# Peer Review Publications

Marganit Cohen-Avrahami, Alexander I Shames, Francesca M Ottaviani, Abraham Aserin, and Nissim. Garti. 2014. “On the correlation between the structure of lyotropic carriers and the delivery profiles of two common NSAIDs.” Colloids and Surfaces, B: Biointerfaces, 122, Pp. 231–240. Abstract
Two non-steroidal anti-inflammatory drugs (NSAIDs), sodium diclofenac (Na-DFC) and celecoxib (CLXB) were solubilized within cubic and lamellar mesophases as carriers for transdermal drug delivery. SD-NMR, SAXS, ATR-FTIR, and EPR measurements were performed to examine the systems' characteristics and the interactions between the drugs and their hosting mesophases. The amphiphilic drug Na-DFC was found to incorporate at the interfaces of the cubic and lamellar mesophases and thus to act as a cosurfactant and a "structure stabilizer". It increased the order degree and the interactions between the GMO mols. and led the systems toward denser packing. CLXB exhibits an opposite effect on the mesophases. Its solubilization within both systems is accompanied with significant channel swelling and decrease in the order degree. The hydrophobic, rigid and bulky CLXB behaves as a "structure breaker", incorporated between the GMO tails, disturbing the mesophase packing and enhancing the repulsion at the tails region, limiting their close binding. Release expts. from Franz cells revealed that Na-DFC release is dependent on the quantity of water within the hosting mesophase as the water-rich formulation exhibits 1.5-fold enhancement in the release of the drug, compared to the lamellar phase. In contrast, CLXB release was not influenced by the water quantity, hinting that the release mechanisms of the drugs are different while Na-DFC diffuses from the water channels to the external phase, CLXB diffusion occurs through the continuous lipophilic region. The difference in the solubilization sites and interactions of each drug with the mesophases affect their release profiles and det. the preferred formulations for each drug's delivery vehicle. [on SciFinder(R)]
Alon Elyada, Nissim Garti, and Helga. Furedi-Milhofer. 2014. “Polyelectrolyte Multilayer-Calcium Phosphate Composite Coatings for Metal Implants.” Biomacromolecules, 15, 10, Pp. 3511–3521. Abstract
The prepn. of org.-inorg. composite coatings with the purpose to increase the bioactivity of bioinert metal implants was investigated. As substrates, glass plates and rough titanium surfaces (Ti-SLA) were employed. The method comprises the deposition of polyelectrolyte multilayers (PEMLs) followed by immersion of the coated substrate into a calcifying soln. of low supersatn. (MCS). Single or mixed PEMLs were constructed from poly-L-lysine (PLL) alternating with poly-L-glutamate, (PGA), poly-L-aspartate (PAA), and/or chondroitin sulfate (CS). ATR-FTIR spectra reveal that (PLL/PGA)10 multilayers and mixed multilayers with a (PLL/PGA)5 base contain intermol. $\beta$-sheet structures, which are absent in pure (PLL/PAA)10 and (PLL/CS)10 assemblies. All PEML coatings had a grainy topog. with aggregate sizes and size distributions increasing in the order: (PLL/PGA)n \textless (PLL/PAA)n \textless (PLL/CS)n. In mixed multilayers with a (PLL/PGA)n base and a (PLL/PAA)n or (PLL/CS)n top, the aggregate sizes were greatly reduced. The PEMLs promoted calcium phosphate nucleation and early crystal growth, the intensity of the effect depending on the compn. of the terminal layer(s) of the polymer. In contrast, crystal morphol. and structure depended on the supersatn., pH, and ionic strength of the MCS, rather than on the compn. of the org. matrix. Crystals grown on both uncoated and coated substrates were mostly platelets of calcium deficient carbonate apatite, with the Ca/P ratio depending on the pptn. conditions. [on SciFinder(R)]
Nissim Garti, Dima Libster, and Abraham Aserin. 2014. “Solubilization and Delivery of Drugs from GMO-Based Lyotropic Liquid Crystals.” In NANOSCIENCE WITH LIQUID CRYSTALS: FROM SELF-ORGANIZED NANOSTRUCTURES TO APPLICATIONS, edited by Q Li, Pp. 355–414. Abstract
Self-assembled lyotropic liquid crystals (LLCs) of lipids and water are interesting mesophases that can be considered among other applications as delivery vehicles due to their remarkable structural complexity. The phase behavior of mixtures of glycerol monooleate (monoolein, GMO) and phytantriol were particularly well studied in drug delivery systems, food products, and encapsulation and crystallization of proteins. We are summarizing in this chapter our contribution to modified LLCs and their structural features and recent systematic efforts to utilize them for solubilization, and potential release of drugs and biomacromolecules. Some of the most interesting applications are the implementation of peptides and proteins in the reversed cubic and hexagonal mesophases, to enhance penetrating pattern of a model drugs. LLC vehicles were shown to allow on demand'' targeted release, based on controlling the polymorphism of lyotropic liquid crystalline mesophases. A new pathway to responsive LLCs, enabling the controlled release of hydrophilic drugs diffusing through the water channels of the mesophases was also investigated. The system is capable of self-assembling into a reverse bicontinuous cubic phase of Im3m symmetry and transform into a reverse columnar hexagonal as a function of pH, pressure or enzymes. LLCs were shown to entrap several peptides enzymes, proteins and nucleotides into cubic and lamellar monoolein-based mesophases in order to protect them and enable their release. The main outcomes of the described research demonstrated that control of the physical properties of hexagonal LLC on different length scales is key for rational design of these systems as delivery vehicles for both low molecular weight therapeutics and biomacromolecules.
Vesselin L Kolev, Anela N Ivanova, Galia K Madjarova, Abraham Aserin, and Nissim. Garti. 2014. “Unit Cell Structure of Water-Filled Monoolein into Inverted Hexagonal (HII) Mesophase Modeled by Molecular Dynamics.” Journal of Physical Chemistry B, 118, 20, Pp. 5459–5470. Abstract
The study investigates the unit cell structure of inverted hexagonal (HII) mesophase composed of monoolein (1-monoolein, GMO) and water using atomistic mol. dynamics methods without imposing any restraints on lipid and water mols. Statistically meaningful and very contrast images of the radial mass d. distribution, scrutinizing also the sep. components water, monoolein, the polar headgroups of the lipids, the double bond, and the termini of the hydrocarbon chain (the tail), are obtained. The lipid/water interface structure is analyzed based on the obtained water d. distribution, on the estd. no. of hydrogen bonds per monoolein headgroup, and on the headgroup-water radial distribution functions. The headgroup mass d. distribution demonstrates hexagonal shape of the monoolein/water interface that is well-defined at higher water/monoolein ratios. Water interacts with the headgroups by forming a three-layer diffusive mass d. distribution, and each layer's shape is close to hexagonal, which is an indication of long-range structural interactions. It is found that the monoolein headgroups form a const. no. of hydrogen bonds leaving an excessive amt. of water mols. outside the first lipid coordination sphere. Furthermore, the quantity of water at the monoolein/water interface increases steadily upon extension of the unit cell, so the interface should have a very dynamic structure. Investigation of the hydrocarbon residues reveals high compression and well-expressed structuring of the tails. The tails form a very compressed and constrained structure of defined layers across the unit cell with properties corresponding to a more densely packed nonpolar liq. (oil). Due to the hexagonal shape the 2D packing frustration is const. and does not depend on the water content. All reported structural features are based on averaging of the at. coordinates over the time-length of the simulation trajectories. That kind of processing allows the observation of the water/GMO interface shape and its stability and mobility at a time scale close to the ones of the intermol. interactions. [on SciFinder(R)]
Meital Aviv-Gavriel, Nissim Garti, and Helga. Furedi-Milhofer. 2013. “Preparation of a Partially Calcified Gelatin Membrane as a Model for a Soft-to-Hard Tissue Interface.” Langmuir, 29, 2, Pp. 683–689. Abstract
Cartilage and/or bone tissue engineering is a very challenging area in modern medicine. Since cartilage is an avascular tissue with limited capacity for self-repair, using scaffolds provides a promising option for the repair of severe cartilage damage caused by trauma, age-related degeneration, and/or diseases. Our aim in this study was to design a model for a functional biomedical membrane to form the interface between a cartilage-forming scaffold and bone. To realize such a membrane gelatin gels contg. calcium or phosphate ions were exposed from one side to a soln. of the other constituent ion (i.e., a sodium phosphate soln. was allowed to diffuse into a calcium-contg. gel and vice versa). The partially calcified gels were analyzed by XRD, ATR-FTIR spectra, E-SEM, and EDX. Thus, we confirmed the existence of a gradient of crystals, with a dense top layer, extending several micrometers into the gel. XRD spectra and Ca/P at. ratios confirmed the existence of calcium deficient apatites. The effect of different exptl. parameters on the calcification process within the gelatin membranes has been elucidated. It was shown that increasing the gelatin concn. from 5 wt % to 10 wt. % retards calcification. A similar effect was obsd. when glycerol, which is frequently used as plasticizer, was added to the system. With increasing calcium concn. within the org. matrix, the quantity and d. of calcium phosphate crystals over/within the gel increased. The possible explanations for the above phenomena are discussed. [on SciFinder(R)]
Liron Bitan-Cherbakovsky, Abraham Aserin, and Nissim. Garti. 2013. “Structural characterization of lyotropic liquid crystals containing a dendrimer for solubilization and release of gallic acid.” Colloids and Surfaces, B: Biointerfaces, 112, Pp. 87–95. Abstract
The role of 2nd generation polypropyleneimine (PPIG2) dendrimer in controlling the release of gallic acid (GA) as a model drug from lyotropic liq. crystal was explored. GA (0.2 wt%) was solubilized in three types of mesophases: lamellar (L$\alpha$), cubic (space group of Ia3d, QG), and reverse hexagonal (HII), composed of GMO and water (and D-$\alpha$-tocopherol, or tricaprylin in the case of HII mesophases). Small angle X-ray scattering (SAXS) and attenuated total reflectance Fourier transform IR (ATR-FTIR) along with UV spectrophotometry were utilized to elucidate the structure modifications and release resulting from the cosolubilization of GA and PPIG2. Solubilization of PPIG2 into L$\alpha$ and QG phases caused transformation of both structures to HII. The diffusion of GA out of the mesophases was found to be dependent on water content and PPIG2 concn. Rapid release from L$\alpha$ + PPIG2 and QG + PPIG2 mesophases was recorded. The release from both HII mixts. (with D-$\alpha$-tocopherol and tricaprylin) was shown to be dependent on the type of oil. Release studies conducted for 72 h showed that GA release can be modulated and sustained by the presence of PPIG2, supposedly due to the electrostatic interactions between the dendrimer and the drug mol. [on SciFinder(R)]
Laziz Bouzidi, Tolibjon S Omonov, Nissim Garti, and Suresh S Narine. 2013. “Relationships between molecular structure and kinetic and thermodynamic controls in lipid systems. Part I: propensity for oil loss of saturated triacylglycerols.” Food & Function, 4, 1, Pp. 130–143. Abstract
Pure satd. triacylglycerols (TAGs) in canola oil were used as model systems to analyze oil loss in structured oil both from thermodn. and kinetic perspectives. Two important parameters which effectively and predictively measure the relative propensity of a solid network to lose/hold oil were defined: (1) the rate of oil loss, K, which is a quantified representation of the kinetics of oil loss and (2) the initial amt. of oil susceptible to be lost, i.e., the propensity for oil loss (POL), which is a representation of the thermodn. of oil binding. It was found that the POL and K values do not always trend in the same fashion, suggesting that the mechanism of oil binding is complex, depending on the structurant's cryst. form locked within the oil network. The two parameters were, however, correlated to the melting and thermal behavior of the structurants, to the polymorphic structures that are obtained during the cooling process and to the habit (shape, size and morphol.) of the cryst. phase in the oil. Both POL and K had a strong correlation to the oil loss. [on SciFinder(R)]
Sarah Fisher, Ellen J Wachtel, Abraham Aserin, and Nissim. Garti. 2013. “Solubilization of simvastatin and phytosterols in a dilutable microemulsion system.” Colloids and Surfaces, B: Biointerfaces, 107, Pp. 35–42. Abstract
The usual treatment of hypercholesterolemia includes a class of drugs known as statins (simvastatin among them), which inhibit the prodn. of cholesterol. Another way of reducing cholesterol levels is with the use of phytosterols, which reduce the transport of exogenic cholesterol from the intestine into the blood stream. The 2 treatments can be combined, achieving an additive effect. However, both simvastatin and phytosterols are practically insol. in water, and therefore their absorption and activity are low. Nanosized self-assembled structured liq. systems are modified microemulsions that present an alternative pathway for improving the bioavailability of poorly water-sol. drugs. The goal of this study was to solubilize the maximal quantity of both simvastatin and phytosterols in a single, fully dilutable microemulsion system. The authors constructed a water-dilutable liq. drug delivery system that includes sucrose monolaurate, propylene glycol, and oleyl lactate. This system exhibits high solubilization capacity for both simvastatin (7.0 wt%) and phytosterols (3.5 wt%) when each is solubilized sep. in a water-free conc. When simvastatin and phytosterols were solubilized together at a wt ratio of 2.5:1, max. solubilization was obtained with 4.7 wt% simvastatin and 1.9 wt% phytosterols. Structural and anal. methods were applied including rheol., DSC, SD-NMR, SAXS, and cryo-TEM. The water-free "conc." consisted of direct micelles for which propylene glycol served as the hydrophilic phase. Upon water diln., the direct micelles appear to form "lipophilic compds. dispersed in hydrophilic continuous phase". The solubilizates are located in the droplet core and/or at the interface. [on SciFinder(R)]
K Gardikis, EA Mourelatou, M Ionov, A Aserin, D Libster, B Klajnert, M Bryszewska, N Garti, J.-P. Majoral, K Dimas, and C Demetzos. 2013. “Natural and synthetic biomaterials as composites of advanced drug delivery nano systems (ADDNSS). Biomedical applications.” In Dendrimers Biomed. Appl., Pp. 30–39. Royal Society of Chemistry. Abstract
A review. This article reviews the creation of advanced drug delivery nano systems (aDDnSs) comprised of liposomes and polymers focusing on the interactions of the structural components and their biomedical applications. ADDnSs have been shown to significantly: (a) increase the load of the bioactive substance into the system, which is very important both for manufg.-economic reasons and for toxicity reasons (as less quantity of carrier is used for the same amt. of drug), (b) lower the release rate of the encapsulate drug, a fact that could create a more controlled and/or sustained release profile of the drug in the bloodstream, leading to lower toxicity and higher effectiveness (c) advanced pharmacol. toxicity compared to the free drug and at least equal toxicity compared to the resp. conventional liposomal formulation. A plethora of physicochem. data has begun to shed light to the interactions of the components of these complicate systems that seem to be responsible for the advantages presented by the aDDnSs. [on SciFinder(R)]
Nissim Garti, Dima Libster, Liron Bitan-Cherbachovsky, and Abraham. Aserin. 2013. “Dendrimer-lyotropic liquid crystal systems for drug delivery.”. Abstract
This invention relates to novel complex dendrimer-lyotropic liq. crystal systems for drug delivery,. A second generation polypropylenimine dendrimer was solubilized into lamellar, diamond reverse cubic and reverse hexagonal lyotropic mesophases composed of glycerol monooleate and water. [on SciFinder(R)]
Tehila Mishraki, Paul Ben Ishai, Dmitry Babukh, Abraham Aserin, Yuri Feldman, and Nissim. Garti. 2013. “Modulation of physical properties of reverse hexagonal mesophases: A dielectric spectroscopy study.” Journal of Colloid and Interface Science, 396, Pp. 178–186. Abstract
The structural, dynamic, and kinetic aspects of the HII systems based on glycerol monooleate (GMO), phosphatidylcholine (PC), triacylglycerol (TAG), and water were investigated by dielec. spectroscopy in a frequency range of 10-2-106 Hz, and a temp. range of 290-320 K. Three distinct processes as well as a temp.-activated dc cond. were detected and examd. These were assigned to the reorientation of the GMO polar heads, the tangential movement of counterions at the interface, the transport of TAGs through the lipids tails, and the ion mobility within the water cylinders. Upon addn. of PC, the crit. temp. (T0) of the dehydration of the GMO headgroups increased. The optimal concn. found for structural stabilization of the HII mesophase was 10 wt% PC, since it imparted the strongest bonding at the interfacial layer and increased the assocn. between the lipid tails. Within the HII cluster, TAG percolated and shifted between the hexagonal rods themselves. The present study demonstrated the benefit of controlling the crit. temp. of the HII mesophase partial dehydration and softening, as well as the percolation of TAGs. These factors influence the diffusion mode of embedded drugs in the physiol. temp. range. [on SciFinder(R)]
MF Ottaviani, D Appelhans, Javier F de la Mata, S Garcia-Gallego, A Fattori, C Coppola, M Cangiotti, L Fiorani, JP Majoral, AM Caminade, M Bryszewska, DK Smith, N Garti, and B Klajnert. 2013. “Characterization of dendrimers and their interactions with biomolecules for medical use by means of electron magnetic resonance.” In Dendrimers Biomed. Appl., Pp. 115–133. Royal Society of Chemistry. Abstract
In the first part of this study, a computer aided EPR anal. was performed to intensively study the Cu(II) complexation behavior of different dendrimers: (a) a series of PPI dendrimers ranging up to the fifth generation that had either a dense maltose or maltotriose shell; (b) sulfonated or carboxylated carbosilane dendrimers; (c) self-assembling amine- terminated dendrons. The Cu(II) coordination and symmetry of the generated complexes depend on the dendrimer chem. structure, the functionalization in the periphery, dendrimer generation and the ratio of the copper and dendrimer concns. As generation increased, the glycodendrimers showed (a) increased nitrogen coordination in a axial symmetry, due to the increased no. of nitrogen sites in the dendrimer interior, and (b) a rhombic structure which forms in the congested dendrimer periphery where the sugar units are also able to coordinate the copper ions. [on SciFinder(R)]
Improved technologies for the encapsulation, protection, release and enhanced bioavailability of food ingredients and nutraceutical components are vital to the development of future foods. Encapsulation technologies and delivery systems for food ingredients and nutraceuticals provides a comprehensive guide to current and emerging techniques.Part one provides an overview of key requirements for food ingredient and nutraceutical delivery systems, discussing challenges in system development and analysis of interaction with the human gastrointestinal tract. Processing technologies for enca
Idit Amar-Yuli, Abraham Aserin, and Nissim. Garti. 2012. “Synthesis and alignment of nanostructured materials using liquid crystals.” In Self-Assem. Supramol. Archit., Pp. 193–218. John Wiley & Sons, Inc. Abstract
A review. Liq. crystal (LC) science and technol. have made important contributions to nanoscience and nanotechnol. in areas such as medical diagnostics, drug delivery, and in high-tech devices. The major nanotechnol. contribution is their capability to provide new preparative procedures, self-assembly, and alignment of nanoscale materials with controlled uniform size, shape, and dimensionality. The self-assembly of the liq. cryst. systems, particularly the lyotropic LC type, enables the integration of lipophilic and hydrophilic reagents that meet to react at the interface. Therefore the reaction and the products properties are governed by the host liq. cryst. medium and by the external conditions (e.g., light, heat, chem. environment, and elec. and magnetic field), which directly affect the LC hosting system. This review attempts to give an overview of current research in the fields of prepn., self-assembly, and alignment of nanomaterials using mainly lyotropic LCs and partially thermotropic LCs as direct and reverse templates. [on SciFinder(R)]
Meital Gavriel Aviv, Boaz Amit, Avner Yayon, Nissim Garti, and Helga Furedi. Milhofer. 2012. “Gradient organic inorganic nanocomposites for tissue repair at the cartilage/bone interface.” Key Engineering Materials, 493-494, Bioceramics 23, Pp. 577–581. Abstract
Damages to articular cartilage that are caused by trauma, age-related diseases (arthritis, arthrosis) and/or phys. stress pose major medical problems. A possible soln. is to introduce a biodegradable sponge-like scaffold contg. cartilage-forming cells. In the current work we developed a model for a partially calcified functional biomedical membrane with a gradient of calcium phosphate crystal d. to form the interface between bone and a sponge-like cell contg. scaffold for cartilage regeneration. The membrane consists of a biocompatible, biodegradable, partially calcified hydrogel, in our case gelatin was used. One part is an org.-inorg. nanocomposite consisting of nanocryst. calcium phosphate particles, formed in situ within the hydrogel, while the other part is the hydrogel without inorg. crystals. The exptl. method used was one-dimensional single diffusion. Gelatin gels contg. calcium or phosphate ions, resp., were exposed from the upper side to a soln. of the other constituent ion (i.e. a sodium phosphate soln. was allowed to diffuse into a calcium contg. gel and vice versa). SEM (E-SEM), EDX, XRD and ATR-FTIR spectroscopy confirmed the existence within the gel of a d. gradient of carbonate apatite crystals, with a dense top layer extending several microns into the gel. Ca/P at. ratios were in the range characteristic of calcium deficient apatites. The effect of different exptl. parameters on the calcification process within the gelatin membranes is discussed. [on SciFinder(R)]