiming to fight infections by modulating the virulence, behavior and formation of resistance structures such as biofilms. The utilization of such formulations would offer the advantage of reducing the selection of resistant isolates, since most of the proposed molecules do not interfere with the population fitness if utilized in low amounts. Despite the promising results, these therapies are delaying to be applied in the clinical context mainly because of the following: (i) limited knowledge regarding their long and medium term effect, (ii) specific properties that make most of these molecules difficult to be utilized in pharmacological formulations, (iii) low stability, (iv) difficulty to reach a target within the host body, and (v) limited availability. For reducing most of these disadvantages, nanotechnology seem to offer the best option through the development of nanostructured materials and nanoparticles able to improve the efficiency of molecular virulence modulators and novel antimicrobial compounds and to ensure their targeted delivery and controlled release.
Keywords: Antimicrobial nanoparticles; Virulence modulators; Signaling molecules; Functionalized nanomaterials; Biofilm control;

Polymeric protective agents for nanoparticles in drug delivery and targeting by George Dan Mogoşanu; Alexandru Mihai Grumezescu; Cornelia Bejenaru; Ludovic Everard Bejenaru (419-429).
Display OmittedSurface modification/functionalization of nanoparticles (NPs) using polymeric protective agents is an issue of great importance and actuality for drug delivery and targeting. Improving the blood circulation half-life of surface-protected nanocarriers is closely related to the elimination of main biological barriers and limiting factors (protein absorption and opsonization), due to the phagocytic activity of reticuloendothelial system. For passive or active targeted delivery, in biomedical area, surface-functionalized NPs with tissue-recognition ligands were designed and optimized as a result of modern research techniques. Also, multi-functionalized nanostructures are characterized by enhanced bioavailability, efficacy, targeted localization, active cellular uptake, and low side effects. Surface-protected NPs are obtained from biocompatible, biodegradable and less toxic natural polymers (dextran, β-cyclodextrin, chitosan, hyaluronic acid, heparin, gelatin) or synthetic polymers, such as poly(lactic acid), poly(lactic-co-glycolic) acid, poly(ε-caprolactone) and poly(alkyl cyanoacrylates). PEGylation is one of the most important functionalization methods providing steric stabilization, long circulating and ‘stealth’ properties for both polymeric and inorganic-based nanosystems. In addition, for their antimicrobial, antiviral and antitumor effects, cutting-edge researches in the field of pharmaceutical nanobiotechnology highlighted the importance of noble metal (platinum, gold, silver) NPs decorated with biopolymers.
Keywords: Polymers; Protective agents; PEGylation; Nanoparticles; Delivery; Targeting;

Preparation and characterization of undoped and cobalt doped ZnO for antimicrobial use by Angelica Oprea Stoica; Ecaterina Andronescu; Cristina Daniela Ghitulica; Georgeta Voicu; Alexandru Mihai Grumezescu; Marcela Popa; Mariana Carmen Chifiriuc (430-438).
Display OmittedThe objective of this study was to carry out the synthesis by sol-gel method of undoped and cobalt doped ZnO, with different cobalt concentrations (0.5–5 mol%), using as stabilizer monoethanolamine (MEA) in a molar ratio ZnO:MEA = 1:2. The dry gel was thermally treated at 500 °C/5 h, respectively at 1100 °C/30 min. All the thermal treated samples were of wurtzite type with an hexagonal structure. The doping with Co2+ induced change of lattice parameters and of crystallite size, proving the successful interleaving of Co2+ into the ZnO lattice.From the morphological point of view, the thermal treatment at 1100 °C/30 min led to a higher degree of compactness of the ZnO granules. At 500 °C/5 h there were formed polyhedral or spherical nanometric particles (25–50 nm) which have been agglomerated into aggregates with sizes over 1 μm.From the biological point of view, the quantitative analyses of antimicrobial activity have shown that the ZnO doped with cobalt has inhibited the ability of the Bacillus subtilis and Escherichia coli bacterial strains to colonize the inert substrate and therefore, can be used in the design of new antimicrobial strategies.
Keywords: Sol–gel; Zinc oxide; Monoethanolamine; Antimicrobial properties;

Influence of hot isostatic pressing on ZrO2–CaO dental ceramics properties by Alin Gionea; Ecaterina Andronescu; Georgeta Voicu; Coralia Bleotu; Vasile-Adrian Surdu (439-448).
Display OmittedDifferent hot isostatic pressing conditions were used to obtain zirconia ceramics, in order to assess the influence of HIP on phase transformation, compressive strength, Young’s modulus and density. First, CaO stabilized zirconia powder was synthesized through sol–gel method, using zirconium propoxide, calcium isopropoxide and 2-metoxiethanol as precursors, then HIP treatment was applied to obtain final dense ceramics. Ceramics were morphologically and structurally characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). Density measurements, compressive strength and Young’s modulus tests were also performed in order to evaluate the effect of HIP treatment. The zirconia powders heat treated at 500 °C for 2 h showed a pure cubic phase with average particle dimension about 70 nm. The samples that were hot isostatic pressed presented a mixture of monoclinic–tetragonal or monoclinic–cubic phases, while for pre-sintered samples, cubic zirconia was the single crystalline form. Final dense ceramics were obtained after HIP treatment, with relative density values higher than 94%. ZrO2–CaO ceramics presented high compressive strength, with values in the range of 500–708.9 MPa and elastic behavior with Young’s modulus between 1739 MPa and 4372 MPa. Finally zirconia ceramics were tested for biocompatibility allowing the normal development of MG63 cells in vitro.
Keywords: Sol–gel; Hot isostatic pressing; ZrO2; Biomedical applications; Ceramics;

Vitroceramic interface deposited on titanium substrate by pulsed laser deposition method by Georgeta Voicu; Dana Miu; Ionut Dogaru; Sorin Ion Jinga; Cristina Busuioc (449-456).
Display OmittedPulsed laser deposition (PLD) method was used to obtain biovitroceramic thin film coatings on titanium substrates. The composition of the targets was selected from SiO2–CaO–P2O5–(CaF2) systems and the corresponding masses were prepared using the sol–gel method. The depositions were performed in oxygen atmosphere (100 mTorr), while the substrates were heated at 400 °C. The PLD deposited films were analysed through different experimental techniques: X-ray diffraction, scanning (SEM, EDX) and transmission (HRTEM, SAED) electron microscopy and infra-red spectroscopy coupled with optical microscopy. They were also biologically tested by in vitro cell culture and the contact angle was determined. The bioevaluation results indicate a high biocompatibilty of the obtained materials, demonstrating their potential use for biomedical applications.
Keywords: Titanium implants; Bioactive coatings; Glass-ceramics; Sol–gel; Pulsed laser deposition;

Extended release of vitamins from magnetite loaded polyanionic polymeric beads by Maria Sonmez; Cristina Verisan; Georgeta Voicu; Denisa Ficai; Anton Ficai; Alexandra Elena Oprea; Mihaela Vlad; Ecaterina Andronescu (457-464).
Display OmittedHere we explore a novel approach of increasing the release duration of folic and ascorbic acid from magnetite entrapped into calcium–alginate beads. Synthesis and characterization of magnetite-vitamins complexes are reported. The magnetite–vitamins complexes were characterized by FT-IR, XRD, SEM, BET and DTA-TG. Also calcium–alginate magnetic beads were prepared by dripping a mixture of sodium alginate with magnetite-vitamins complexes into calcium chloride solution. Extended release profile of the two experimental models was evaluated and quantified by UV–vis.
Keywords: Magnetite–vitamins; Folic acid; Ascorbic acid; Polymeric beads;

Electrochromic properties of polyaniline-coated fiber webs for tissue engineering applications by Mihaela Beregoi; Cristina Busuioc; Alexandru Evanghelidis; Elena Matei; Florin Iordache; Mihaela Radu; Anca Dinischiotu; Ionut Enculescu (465-473).
Display OmittedBy combining the electrospinning method advantages (high surface-to-volume ratio, controlled morphology, varied composition and flexibility for the resulting structures) with the electrical activity of polyaniline, a new core–shell-type material with potential applications in the field of artificial muscles was synthesized. Thus, a poly(methylmethacrylate) solution was electrospun in optimized conditions to obtain randomly oriented polymer fiber webs. Further, a gold layer was sputtered on their surface in order to make them conductive and improve the mechanical properties. The metalized fiber webs were then covered with a PANI layer by in situ electrochemical polymerization starting from aniline and using sulphuric acid as oxidizing agent. By applying a small voltage on PANI-coated fiber webs in the presence of an electrolyte, the oxidation state of PANI changes, which is followed by the device color modification. The morphological, electrical and biological properties of the resulting multilayered material were also investigated.
Keywords: Polyaniline; Fibers; Electrospinning; Artificial muscles; Tissue engineering; Biomimetics;

Synthesis, characterization and bioevaluation of drug-collagen hybrid materials for biomedical applications by Georgeta Voicu; Ruxandra-Elena Geanaliu-Nicolae; Adrian-Alexandru Pîrvan; Ecaterina Andronescu; Florin Iordache (474-484).
Display OmittedThis work presents a study based on the preparation and characterization of drug-collagen hybrid materials. Materials used for obtaining drug-collagen hybrids were collagen type I (Coll) as matrix and fludarabine (F) and epirubicin (E) as hydrophilic active substances. After incorporation of drugs into Coll in different ratios, the obtained hybrid materials (Coll/F and Coll/E) could be used according to our results as potential drug delivery systems in medicine for the topical (local) treatment of cancerous tissues (e.g. the treatment of breast, stomach, lung, colorectal or advanced ovarian cancer).The materials were characterized considering their composition (by XRD, FT-IR and DTA–TG) and their morphology (by SEM). The delivery of drug was assessed by UV–vis.The in vitro citotoxicity demonstrates an antitumoral activity of the obtained hybrid materials and their potential use for biomedical applications as drug delivery systems in tumoral treatments.
Keywords: Epirubicin; Fludarabine; Collagen; Hybrid materials; Cancer treatment; Drug delivery systems;

Drug release kinetics from carboxymethylcellulose-bacterial cellulose composite films by Gheorghe Juncu; Anicuta Stoica-Guzun; Marta Stroescu; Gabriela Isopencu; Sorin Ion Jinga (485-492).
Display OmittedComposite films of sodium carboxymethyl cellulose and bacterial cellulose (NaCMC–BC) cross-linked with citric acid (CA) were prepared by solution casting method. Ibuprofen sodium salt (IbuNa) has been used to study the mechanism of drug release from composite films. Surface morphology was investigated by scanning electron microscopy (SEM) and proved that the BC content influences the aspect of the films. Fourier transformed infrared spectroscopy (FTIR) revealed specific peaks in IR spectra of composite films which sustain that NaCMC was cross-linked with CA. Starting from swelling observations, the release kinetic of IbuNa was described using a model which neglects the volume expansion due to polymer swelling and which considers non-linear diffusion coefficients for drug and solvent. The IbuNa release is also influenced by BC content, the drug release rate was decreasing with the increase of BC content.
Keywords: Sodium carboxymethyl cellulose; Bacterial cellulose; Citric acid cross-linking; Ibuprofen sodium salt; Controlled release; Mathematical modeling;

Microfluidic assisted synthesis of silver nanoparticle–chitosan composite microparticles for antibacterial applications by Chih-Hui Yang; Lung-Shuo Wang; Szu-Yu Chen; Mao-Chen Huang; Ya-Hua Li; Yun-Chul Lin; Pei-Fan Chen; Jei-Fu Shaw; Keng-Shiang Huang (493-500).
A new microfluidic approach for one step and in situ synthesis of silver nanoparticles-loaded chitosan composite microparticles was presented. The diameter of the composites could be tuned by flow adjustment on the flow rates. The results of antibacterial tests indicate that chitosan and composite particles showed against bacterial ability, and Ag NPs could enhance inhibition rate and present dose-dependent antibacterial ability.Display OmittedSilver nanoparticle (Ag NP)-loaded chitosan composites have numerous biomedical applications; however, fabricating uniform composite microparticles remains challenging. This paper presents a novel microfluidic approach for single-step and in situ synthesis of Ag NP-loaded chitosan microparticles. This proposed approach enables obtaining uniform and monodisperse Ag NP-loaded chitosan microparticles measuring several hundred micrometers. In addition, the diameter of the composites can be tuned by adjusting the flow on the microfluidic chip. The composite particles containing Ag NPs were characterized using UV–vis spectra and scanning electron microscopy-energy dispersive X-ray spectrometry data. The characteristic peaks of Ag NPs in the UV–vis spectra and the element mapping or pattern revealed the formation of nanosized silver particles. The results of antibacterial tests indicated that both chitosan and composite particles showed antibacterial ability, and Ag NPs could enhance the inhibition rate and exhibited dose-dependent antibacterial ability. Because of the properties of Ag NPs and chitosan, the synthesized composite microparticles can be used in several future potential applications, such as bactericidal agents for water disinfection, antipathogens, and surface plasma resonance enhancers.
Keywords: Silver; Nanoparticles; Chitosan; Microfluidic; Synthesis; Antibacterial;

New composite materials based on alginate and hydroxyapatite as potential carriers for ascorbic acid by Andreia Ilie; Cristina Ghiţulică; Ecaterina Andronescu; Andrei Cucuruz; Anton Ficai (501-507).
Display OmittedThe purpose of this article was to obtain prolonged drug release systems in which the drug (ascorbic acid) to reach intact the target area in an environment that is able to control the administration of the active component by chemical or physiological pathways. As support for drug, it was used a material based on calcium phosphate – hydroxyapatite and a natural polymer – alginate, since it is one of the most investigated composite materials for medical applications due to its positive response to biological testing: bioactivity, biocompatibility and osteoconductivity. Three composites with different ratios between alginate and hydroxyapatite were obtained: (a) Alg/HA/AA 1:1 (the mass ratio between Alg and HA being of 1:1), (b) Alg/HA/AA 1:3 (Alg:HA mass ratio of 1:3) and (c) Alg/HA/AA 3:1 (Alg:HA mass ratio of 3:1).The synthesized materials were characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and to observe the drug release process, UV–vis spectroscopy.
Keywords: Sodium alginate; Hydroxyapatit; Ascorbic acid; Biocompatibility; Composite materials;

All natural cellulose acetate—Lemongrass essential oil antimicrobial nanocapsules by Ioannis L. Liakos; Francesca D’autilia; Alice Garzoni; Cristina Bonferoni; Alice Scarpellini; Virgilio Brunetti; Riccardo Carzino; Paolo Bianchini; Pier Paolo Pompa; Athanassia Athanassiou (508-515).
Display OmittedNanocapsules and nanoparticles play an essential role in the delivery of pharmaceutical agents in modern era, since they can be delivered in specific tissues and cells. Natural polymers, such as cellulose acetate, are becoming very important due to their availability, biocompatibility, absence of toxicity and biodegradability. In parallel, essential oils are having continuous growth in biomedical applications due to the inherent active compounds that they contain. A characteristic example is lemongrass oil that has exceptional antimicrobial properties. In this work, nanocapsules of cellulose acetate with lemongrass oil were developed with the solvent/anti-solvent method with resulting diameter tailored between 95 and 185 nm. Various physico-chemical and surface analysis techniques were employed to investigate the formation of the nanocapsules. These all-natural nanocapsules found to well bioadhere to mucous membranes and to have very good antimicrobial properties at little concentrations against Escherichia coli and Staphylococcus aureus.
Keywords: Nanocapsules; Nanoparticles; Antimicrobial; Essential oils; Drug delivery; Nano-pharmaceutics; Cellulose acetate; Escherichia coli; Staphylococcus aureus; Lemongrass oil; Bio-adhesion;

Synthesis and characterization of new composite materials based on poly(methacrylic acid) and hydroxyapatite with applications in dentistry by Andrei Tiberiu Cucuruz; Ecaterina Andronescu; Anton Ficai; Andreia Ilie; Florin Iordache (516-523).
Display OmittedThe use of methacrylic acid (MAA) in medicine was poorly investigated in the past but can be of great importance because the incorporation of hydroxyapatite (HA) can lead to new composite materials with good properties due to the strong electrostatic interactions between carboxylate groups of polymer and Ca2+ ions from HA. The scope of this study was to determine the potential of using composite materials based on poly(methacrylic acid) (PMAA) and hydroxyapatite in dentistry. Two routes of synthesis were taken into account: i) HA was synthesised in situ and ii) commercial HA was used. Fourier transform infrared spectroscopy and X-ray diffraction were used for compositional assessments. Scanning electron microscopy was performed to determine the morphology and differential thermal analysis (DTA) coupled with thermogravimetric analysis (TG) was used to study the thermal behaviour and to observe quantitative changes. In-vitro tests were also performed in order to evaluate the biocompatibility of both PMAA/HA composites by monitoring the development potential of human endothelial cells using MTT assay and fluorescent microscopy.
Keywords: Poly(methacrylic acid); Hydroxyapatite; Biocompatibility; Dental material;

Mesostructured silica and aluminosilicate carriers for oxytetracycline delivery systems by D. Berger; S. Nastase; R.A. Mitran; M. Petrescu; E. Vasile; C. Matei; T. Negreanu-Pirjol (524-531).
Display OmittedOxytetracycline delivery systems containing various MCM-type silica and aluminosilicate with different antibiotic content were developed in order to establish the influence of the support structural and textural properties and aluminum content on the drug release profile. The antibiotic molecules were loaded into the support mesochannels by incipient wetness impregnation method using a drug concentrated aqueous solution. The carriers and drug-loaded materials were investigated by small- and wide-angle XRD, FTIR spectroscopy, TEM and N2 adsorption-desorption isotherms. Faster release kinetics of oxytetracycline from uncalcined silica and aluminosilicate supports was observed, whereas higher drug content led to lower delivery rate. The presence of aluminum into the silica network also slowed down the release rate. The antimicrobial assays performed on Staphylococcus aureus clinical isolates showed that the oxytetracycline-loaded materials containing MCM-41-type mesoporous silica or aluminosilicate carriers inhibited the bacterial development.
Keywords: Oxytetracycline; Drug delivery system; MCM-41; Aluminosilicates; Staphylococcus aureus clinical strains;

Biocompatible hybrid silica nanobiocomposites for the efficient delivery of anti-staphylococcal drugs by Paul Cătălin Balaure; Raisa Anamaria Popa; Alexandru Mihai Grumezescu; Georgeta Voicu; Marius Rădulescu; Laurențiu Mogoantă; Tudor-Adrian Bălşeanu; George Dan Mogoşanu; Mariana Carmen Chifiriuc; Coralia Bleotu; Alina Maria Holban; Alexandra Bolocan (532-542).
Display OmittedThis work reports the non-surfactant templated synthesis and characterization of a new tyrosine—silica/antibiotics (TyR-SiO2/ATBs) nanocomposite, as well as both in vitro and in vivo cytotoxicity and antimicrobial activity against the microbial pathogen Staphylococcus aureus. The in vitro microbiological tests proved that the obtained nanobiostructure significantly enhance the antimicrobial activity of three commonly used antibiotics against S. aureus (i.e. erythromycin (ERI), gentamicin (GEN), and cloxacillin (CLO)) as revealed by the increased diameters of the growth inhibition zones and the decreased minimal inhibitory concentration values, as well as by the inhibitory effect of sub-lethal antibiotic concentrations on the ability of the respective pathogenic strains to adhere and colonize different substrata. These results, correlated with the lack of toxicity against mesenchymal stem cells along with an appropriate in vivo biodistribution highlight the promising therapeutic potential of this carrier that allows a decrease of the required active doses while significantly lessening the harmful side effects of the medication on the host organism.
Keywords: Improved efficiency of antibiotics; Tyrosine-silica nanobiocomposites; Non-surfactant templated synthesis; Sol-gel polymerization; Staphylococcus aureus; Drug delivery;