Morphology and Dynamics in Hydrated Graphene Oxide/Branched Poly(ethyleneimine) Nanocomposites: An In Silico Investigation.

Graphene oxide (GO)-branched poly(ethyleneimine) (BPEI) hydrated mixtures were studied by means of fully atomistic molecular dynamics simulations to assess the effects of the size of polymers and the composition on the morphology of the complexes, the energetics of the systems and the dynamics of water and ions within composites. The presence of cationic polymers of both generations hindered the formation of stacked GO conformations, leading to a disordered porous structure. The smaller polymer was found to be more efficient at separating the GO flakes due to its more efficient packing. The variation in the relative content of the polymeric and the GO moieties provided indications for the existence of an optimal composition in which interaction between the two components was more favorable, implying more stable structures. The large number of hydrogen-bonding donors afforded by the branched molecules resulted in a preferential association with water and hindered its access to the surface of the GO flakes, particularly in polymer-rich systems. The mapping of water translational dynamics revealed the existence of populations with distinctly different mobilities, depending upon the state of their association. The average rate of water transport was found to depend sensitively on the mobility of the freely to move molecules, which was varied strongly with composition. The rate of ionic transport was found to be very limited below a threshold in terms of polymer content. Both, water diffusivity and ionic transport were enhanced in the systems with the larger branched polymers, particularly with a lower polymer content, due to the higher availability of free volume for the respective moieties. The detail afforded in the present work provides a new insight for the fabrication of BPEI/GO composites with a controlled microstructure, enhanced stability and adjustable water transport and ionic mobility.

Effects of the structure of lipid-based agents in their complexation with a single stranded mRNA fragment: a computational study.

In this work we employed fully atomistic molecular dynamics simulations, aiming towards a better understanding of the mechanisms associated with the formation and the stability of lipid-based RNA nanoassemblies, in an aqueous environment. We examined two groups of lipid-based complexation agents, differing in the degree of hydrophobicity and in the overall charge. The first group was comprised of cationic ionizable agents while the second included electrically neutral amphoteric phosphatidylcholine lipids. It was found that the overall charge of the complexation agents played the most decisive role in the energetics of the lipid/RNA association, while their degree of hydrophobicity affected their self-assembly and their complexation kinetics. The latter also affected the structural stability of the formed complexes since the water entrapped within the clusters of the less hydrophobic agents appeared to reduce the coherence of the lipid-RNA nanoassemblies. The combined effects of the aforementioned attributes dictated also the RNA conformation after complexation. The results from the present study provide thus new insight towards controlling the morphology, the energetic stability and the structural integrity of the formed complexes.

Molecular Dynamics Simulations of Essential Oil Ingredients Associated with Hyperbranched Polymer Drug Carriers.

Our work concerns the study of four candidate drug compounds of the terpenoid family, found as essential oil ingredients in species of the Greek endemic flora, namely carvacrol, p-cymene, γ-terpinene, and thymol, via the simulation method of molecular dynamics. Aquatic solutions of each compound, as well as a solution of all four together in realistic (experimental) proportions, are simulated at atmospheric pressure and 37 °C using an OPLS force field combined with TIP3P water. As verified, all four compounds exhibit a strong tendency to phase-separate, thereby calling for the use of carrier molecules as aids for the drug to circulate in the blood and enter the cells. Systems of two such carrier molecules, the hyperbranched poly(ethylene imine) (HBPEI) polyelectrolyte and hyperbranched polyglycerol (HPG), are examined in mixtures with carvacrol, the most abundant among the four compounds, at a range of concentrations, as well as with all four compounds present in natural proportions. Although a tendency of the terpenoids to cluster separately persists at high concentrations, promising association effects are observed for all drug-polymer ratios. HBPEI systems tend to form diffuse structures comprising small mixed clusters as well as freely floating polymer and essential oil molecules, a finding attributed to the polymer-polymer electrostatic repulsions, which here are only partially screened by the counterions. On the other hand, the electrically neutral HPG molecules cluster together with essential oil species to form a single nanodroplet. Currently, terpenoid-polymer clusters near lipid bilayer membranes are being studied to determine the propensity of the formed complexes to enter cell membranes.

Complexation of single stranded RNA with an ionizable lipid: an all-atom molecular dynamics simulation study.

Complexation of a lipid-based ionizable cationic molecule (referred to as DML: see main text) with RNA in an aqueous medium was examined in detail by means of fully atomistic molecular dynamics simulations. The different stages of the DML-RNA association process were explored, while the structural characteristics of the final complex were described. The self-assembly process of the DML molecules was examined in the absence and in the presence of nucleotide sequences of different lengths. The formed DML clusters were described in detail in terms of their size and composition and were found to share common features in all the examined systems. Different timescales related to their self-assembly and their association with RNA were identified. It was found that beyond a time period of a few tens of ns, a conformationally stable DML-RNA complex was formed, characterized by DML clusters covering the entire contour of RNA. In a system with a 642-nucleotide sequence, the average size of the complex in the longest dimension was found to be close to 40 nm. The DML clusters were characterized by a rather low surface charge, while a propensity for the formation of larger size clusters close to RNA was noted. Apart from hydrophobic and electrostatic interactions, hydrogen bonding was found to play a key-role in the DML-DML and in the DML-RNA association. The information obtained regarding the structural features of the final complex, the timescales and the driving forces associated with the complexation and the self-assembly processes provide new insight towards a rational design of optimized lipid-based ionizable cationic gene delivery vectors.

Liposome-Templated Indocyanine Green J- Aggregates for In Vivo Near-Infrared Imaging and Stable Photothermal Heating.

Indocyanine green (ICG) is an FDA-approved near-infrared fluorescent dye that has been used in optical imaging and photothermal therapy. Its rapid in vivo clearance and photo-degradation have limited its application. ICG pharmacokinetics and biodistribution have been improved via liposomal encapsulation, while its photothermal stability has been enhanced by ICG J-aggregate (IJA) formation. In the present work, we report a simple approach to engineer a nano-sized, highly stable IJA liposomal formulation. Our results showed that lipid film hydration and extrusion method led to efficient IJA formation in rigid DSPC liposomes, as supported by molecular dynamics modeling. The engineered DSPC-IJA formulation was nano-sized, and with spectroscopic and photothermal properties comparable to free IJA. Promisingly, DSPC-IJA exhibited high fluorescence, which enabled its in vivo tracking, showing prolonged blood circulation and significantly higher tumor fluorescence signals, compared to free ICG and IJA. Furthermore, DSPC-IJA demonstrated high photo-stability in vivo after multiple cycles of 808 nm laser irradiation. Finally, doxorubicin was loaded into liposomal IJA to utilize the co-delivery capabilities of liposomes. In conclusion, with both liposomes and ICG being clinically approved, our novel liposomal IJA could offer a clinically relevant theranostic platform enabling multimodal imaging and combinatory chemo- and photothermal cancer therapy.

Molecular Dynamics Simulation of the Capillary Leveling of a Glass-Forming Liquid.

Motivated by recent experimental studies probing (i) the existence of a mobile layer at the free surface of glasses and (ii) the capillary leveling of polymer nanofilms, we study the evolution of square-wave patterns at the free surface of a generic glass-forming binary Lennard-Jones mixture over a wide temperature range, by means of molecular dynamics simulations. The pattern's amplitude is monitored, and the associated decay rate is extracted. The evolution of the latter as a function of temperature exhibits a crossover between two distinct behaviors, over a temperature range typically bounded by the glass-transition temperature and the mode-coupling critical temperature. Layer-resolved analysis of the film particles' mean-squared displacements further shows that diffusion at the surface is considerably faster than in the bulk, below the glass-transition temperature. The diffusion coefficient of the surface particles is larger than its bulk counterpart by a factor that reaches 105 at the lowest temperature studied. This factor decreases upon heating, in agreement with recent experimental studies.

A microscopic view of graphene-oxide/poly(acrylic acid) physical hydrogels: effects of polymer charge and graphene oxide loading.

In this work we have examined in detail by means of fully atomistic molecular dynamics simulations, physical hydrogels formed by a polymer electrolyte, poly(acrylic acid), and graphene oxide, at two different charging states of the polymer and two different graphene oxide concentrations. It was found that variations of these parameters incurred drastic changes in general morphological characteristics of the composite materials, the degree of physical adsorption of polyelectrolyte chains onto the graphene oxide surface, the polymer dynamic response at local and global length scales, in the charge distributions around the components, and in the mobility of the counterions. All these microscopic features are expected to significantly affect macroscopic physical properties of the hydrogels, such as their mechanical responses and their electrical behaviors.

Frequency Dependent Non- Thermal Effects of Oscillating Electric Fields in the Microwave Region on the Properties of a Solvated Lysozyme System: A Molecular Dynamics Study.

The use of microwaves in every day's applications raises issues regarding the non thermal biological effects of microwaves. In this work we employ molecular dynamics simulations to advance further the dielectric studies of protein solutions in the case of lysozyme, taking into consideration possible frequency dependent changes in the structural and dynamic properties of the system upon application of electric field in the microwave region. The obtained dielectric spectra are identical with those derived in our previous work using the Fröhlich-Kirkwood approach in the framework of the linear response theory. Noticeable structural changes in the protein have been observed only at frequencies near its absorption maximum. Concerning Cα position fluctuations, different frequencies affected different regions of the protein sequence. Furthermore, the influence of the field on the kinetics of protein-water as well as on the water-water hydrogen bonds in the first hydration shell has been studied; an extension of the Luzar-Chandler kinetic model was deemed necessary for a better fit of the applied field results and for the estimation of more accurate hydrogen bond lifetime values.

Detailed study of the dielectric function of a lysozyme solution studied with molecular dynamics simulations.

The spread of microwave technology and new microwave applications in medicine have revitalized interest in the dielectric behavior of biological systems. In this work, the Fröhlich-Kirkwood approach and the linear response theory have been applied in conjunction with molecular dynamics simulations to study the dielectric response of a lysozyme solution as a model. The overall experimental dielectric behavior of a 9.88 mM lysozyme solution has been reproduced in a quantitative manner by employing a method based on the decomposition of the hydration shells close to the solute. Detailed analysis of the calculated spectra identified two δ-processes located at 200 MHz (δ1) and about 1 GHz (δ2), respectively. δ1 is associated mainly with the first hydration shell, while δ2 mainly with bulk water and the second hydration shell. Moreover, indications for the existence of an even faster relaxation in the 10(11)-Hz frequency range were found for the first time. Finally, the static dielectric constants of lysozyme and its first and second hydration shells were calculated based on the Fröhlich-Kirkwood and the linear response theory approaches.

Poly(amidoamine)-based dendrimer/siRNA complexation studied by computer simulations: effects of pH and generation on dendrimer structure and siRNA binding.

In this work we report, compare and discuss the results obtained from fully atomistic molecular dynamics simulations of generations 4, 5, and 6 of PAMAM-based dendrimers having NH(3) and triethanolamine as cores, forming complexes with a short interfering RNA (siRNA) at different pH values and at physiological ionic strength. By employing a detailed analysis we demonstrate how features such as molecular size, structural details, and protonation level of this category of dendrimers affect the dendrimer/siRNA complexation. Properties like the conformational flexibility of the dendrimer, the effective charge distribution of the assembly, and the level of intra- and intermolecular hydrogen bonding between the two molecular entities are all found to play a significant role in the mutual interactions between the nucleic acid and the hyperbranched molecules. All these features are of key importance in the multifaceted mechanism of dendrimer/gene complexation, and their understanding can provide valuable insight toward the design of more efficient nucleic acid nanocarriers.

Chimeric advanced drug delivery nano systems (chi-aDDnSs) for shikonin combining dendritic and liposomal technology.

The interest of drug delivery has focused on the creation of new formulations with improved properties, taking much attention to the drug release from the carrier. Liposomes have already been commercialized, while dendrimers and hyperbranched polymers are emerging as potentially ideal drug delivery vehicles. Chimeric advanced drug delivery nano systems (chi-aDDnSs) are mixed nanosystems combining different biomaterials that can offer advantages as drug carriers. Alkannin and shikonin (A/S) are naturally occurring hydroxynaphthoquinones with a well-established spectrum of wound healing, antimicrobial, anti-inflammatory, antioxidant and recently established antitumor activity. In this work three generations of hyperbranched aliphatic polyesters were used for the first time to form complexes with shikonin, as well as liposomal chi-aDDnSs. Characterization of the shikonin-loaded chi-aDDnSs was performed by measuring their particle size distribution, ζ-potential, drug encapsulation efficiency and the in vitro release profile. The analysis revealed sufficient drug encapsulation and appropriately featured release profiles. Chi-aDDnSs were also examined for their physical stability at 4°C. The results are considered promising and could be used as a road map for designing in vivo experiments.

Structural effects in overcharging in complexes of hyperbranched polymers with linear polyelectrolytes.

New insight is provided by a combined theoretical and simulational approach regarding the effects of structural characteristics of the constituents, on the overcharging phenomena in complexes formed by hyperbranched polymers with linear polyelectrolytes.