M. Silvina Tomassone

Biodegradable Janus Nanoparticles for Local Pulmonary Delivery of Hydrophilic and Hydrophobic Molecules to the Lungs

The aim of the present work is to synthesize, characterize, and test self-assembled anisotropic or Janus particles designed to load anticancer drugs for lung cancer treatment by inhalation. The particles were synthesized using binary mixtures of biodegradable and biocompatible materials. The particles did not demonstrate cyto- and genotoxic effects. Janus particles were internalized by cancer cells and accumulated both in the cytoplasm and nuclei. After inhalation delivery, nanoparticles accumulated preferentially in the lungs of mice and retained there for at least 24 h. Two drugs or other biologically active components with substantially different aqueous solubility can be simultaneously loaded in two-phases (polymer-lipid) of these nanoparticles. In the present proof-of-concept investigation, the particles were loaded with two anticancer drugs: doxorubicin and curcumin as model anticancer drugs with relatively high and low aqueous solubility, respectively. However, there are no obstacles for loading any hydrophobic or hydrophilic chemical agents. Nanoparticles with dual load were used for their local inhalation delivery directly to the lungs of mice with orthotopic model of human lung cancer. In vivo experiments showed that the selected nanoparticles with two anticancer drugs with different mechanisms of action prevented progression of lung tumors. It should be stressed that anticancer effects of the combined treatment with two anticancer drugs loaded in the same nanoparticle significantly exceeded the effect of either drug loaded in similar nanoparticles alone.

Atomistic simulation study of surfactant and polymer interactions on the surface of a fenofibrate crystal

It is currently of great interest to the pharmaceutical industry to control the size and agglomeration of nano- and micro-particles for the enhancement of drug delivery. Typically, surfactants and polymers are used as additives to interact with and stabilize the growing crystal surface, thus controlling size and agglomeration; however, selection is traditionally done empirically or using heuristics. The objective of this study was to use molecular dynamic simulations to investigate and predict additive interactions, and thus, evaluate the stabilization potential of individual and multiple additives on the surface of the model drug fenofibrate. Non-ionic surfactant Tween 80, anionic surfactant sodium dodecyl sulfate (SDS), and polymers hydroxypropyl methylcellulose (HPMC) and Pullulan were evaluated individually on three distinct crystal surfaces [(001), (010), (100)], as well as in surfactant-polymer combinations. HPMC was determined to have the strongest interaction with the surfaces of the fenofibrate crystal, and therefore, was predicted to be the most effective individual additive. A mixture of HPMC with SDS was determined to be the most effective mixture of additives, and more effective than HPMC alone, indicating a synergistic effect. The predictions of mixed additives indicated a relative order of effectiveness as follows: HPMC-SDS>HPMC-Tween 80>Pullulan-Tween 80>Pullulan-SDS. The simulations were subsequently validated by an anti-solvent crystallization of fenofibrate where it was found that HPMC individually, and a mixture of HPMC-SDS, produced the smallest and most stable crystals, as measured by laser diffraction; this, in combination with measurements of the crystal growth rate in the presence and absence of additives confirmed the results of the simulations.

Molecular dynamics simulations of rupture in lipid bilayers

Magnetic fluid hyperthermia is a promising cancer therapy in which magnetic nanoparticles are acted upon by a high-frequency oscillating magnetic field. While the accepted mechanism is localized hyperthermia, it is plausible that shear stresses due to nanoparticles rotating near a cell membrane may induce rupture, enhancing the effectiveness of the treatment. With the goal of understanding this further, molecular dynamics simulations were carried out on a model cell membrane. A bilayer composed of dipalmitoylphosphatidylcholine lipids was subjected to an incremental tension as well as an incremental shear stress. In both cases, it was found that the bilayer could withstand a surface tension of approximately 90 mN/m prior to rupture. Under tension, the bilayer ruptured at double its initial area, whereas under shear, the bilayer ruptured at 1.8 times its initial area. The results show that both incremental tension and incremental shearing are able to produce bilayer rupture, with shear being more injurious, yielding a larger surface tension for a smaller deformation. This information allows for comparison between the estimated energy required to rupture a cell membrane and the energy that a magnetic nanoparticle would be able to generate while rotating in a cellular environment. Our estimates indicate that magnetically blocked nanoparticles with diameters larger than 50 nm may result in rupture due to shear.

Interactions of silica nanoparticles in supercritical carbon dioxide

We report molecular simulation studies on the interaction forces between silica nanoparticles in supercritical carbon dioxide at 318 K. Our goal is to find a better understanding of the interparticle solvation forces during rapid expansion of supercritical solutions. The parameters for interatomic potentials of fluid-fluid and solid-fluid interactions are obtained by fitting our simulations to (i) experimental bulk CO(2) phase diagram at a given temperature and pressure and (ii) CO(2) sorption isotherms on silica at normal boiling and critical temperatures. Our simulations show that the interaction forces between particles and supercritical CO(2) at near-critical pressure of p=69 atm (i.e., slightly below critical condition) reaches a minimum at distances of 0.5-0.8 nm between the outer surfaces of the particles and practically vanishes at distances of approximately 3 nm. The attraction is most prominent for densely hydroxylated particle surfaces that interact strongly with CO(2) via hydrogen bonds. The effective attraction between silica and CO(2) is significantly weaker for dehydroxylated particles. We also compared fluid sorption and interparticle forces between supercritical CO(2) and subcritical nitrogen vapor, and our results showed qualitative similarities, suggesting that the CO(2) configuration between the particles resembles a liquidlike junction.

Coarse Grained Molecular Dynamics of Engineered Macromolecules for the Inhibition of Oxidized Low Density Lipoprotein Uptake by Macrophage Scavenger Receptors

Atherosclerosis is a condition resulting from the accumulation of oxidized low-density lipoproteins (oxLDLs) in arterial walls. Previously developed macromolecules consisting of alkyl chains and polyethylene glycol (PEG) on a mucic acid backbone, termed nanolipoblockers (NLBs) are hypothesized to mitigate the uptake of oxLDL by macrophage scavenger receptors. In this work, we developed a coarse grained model to characterize the interactions between NLBs with a segment of human scavenger receptor A (SR-A), a key receptor domain that regulates cholesterol uptake and foam cell conversion of macrophages, and studied NLB ability to block oxLDL uptake in PBMC macrophages. We focused on four different NLB configurations with variable molecular charge, charge location, and degree of NLB micellization. Kinetic studies showed that three of the four NLBs form micelles within 300 ns and of sizes comparable to literature results. In the presence of SR-A, micelle-forming NLBs interacted with the receptor primarily in an aggregated state rather than as single unimers. The model showed that incorporation of an anionic charge near the NLB mucic acid head resulted in enhanced interaction with the proposed binding pocket of SR-A compared to uncharged NLBs. By contrast, NLBs with an anionic charge located at the PEG tail showed no interaction increase as NLB aggregates were predominately observed to interact away from the oxLDL binding site. Additionally, using two different methods to assess the number of contacts that each NLB type formed with SR-A, we found that the rank order of contacts coincided with our experimental flow cytometry results evaluating the ability of the different NLBs to block the uptake of oxLDL.

Experimentally Validated Numerical Modeling of Heat Transfer in Granular Flow in Rotating Vessels

Heat transfer in particulate materials is a ubiquitous phenomenon in nature, affecting a great number of applications ranging from multi-phase reactors to kilns and calciners. The materials used in these type of applications are typically handled and stored in granular form, such as catalyst particles, coal, plastic pellets, metal ores, food products, mineral concentrates, detergents, fertilizers and many other dry and wet chemicals. Oftentimes, these materials need to be heated and cooled prior to or during processing. Rotary calciners are most commonly used mixing devices used in metallurgical and catalyst industries (Lee, 1984; Lekhal et. al., 2001). They are long and nearly horizontal rotating drums that can be equipped with internal flights (baffles) to process various types of feedstock. Double cone impregnators are utilized to incorporate metals or other components into porous carrier particles while developing supported catalysts. Subsequently, the impregnated catalysts are heated, dried and reacted in rotating calciners to achieve the desired final form. In these processes, heat is generally transferred by conduction and convection between a solid surface and particles that move relative to the surface. Over the last fifty years, there has been a continued interest in the role of system parameters and in the mechanisms of heat transfer between granular media and the boundary surfaces in fluidized beds (Mickey & Fairbanks, 1955; Basakov, 1964; Zeigler & Agarwal, 1969; Leong et.al., 2001; Barletta et. al., 2005), dense phase chutes, hoppers and packed beds (Schotte, 1960; Sullivan & Sabersky, 1975; Broughton & Kubie, 1976; Spelt et. al., 1982; Patton et. al., 1987; Buonanno & Carotenuto, 1996; Thomas et. al., 1998; Cheng et. al., 1999), dryers and rotary reactors and kilns (Wes et. al., 1976; Lehmberg et. al., 1977). More recently, experimental work on fluidized bed calciner and rotary calciners/kilns have been reported by LePage et.al, 1998; Spurling et.al., 2000, and Sudah. et al., 2002. In many of these studies, empirical correlations relating bed temperature to surface heat transfer coefficients for a range of operating variables have been proposed. Such correlations are of restricted validity because they cannot be easily generalized to different equipment geometries and it is risky to extrapolate their use outside the experimental range of variables studied. Moreover, most of these models do not capture particle-surface interactions or the detailed microstructure of the

Solvation Forces Between Silica Bodies in Supercritical Carbon Dioxide

We report Monte Carlo simulations of the solvation pressure between two planar surfaces, which represent the interface of spherical silica nanoparticles in supercritical carbon dioxide. Carbon dioxide (CO2) was modeled as an atomistic dumbbell or a spherical Lennard-Jones particle. The interaction between CO2 molecules and silica surfaces was characterized by the standard Steele potential with energetic heterogeneities representing the hydrogen bonds. The parameters for the solid-fluid interaction potentials were obtained by fitting our simulations to the experimental isotherms of CO2 sorption on mesoporous siliceous materials. We studied the dependence of the solvation force on the distance between planar silica surfaces at T = 318 K, at equilibrium bulk pressures p(bulk) ranging from 69 to 200 atm. At 69 atm, we observed a long-range attraction between the two surfaces, and it vanished when the pressure was increased to 102 and then 200 atm. The results obtained with different fluid models were consistent with each other. According to our observations, energetic heterogeneities of the surface have negligible influence on the solvation pressure. Using the Derjaguin approximation, we calculated the solvation forces between spherical silica nanoparticles in supercritical CO2 from the solvation pressures between the planar surfaces.