Therapeutic Response of Multifunctional Lipid and Micelle Formulation in Hepatocellular Carcinoma.

Hepatic stellate cells (HSCs), as an important part of the tumor microenvironment (TME), could be activated by tumor cells as cancer-associated fibroblasts (CAFs), thereby promoting the production of extracellular matrix (ECM) and favoring the development of tumors. Therefore, blocking the "CAFs-ECM" axis is a promising pathway to improve antitumor efficacy. Based on this, we developed a multifunctional nanosized delivery system composed of hyaluronic acid-modified pH-sensitive liposomes (CTHLs) and glycyrrheic acid-modified nanomicelles (DGNs), which combines the advantages of targeted delivery, pH-sensitivity, and deep drug penetration. To mimic actual TME, a novel HSCs+BEL-7402 cocultured cell model and a m-HSCs+H22 coimplanted mice model were established. As expected, CTHLs and DGNs could target CAFs and tumor cells, respectively, and promote the drug penetration and retention in tumor regions. Notably, CTHLs+DGNs not only exhibited a superior antitumor effect in three-level tumor-bearing mice but also presented excellent antimetastasis efficiency in lung-metastatic mice. The antitumor mechanism revealed that the lipid&micelle mixed formulations effectively inhibited the activation of CAFs, reduced the deposition of ECM, and reversed the epithelial-mesenchymal transition (EMT) of tumor cells. In brief, the nanosized delivery system composed of CTHLs and DGNs could effectively improve the therapeutic effect of liver cancer by blocking the "CAFs-ECM" axis, which has a good clinical application prospect.

Walled vessel-mimicking phantom for ultrasound imaging using 3D printing with a water-soluble filament: design principle, fluid-structure interaction (FSI) simulation, and experimental validation.

The geometry and stiffness of a vessel are pertinent to blood dynamics and vessel wall mechanical behavior and may alter in diseased conditions. Ultrasound-based ultrafast Doppler (uDoppler) imaging and shear wave imaging (SWI) techniques have been extensively exploited for the assessment of vascular hemodynamics and mechanics. Their performance is conventionally validated on vessel-mimicking phantoms (VMPs) prior to their clinical use. Compared with commercial ones, customized VMPs are favored for research use because of their wider range of material properties, more complex lumen geometries, or wall structures. Fused deposition modeling (FDM) 3D printing technique with plastic filaments is a promising method for making VMPs with a complex vessel lumen. However, it may require a toxic solvent or a long dissolution time currently. In this paper, we present a safe, efficient and geometrically flexible method where FDM 3D printing with a water-soluble polyvinyl alcohol (PVA) filament is exploited to fabricate a walled three-branch VMP (VMP-I). As a key step in fabrication, to avoid dissolution of the PVA-printed vessel core by the solution of the tissue-mimicking material, paraffin wax was used for isolation. Paraffin wax is easy to coat (i.e. without any special equipment), of satisfactory thickness (∼0.1 mm), chemically stable, and easy to remove after fabrication, thus making the proposed method practicable for ultrasound imaging studies. VMP-I was examined by B-mode imaging and power Doppler imaging (PDI) to verify complete dissolution of PVA-printed vessel core in its lumen, confirming good fabrication quality. The flow velocities in VMP-I were estimated by uDoppler imaging with a -0.8% difference, and the shear wave propagation speeds for the same phantom were estimated by SWI with a -6.03% difference when compared with fluid-structure interaction (FSI) simulation results. A wall-less VMP of a scaled and simplified coronary arterial network (VMP-II) was additionally fabricated and examined to test the capability of the proposed method for a complex lumen geometry. The proposed fabrication method for customized VMPs is foreseen to facilitate the development of ultrasound imaging techniques for blood vessels.

Modifications of surfactant distributions and surface morphologies in latex films due to moisture exposure.

Migration of surfactants in water-based, pressure-sensitive adhesive (PSA) films exposed to static and cyclic relative humidity conditions was investigated using confocal Raman microscopy (CRM) and atomic force microscopy (AFM). Studied PSA films contain monomers n-butyl acrylate, vinyl acetate, and methacrylic acid and an equal mass mixture of anionic and nonionic nonylphenol ethoxylate emulsifiers. A leveling of surfactant concentration distributions is observed via CRM after films stored at 50% relative humidity (RH) are exposed to a 100% RH for an extended time period, while relatively small increases in surface enrichment occur when films are stored at 0% RH. Use of CRM for binary mixtures containing anionic or nonionic surfactant and latex that has undergone dialysis to remove nonpolymeric components indicates that surfactant-polymer compatibility governs to a great extent surface enrichment, but not changes observed with humidity variations. AFM images show that upon drying latex coatings, surfactant and other additives collect in large aggregation regions, which protrude from film surfaces. These structures are absent at high humidity, which appears to result from lateral spreading across the polymer surface. When humidity is reduced, aggregation regions reform but appear to be smaller and more evenly dispersed, and by cycling humidity between 0 and 100% RH, interfacial enrichment can be seen to diminish. Presented results provide greater insights into the distribution behavior of surfactants in latex films and potential mechanisms for observed issues arising for these systems.

Effect of the coating morphology on the drug release from engineered drug-polymer nanocomposites.

The ElectroNanospray process (Nanocopoeia, Inc) transforms drugs and polymers into many nanoscale material states including powders, liquids, encapsulated particles, and coatings. This enabling technology platform allows application of polymers and drugs to the surface of medical devices such as coronary stents in a single-stage process. Modification of ElectroNanospray process parameters resulted in surface coatings with rich morphologies ranging in appearance from smooth and heterogeneous to highly porous and rough (open matrix). The traditional approach of measuring percent release over time by HPLC shows that the drug release profiles change significantly with coating morphology. In this study, we employed high resolution imaging techniques such as SEM, Atomic Force Microscopy (AFM) and Confocal Raman Microscopy to elucidate the drug release process on these coatings in situ, indicating a correlation of release kinetics with coating morphology.

Multimodal dynamic imaging of therapeutic biomedical coatings in aqueous medium.

Drug release from therapeutic biomedical films such as drug-polymer composite coatings on drug eluting stents is a highly complex and poorly understood process. The dynamics of drug release and the evolution of surface morphology during release have direct impact on the performance of the device. This information is not easily accessible, and there have been few systematic studies to investigate drug release from biomedical coatings in real time. In this study, the complementary analytical techniques of confocal Raman microscopy, in-liquid atomic force microscopy, scanning electron microscopy, and high performance liquid chromatography were used to examine real-time mobilization and release of the drug rapamycin from polyisobutylene-block-polystyrene thin films, during immersion in buffered saline for 12 h. Each technique was found to have distinct limitations in either temporal or spatial resolution; in combination, however, the overlapping techniques provided a level of detail that is not available using any single approach.

Drug-eluting stent coatings.

This paper reviews the development of coronary stents from a polymer scientist's view point, and presents the first results of an interdisciplinary team assembled for the development of new stent systems. Poly(styrene-b-isobutylene-b-styrene) block copolymer (SIBS), a nanostructured thermoplastic elastomer, is used in clinical practice as the drug-eluting polymeric coating on the Taxus coronary stent (trademark of Boston Scientific Co.). Our group has been developing new architectures comprising of arborescent (dendritic) polyisobutylene cores (D_SIBS), which were shown to be as biocompatible as SIBS. ElectroNanospray (Nanocopoeia Inc.) was used to coat test coupons and coronary stents with selected D(S)IBS polymers loaded with dexamethasone, a model drug. The surface topology varied from smooth to nanosized particulate coating. This paper will demonstrate how drug release profiles were influenced by both the molecular weight of the polyisobutylene core and spraying conditions of the polymer-drug mixture.

Nanoscale aggregate structures of trisiloxane surfactants at the solid-liquid interface.

The self-associating structures at the solid-liquid interface of three nonionic trisiloxane surfactants ((CH3)3SiO)2Si(CH3)(CH2)3(OCH2CH2)n OH (n = 6, 8, and 12), or BEn, are studied as a function of substrate properties by atomic force microscopy (AFM) imaging and force measurement. These trisiloxane surfactants are known as superwetters, which promote rapid spreading of dilute aqueous solutions on low-energy surfaces. This study also attempts to relate the BEn surface aggregate structures at the solid-liquid interface to their superwetting behavior. Four substrates are used in the study: muscovite mica, highly oriented pyrolytic graphite, and oxidized silicon wafer with and without a full monolayer of self-assembled n-octadecyltrichlorosilane (OTS). The concentration of BEn is fixed at 2 times the critical aggregation concentration (CAC). The BEn surfactants are only weakly attracted to hydrophilic surfaces, more on oxidized silicon than on mica. All three form ordinary planar monolayers on HOPG and OTS-covered oxidized silicon. The significance of surfactant adsorption on the AFM tip is investigated by comparing the force curves obtained by tips with and without thiol modification. The surface aggregate structures of the BEn surfactants correlate with their bulk structures and do not exhibit anomalous adsorption behavior. The adsorption behavior of the BEn superwetters is similar to that of the CmEn surfactants. Thus, our results confirm previous work showing that superwetting shares its main features with other classes of surfactants.