Interaction forces between ternary lipid bilayers containing cholesterol.

Interaction force-distance profiles between substrate-supported membranes composed of equimolar ternary mixtures of unsaturated phosphotidylcholine (PC) lipid, saturated PC lipid, and cholesterol were determined using the surface force apparatus. Both double and single unsaturated PC lipids were studied. In all cases, the membranes were slightly negatively charged, resulting in a weak, long-range electrostatic repulsion. Corroborative atomic force microscopy, zeta potential, and fluorescence microscopy measurements were used to establish that a small level of charged lipid impurities (∼1/400 lipid molecules) were responsible for the repulsive electrostatic interaction between the membranes. At contact, the membranes were adhesive. The magnitude of the adhesion was greater than the van der Waals interaction between pure PC membranes without cholesterol. The enhanced adhesion was primarily attributed to hydrophobic attraction due to the presence of nanoscopic membrane defects which exposed the underlying membrane leaflet. The interaction force-distance profiles also demonstrated that the nanoscopic defects enabled membrane restructuring in the contact region.

High-Resolution Imaging of Polyethylene Glycol Coated Dendrimers via Combined Atomic Force and Scanning Tunneling Microscopy.

Dendrimers have shown great promise as drug delivery vehicles in recent years because they can be synthesized with designed size and functionalities for optimal transportation, targeting, and biocompatibility. One of the most well-known termini used for biocompatibility is polyethylene glycol (PEG), whose performance is affected by its actual conformation. However, the conformation of individual PEG bound to soft materials such as dendrimers has not been directly observed. Using atomic force microscopy (AFM) and scanning tunneling microscopy (STM), this work characterizes the structure adopted by PEGylated dendrimers with the highest resolution reported to date. AFM imaging enables visualization of the individual dendrimers, as well as the differentiation and characterization of the dendrimer core and PEG shell. STM provides direct imaging of the PEG extensions with high-resolution. Collectively, this investigation provides important insight into the structure of coated dendrimers, which is crucial for the design and development of better drug delivery vehicles.

High-resolution imaging of the intramolecular structure of indomethacin-carrying dendrimers by scanning tunneling microscopy.

Dendrimers have shown great potential in drug delivery because of their enhancement of drug solubility in aqueous media, leading to an increase in in vivo circulation and efficacy to targets. The structure of drug-dendrimer complexes however, is not well-known owing to the difficulties associated with visualizing individual drug molecules attached to dendrimers. Scanning tunneling microscopy (STM) enables visualization of dendrimer intramolecular structures using our approach of metal ion tagging. This work extends the approach to reveal the hierarchical structure of indomethacin-loaded poly(amidoamine) hydroxyl-terminated dendrimers. STM imaging provides structural information such as their height, lateral dimensions, and volume. High-resolution STM images enable the identification and count of individual indomethacin molecules bound to the anterior of dendrimers. Removal of drug molecules by the STM tip allows the calculation of individual drug-dendrimer binding energy, which is consistent with 1-3 hydrogen bonds. These investigations provide new insight into the hierarchical structure and nature of indomethacin-dendrimer interactions and deepen our understanding of the stability and pharmacokinetic behavior of dendrimer-based drug delivery vehicles.

High-Resolution Imaging of Dendrimers Used in Drug Delivery via Scanning Probe Microscopy.

Dendrimers and telodendrimer micelles represent two new classes of vehicles for drug delivery that have attracted much attention recently. Their structural characterization at the molecular and submolecular level remains a challenge due to the difficulties in reaching high resolution when imaging small particles in their native media. This investigation offers a new approach towards this challenge, using scanning tunneling microscopy (STM) and atomic force microscopy (AFM). By using new sample preparation protocols, this work demonstrates that (a) intramolecular features such as drug molecules and dendrimer termini can be resolved; and (b) telodendrimer micelles can be immobilized on the surface without compromising structural integrity, and as such, high resolution AFM imaging may be performed to attain 3D information. This high-resolution structural information should enhance our knowledge of the nanocarrier structure and nanocarrier-drug interaction and, therefore, facilitate design and optimization of the efficiency in drug delivery.