The ability to form self-organized thermotropic mesophases of amphiphilic cyclodextrins correlates well with their ability to establish an intermolecular H-bond network.
Glutathione (GSH) sensitive vesicles were prepared by the self-assembly of amphiphilic inclusion complexes. These novel chemically sensitive supramolecular amphiphiles are anticipated to have applications in drug delivery; the nanocarriers can protect the encapsulated cargo and release it via triggered degradation in high concentrations of GSH. Additionally, the sensitivity of the vesicles to GSH indicates that the dynamic covalent disulfide bond at the vesicle surface can be used for post-modification of the nanocarrier via a thiol-disulfide exchange, a strategy that can be exploited to introduce targeting moieties to increase treatment specificity. Supramolecular amphiphiles containing a dynamic covalent disulfide bond were prepared via the host-guest inclusion complexes between alkylated β-cyclodextrin (β-CD) hosts and adamantane terminated polyethylene glycol derivatives. The significant difference between the critical micelle concentrations of the supramolecular amphiphiles and the individual host and guest components confirmed that a unique supramolecular amphiphile was formed. Fluorescence experiments and dynamic light scattering (DLS) revealed that the supramolecular amphiphiles self-assembled into vesicles of 130 nm diameter which were stable for 8 months. Degradation of the vesicles after incubation with GSH was monitored using DLS and by the release of encapsulated 5,6-carboxyfluorescein (CF), observed by an increase in fluorescence intensity. Degradation of the nanocarrier was faster at intracellular GSH concentrations than at extracellular GSH concentrations.
Diisobutylaluminium hydride (DIBAL-H) mediated reductive removal of benzyl groups was investigated for perbenzylated α-, β- and γ-cyclodextrins using DIBAL-H in hexane as the reagent. It was found that under the new conditions, the debenzylation can be better controlled to provide sequentially tri- and tetra-debenzylated products in moderate yields and in a regioselective manner. In the case of α-cyclodextrin, the removal of the third and fourth benzyl groups took a different path involving the secondary rim, compared to β- and γ-cyclodextrins which both gave only 6-O-debenzylated products.
Abstract The perfunctionalization of the secondary face of cyclodextrins (CDs) is a challenging task that often results in poor yields. Here, we report that the use of copper‐catalyzedHuisgen 1,3‐dipolar cycloaddition is an efficient and versatile strategy that provides perfunctionalized CDs at the secondary face with good to high yields. A variety of functional groups, such as alkyl, alkenyl, ester, carboxylic acid, amide, and alcohol, have been successfully incorporated on the secondary face of β‐CD from the same starting material. These functionalized CD derivatives could be used as building blocks for further structural modification or as hosts for different applications.
Microarrays have been used to evaluate the expression of thousands of genes in various tissues. However, few studies have investigated the change in gene expression profiles in one of the most easily accessible tissues, whole blood. We utilized an acute inflammation model to investigate the possibility of using a cDNA microarray to measure the gene expression profile in the cells of whole blood. Blood was collected from male Sprague-Dawley rats at 2 and 6 h after treatment with 5 mg/kg (ip) LPS. Hematology showed marked neutrophilia accompanied by lymphopenia at both time points. TNF-alpha and IL-6 levels were markedly elevated at 2 h, indicating acute inflammation, but by 6 h the levels had declined. Total RNA was isolated from whole blood and hybridized to the National Institute of Environmental Health Sciences Rat Chip v.3.0. LPS treatment caused 226 and 180 genes to be differentially expressed at 2 and 6 h, respectively. Many of the differentially expressed genes are involved in inflammation and the acute phase response, but differential expression was also noted in genes involved in the cytoskeleton, cell adhesion, oxidative respiration, and transcription. Real-time RT-PCR confirmed the differential regulation of a representative subset of genes. Principal component analysis of gene expression discriminated between the acute inflammatory response apparent at 2 h and the observed recovery underway at 6 h. These studies indicate that, in whole blood, changes in gene expression profiles can be detected that are reflective of inflammation, despite the adaptive shifts in leukocyte populations that accompany such inflammatory processes.
Outperforming cell-penetrating peptides, cell-penetrating poly(disulfide)s are attracting increasing attention. Recently we have shown that cell-penetrating poly(disulfide)s can be grown directly on substrates of free choice before delivery and depolymerized right afterwards. These unique characteristics are compatible with the general, non-toxic, traceless yet covalent delivery of substrates in an unmodified form. The objective of this study was to elaborate on substrate-initiated co-polymerization. The original propagators contain a strained disulfide for ring-opening disulfide-exchange polymerization and a guanidinium cation to assure cell-penetrating activity. Here, we report individually optimized conditions to polymerize these original propagators together with several other propagators. The nature of these new propagators significantly affected polymerization efficiency and conditions as well as size, polydispersity and transport activity of the final co-polymers. According to gel permeation chromatography, the length of co-polymers increases with hydrophobicity, bulk and valency of the co-propagators, whereas ion pairing with boronates gives shorter co-polymers and branching increases polydispersity. The activity of co-polymers increases with length, π-acidity, superhydrophobicity and boronate counterions. Hydrophobicity, π-basicity, bulk and branching appear less important for activity in fluorogenic vesicles. The here reported design, synthesis and evaluation of substrate-initiated co-polymers will be essential to find the best cell-penetrating poly(disulfide)s.
