Einat Nativ-Roth

Phase Behavior and Shear Alignment in SWNT‐Surfactant Dispersions

The effect of single-walled carbon nanotubes (SWNT) on the phase behavior of the cationic surfactant cetyltrimethylammonium bromide (CTAB) in aqueous solutions is investigated at room temperature. Small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) are used for characterization of bulk dispersions and nanometrically thin films. Additional carbonaceous additives (fullerenes, multi-walled carbon nanotubes, and carbon black) serve as reference systems. It is found that dispersions of carbonaceous additive (excluding fullerenes) at intermediate surfactant concentrations (below the liquid-crystalline region of the native surfactant) induce demixing and macroscopic phase separation in otherwise homogeneous solutions of CTAB. Two coexisting liquid phases of similar CTAB concentrations are observed, with the carbonaceous species residing within the lower phase. At high CTAB concentrations (liquid-crystal region) the SWNTs are found to incorporate into the ordered lyotropic liquid-crystalline phase while preserving the native d-spacing. Investigation of nanometrically thin films at intermediate surfactant concentrations under external shear reveals shear-induced structure (SIS) in the presence of minute amounts of SWNTs. The effect is found to be exclusive to SWNT and does not occur in dispersions of other carbonaceous additives.

Order–disorder transition induced by surfactant micelles in single-walled carbon nanotubes dispersions

The observation of spontaneously formed microns-long islands of orientationally ordered SWNT in isotropic dispersions of spherical surfactant micelles is reported. The micelles co-exist with surfactant-coated individual SWNT of like charge. Inter-tube distances of 25 to 16 nanometres and an unexpected first order transition into a random phase induced by an increased ionic strength cannot be explained by classical depletion interactions or electrostatic repulsion. We suggest that coupling between the nanostructures and the assembled molecules modifies the effective interactions in an unexpected way. As the nanometrically thin SWNT share common features with rigid polymers, rod-like particle suspensions, and biological polymers such as microtubules and actin in crowded cellular environments, the observed phenomenon is believed to be general and expected in other systems.

Rheological investigation of single-walled carbon nanotubes – induced structural ordering in CTAB solutions

The rheological behavior of aqueous dispersions of single-walled carbon nanotubes (SWNTs) in solutions of the cationic surfactant cetyl trimethyl ammonium bromide (CTAB) was investigated. The steady shear viscosity as a function of the applied shear rate was monitored in different concentrations of surfactant which correspond to different mesophases. We found that the presence of SWNTs had a dramatic effect on the behavior of the combined system not observed with other additives: a significant increase in the low shear-rate viscosity of SWNT dispersions, and shear thinning replacing Newtonian behavior were observed for CTAB concentrations below the onset of the surfactant hexagonal phase. As CTAB concentration increases the rheological behavior of the SWNT-CTAB system and the native CTAB solutions become more alike. We suggest that the origin of the observed phenomena is the good size-match between SWNTs and elongated CTAB micelles. Thus dispersed SWNTs may induce the formation of size-matched elongated CTAB micelles that further orient under the action of external shear. A similar effect was not observed in dispersions of multi-walled carbon nanotubes or carbon black particles, suggesting that the cooperative behavior is not invoked when significant size-mismatch exists between the surfactant micelles and the dispersed additives.

Effect of solubilizing agents on mupirocin loading into and release from PEGylated nanoliposomes.

Mupirocin was identified by quantitative structure property relationship models as a good candidate for remote liposomal loading. Mupirocin is an antibiotic that is currently restricted to topical administration because of rapid hydrolysis in vivo to its inactive metabolite. Formulating mupirocin in PEGylated nanoliposomes may potentially expand its use to parenteral administration by protecting it from degradation in the circulation and target it (by the enhanced permeability effect) to the infected tissue. Mupirocin is slightly soluble in aqueous medium and its solubility can be increased using solubilizing agents. The effect of the solubilizing agents on mupirocin remote loading was studied when the solubilizing agents were added to the drug loading solution. Propylene glycol was found to increase mupirocin loading, whereas polyethylene glycol 400 showed no effect. Hydroxypropyl-β-cyclodextrin (HPCD) showed a concentration-dependent effect on mupirocin loading; using the optimal HPCD concentration increased loading, but higher concentrations inhibited it. The inclusion of HPCD in the liposome aqueous phase while forming the liposomes resulted in increased drug loading and substantially inhibited drug release in serum.

On the Route to Compatibilization of Carbon Nanotubes

The behavior of single wall and multi wall carbon nanotubes in aqueous solutions of Gum Arabic, a natural polysaccharide, is described. Using electron microscopy, we observe that while the as-prepared nanotube powders contain highly entangled ropes and bundles, the dispersions are mainly composed of individual tubes. TGA of the dried dispersions indicates that the stability of the tubes is not affected by the procedure. It is suggested that the ability of Gum Arabic to exfoliate the bundles, and stabilize individual tubes in aqueous dispersions, can be utilized in the preparation of carbon nanotube-polymer composites. Here the dispersing polymer can act as a compatabilizer and as an adhesion promoter leading to strengthening of the matrix-nanotube interface.

Utilizing Old Egyptian Wisdom for Stabilization of Individual Carbon Nanotubes in Aqueous Dispersions

The tendency of single wall carbon nanotubes to organize into crystalline ropes and the aggregation of the ropes into tangled networks act as an obstacle for most applications, and diminishes the special properties of the individual tubes. We describe a procedure for dispersing as-produced nanotube powder in aqueous solutions of Gum Arabic. Dispersion results in spontaneous exfoliation of nanotubes ropes into individual tubes, as demonstrated via x-ray scattering and electron microscopy.

Cardinal Role of Intraliposome Doxorubicin-Sulfate Nanorod Crystal in Doxil Properties and Performance

The uniqueness of Doxil can be attributed, to a large extent, to its intraliposomal doxorubicin-sulfate nanorod crystal. We re-examine these nanocrystal features and their mechanism of the formation by studying pegylated liposomal doxorubicins (PLDs) of the same lipid composition, size distribution, and extraliposome medium that were prepared at different ammonium sulfate (AS) concentrations. This study includes a comparison of the thermotropic behavior, morphology, and in vitro ammonia-induced doxorubicin release (relevant to Doxil’s in vivo performance) of these PLDs. In this study, we confirm that a transmembrane ammonium gradient is critical for doxorubicin remote loading, and we demonstrate that the intraliposomal concentration of sulfate counteranions and ammonium ions determine to a large extent the physical state and stability of the PLDs’ remote loaded doxorubicin. “Fully-developed” intraliposome doxorubicin-sulfate nanorod crystals (as defined by cryogenic transmission electron microscopy imaging) develop only when the ammonium sulfate (AS) concentration used for PLD preparation is ≥150 mM. Less than 10% of PLDs prepared with 100 mM AS show fully developed nanorod crystals. Intraliposomal AS concentration ≥200 mM is required to support the stable nanocrystallization in PLDs. The presence of nanocrystals and their melting enthalpy and phase transition co-operativity strongly affect the ammonia-induced doxorubicin release of PLDs. A quick, biphasic release occurs for PLDs that lack the nanorod crystals or have crystals of poor crystallinity, whereas PLDs prepared with ≥200 mM AS show a monophasic, zero-order slow release. This study also demonstrates that after remote loading, residual intraliposomal ammonium concentration and the transmembrane pH gradient related to it also play an important role in doxorubicin-sulfate intraliposomal crystallization and ammonia-induced doxorubicin release.

Practical aspects in size and morphology characterization of drug-loaded nano-liposomes

Graphical abstract Figure. No caption available. ABSTRACT Size and morphology distributions are critical to the performance of nano‐drug systems, as they determine drug pharmacokinetics and biodistribution. Therefore, comprehensive and reliable analyses of these properties are required by both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). In this study, we compare two most commonly used approaches for assessing the size distribution and morphology of liposomal nano‐drug systems, namely, dynamic light scattering (DLS) and cryogenic‐transmission electron microscopy (cryo‐TEM); an automated quantitative analysis method was developed for the latter method. We demonstrate the advantages and disadvantages of each of these two approaches for a commercial formulation of the anti‐cancer drug doxorubicin ‐ Doxil®, in which the drug is encapsulated, mostly in the form of nano‐rod crystals. With increasing drug concentration, these nano‐rods change the shape of the liposomes from spherical, before drug loading, to prolate (oval), post drug loading. Cryo‐TEM analysis provides a detailed size distribution of both the liposomes (minor and major axes) and the nano‐rod drug. Both these values are relevant to the drug performance. In this study, we show that at elevated drug concentration (2.75 mg/ml) the drug grows mainly along the major axis and that this high concentration can result, in some cases, in liposome rupture. We show that the combination of cryo‐TEM and DLS constitutes a reliable tool for demonstrating the stability of the formulation in human plasma at body temperature, a characteristic that is crucial for achieving therapeutic efficacy.

Nematic Ordering of SWNT in Meso-Structured Thin Liquid Films of Polystyrenesulfonate

The formation of nematic-like islands of single-walled carbon nanotubes (SWNT) in polystyrenesulfonate (PSS) dispersions confined into nanometrically thin films is reported. The SWNT are observed to assemble into orientationally ordered phases, where the intertube distance, as measured via transmission electron microscopy at cryogenic temperatures, matches the polyelectrolytes bulk correlation length deduced from X-ray scattering. The micrometers-long islands of orientationally ordered carbon nanotubes are observed in both SWNT and double-walled carbon nanotubes (DWNT) but not in specimens prepared from similar dispersions of multiwalled carbon nanotubes (MWNT). These observations, together with relaxation and rheological experiments, suggest that the orientational ordering may result from coupling between confinement of the polymer-wrapped SWNT and DWNT and the microstructure of the solvated polyelectrolyte.