Differentiating Co-Delivery of Bisphosphonate and Simvastatin by Self-Healing Hyaluronan Hydrogel Formed by Orthogonal “Clicks”: An In-Vitro Assessment

Due to its unique properties resembling living tissues, hydrogels are attractive carriers for the localized and targeted delivery of various drugs. Drug release kinetics from hydrogels are commonly controlled by network properties and the drug-network interactions. However, and simultaneously, the programmable delivery of multiple drugs with opposing properties (hydrophilicity, molecular weight, etc.) from hydrogels with determined network properties is still challenging. Herein, we describe the preparation of injectable self-healing hyaluronic acid (HA) hydrogels that release hydrophobic simvastatin and hydrophilic aminobisphosphonate (BP) drugs independently in response to acidic and thiol-containing microenvironments, respectively. We apply a prodrug strategy to BP by conjugating it to HA via a self-immolative disulfide linker that is stable in the blood plasma and is cleavable in the cytoplasm. Moreover, we utilize HA-linked BP ligands to reversibly bind Ca2+ ions and form coordination hydrogels. Hydrazone coupling of hydrophobic ligands to HA permits the encapsulation of simvastatin molecules in the resulting amphiphilic HA derivative and the subsequent acid-triggered release of the drug. The conjugation of BP and hydrophobic ligands to HA enables preparation of both bulk self-healing hydrogels and nanogels. Moreover, the developed hydrogel system is shown to be multi-responsive by applying orthogonally cleavable linkers. The presented hydrogel is a potential candidate for the combination treatment of osteoporosis and bone cancers as well as for bone tissue regeneration since it can deliver bone anabolic and anti-catabolic agents in response to bone diseases microenvironments.

The Hydrophobic Ligands Entry and Exit from the GPCR Binding Site-SMD and SuMD Simulations

Most G protein-coupled receptors that bind the hydrophobic ligands (lipid receptors and steroid receptors) belong to the most populated class A (rhodopsin-like) of these receptors. Typical examples of lipid receptors are: rhodopsin, cannabinoid (CB), sphingosine-1-phosphate (S1P) and lysophosphatidic (LPA) receptors. The hydrophobic ligands access the receptor binding site from the lipid bilayer not only because of their low solubility in water but also because of a large N-terminal domain plug preventing access to the orthosteric binding site from the extracellular milieu. In order to identify the most probable ligand exit pathway from lipid receptors CB1, S1P1 and LPA1 orthosteric binding sites we performed at least three repeats of steered molecular dynamics simulations in which ligands were pulled in various directions. For specific ligands being agonists, the supervised molecular dynamics approach was used to simulate the ligand entry events to the inactive receptor structures. For all investigated receptors the ligand entry/exit pathway goes through the gate between transmembrane helices TM1 and TM7, however, in some cases it combined with a direction toward water milieu.

The Trouble with 1-Octadecene; Polymerization During Nanocrystal Synthesis

<p>1-octadecene is a widely used solvent for high temperature nanocrystal synthesis (120 – 320 °C). Here, we show that 1-octadecene spontaneously polymerizes under these conditions and the resulting poly(1-octadecene) has a comparable solubility and size to nanocrystals stabilized by hydrophobic ligands. Typical purification procedures (precipitation/redispersion cycles or size exclusion chromatography) fail to separate the poly(1-octadecene) impurity from the nanocrystal product. To avoid formation of poly(1-octadecene), we replaced 1-octadecene with saturated, aliphatic solvents. Alternatively, the native ligands are exchanged for polar ligands, leading to significant solubility differences between nanocrystals and poly(1-octadecene), therefore allowing isolation of pure nanocrystals, free from polymer impurities. These results will help design superior syntheses and improve nanocrystal purity, an important factor in many applications.</p>

The Trouble with 1-Octadecene; Polymerization During Nanocrystal Synthesis

<p>1-octadecene is a widely used solvent for high temperature nanocrystal synthesis (120 – 320 °C). Here, we show that 1-octadecene spontaneously polymerizes under these conditions and the resulting poly(1-octadecene) has a comparable solubility and size to nanocrystals stabilized by hydrophobic ligands. Typical purification procedures (precipitation/redispersion cycles or size exclusion chromatography) fail to separate the poly(1-octadecene) impurity from the nanocrystal product. To avoid formation of poly(1-octadecene), we replaced 1-octadecene with saturated, aliphatic solvents. Alternatively, the native ligands are exchanged for polar ligands, leading to significant solubility differences between nanocrystals and poly(1-octadecene), therefore allowing isolation of pure nanocrystals, free from polymer impurities. These results will help design superior syntheses and improve nanocrystal purity, an important factor in many applications.</p>

Interaction of Arsenic Species with Organic Ligands: Competitive Removal from Water by Coagulation-Flocculation-Sedimentation (C/F/S)

The co-occurrence of arsenic (As) and organic ligands in water bodies has raised environmental concerns due to their toxicity and adverse effects on human health. The present study aims to elucidate the influences of hydrophobic/hydrophilic organic ligands, such as humic acid (HA) and salicylic acid (SA), on the interactive behavior of As species in water. Moreover, the competitive removal behaviors of As(III, V) species and total organic carbon (TOC) were systematically investigated by coagulation-flocculation-sedimentation (C/F/S) under various aqueous matrices. The results showed the stronger binding affinity of As(V) than As(III) species, with a higher complexation ability of hydrophobic ligands than hydrophilic. The media containing hydrophilic ligands require smaller ferric chloride (FC) doses to achieve the higher As(III, V) removal, while the optimum FC dose required for As(III) removal was found to be higher than that for As(V). Moreover, hydrophobic ligands showed higher TOC removal than hydrophilic ligands. The pronounced adverse effect of a higher concentration of hydrophobic ligands on the removal efficiencies of As(V) and TOC was observed. The adsorption of As(V) on Fe precipitates was better fitted with the Langmuir model but the Freundlich isotherm was more suitable for As(III) in the presence of hydrophilic SA. Moreover, TOC removal was substantially decreased in the As(V) system as compared to the As(III) system due to the dissolution of Fe precipitates at higher As(V) concentrations. The results of FC composite flocs demonstrated that the combined effect of oxidation, charge neutralization and adsorption played an important role in the removal of both toxicants during the C/F/S process. In summary, the findings of the present study provide insights into the fate, mobility and competitive removal behavior of As(III, V) species and organic ligands in the water treatment process.

Unraveling the protonation site of oxazole and solvation with hydrophobic ligands by infrared photodissociation spectroscopy

Infrared spectroscopy reveals exclusive N-protonation of the oxazole ring and bifurcated or linear hydrogen bonding with hydrophobic N2and Ar ligands.