Gastro-protective protein-silica nanoparticles formulation for oral drug delivery: In vitro release, cytotoxicity and mitochondrial activity.

Our contribution aims to provide an efficient solution to one of the major challenges of oral delivery of gastro-sensitive drugs, namely preventing their premature release and degradation in the gastric fluid in order to maximize the absorption in the small intestine. Our results show that a pH-responsive protein, i.e., succinylated ß-lactoglobulin (BL), together with the key attributes of mesoporous silica nanoparticles (MSNs), can synergetically reduce the release of the gastro-sensitive drug, omeprazole (OMP), in acidic pH and enhance the dissolution in intestinal pH conditions. Two families of MSNs were synthesized, MCM-48-based and dendritic-type MSNs, and both materials were additionally functionalized with trimethylsilyl groups to produce a hydrophobic surface that can further modulate the interaction of the MSNs with the succinylated protein in the nanoformulation. The methyl-functionalization of the MSNs also impacted on the physical state of the confined OMP and consequently on its release in near neutral pH. Our cytotoxicity screening revealed no particular mitochondrial dysfunction originating from the MSNs. Moreover, upon progressive release of the drug confined into dendritic-type MSNs, the cytotoxicity against tumorigenic and non-tumorigenic cells (Caco-2 and HCEC) was significantly lower in comparison to the drug pre-dissolved in DMSO.

Discovery of Novel Inhibitors of LpxC Displaying Potent in Vitro Activity against Gram-Negative Bacteria.

UDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multidrug resistant Gram-negative bacteria. By using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization, using cocrystal structures of inhibitors bound to Pseudomonas aeruginosa LpxC as guides, resulted in the discovery of multiple chemical series based on (i) isoindolin-1-ones, (ii) 4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-ones, and (iii) 1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physicochemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series, such as 18d, are discussed.

Optimization of LpxC Inhibitor Lead Compounds Focusing on Efficacy and Formulation for High Dose Intravenous Administration.

LpxC inhibitors were optimized starting from lead compounds with limited efficacy and solubility and with the goal to provide new options for the treatment of serious infections caused by Gram-negative pathogens in hospital settings. To enable the development of an aqueous formulation for intravenous administration of the drug at high dose, improvements in both solubility and antibacterial activity in vivo were prioritized early on. This lead optimization program resulted in the discovery of compounds such as 13 and 30, which exhibited high solubility and potent efficacy against Gram-negative pathogens in animal infection models.

Synthesis of Ultrastable Gold Nanoparticles as a New Drug Delivery System.

Nanotechnologies are increasingly being developed for medical purposes. However, these nanomaterials require ultrastability for better control of their pharmacokinetics. The present study describes three types of ultrastable gold nanoparticles stabilized by thiolated polyethylene glycol groups remaining intact when subjected to some of the harshest conditions described thus far in the literature, such as autoclave sterilization, heat and freeze-drying cycles, salts exposure, and ultracentrifugation. Their stability is characterized by transmission electron microscopy, UV-visible spectroscopy, and dynamic light scattering. For comparison purposes, two conventional nanoparticle types were used to assess their colloidal stability under all conditions. The ability of ultrastable gold nanoparticles to encapsulate bimatoprost, a drug for glaucoma treatment, is demonstrated. MTS assays on human corneal epithelial cells is assessed without changing cell viability. The impact of ultrastable gold nanoparticles on wound healing dynamics is assessed on tissue engineered corneas. These results highlight the potential of ultrastable gold nanoparticles as a drug delivery system in ocular therapy.

Gold nanoparticles in ophthalmology.

Many research projects are underway to improve the diagnosis and therapy in ophthalmology. Indeed, visual acuity deficits affect 285 million people worldwide and different strategies are being developed to strengthen patient care. One of these strategies is the use of gold nanoparticles (GNP) for their multiple properties and their ability to be used as both diagnosis and therapy tools. This review exhaustively details research developing GNPs for use in ophthalmology. The toxicity of GNPs and their distribution in the eye are described through in vitro and in vivo studies. All publications addressing the pharmacokinetics of GNPs administered in the eye are extensively reviewed. In addition, their use as biosensors or for imaging with optical coherence tomography is illustrated. The future of GNPs for ophthalmic therapy is also discussed. GNPs can be used to deliver genes or drugs through different administration routes. Their antiangiogenic and anti-inflammatory properties are of great interest for different ocular pathologies. Finally, GNPs can be used to improve stereotactic radiosurgery, brachytherapy, and photothermal therapy because of their many properties.

Insights into gold nanoparticles as a mucoadhesive system.

A large number of drugs are administered on different mucosal surfaces. However, due to the poor mucoadhesion of the current formulations, their bioavailability is often very low. The development of efficient mucoadhesive drug delivery systems is thus crucial for improving the performance of these drugs. The mucoadhesive properties of gold nanoparticles were investigated. First, two types of gold nanoparticles were synthesized: AuNP1 and AuNP2. AuNP1 only contain internal thiol groups on their metallic core, and AuNP2 contain both internal and peripheral thiol groups. Different protocols based on an adapted quantitative colorimetric method, UV-visible and fluorescence spectroscopies were then developed to gather information on their mucoadhesive properties. Moreover, a global correction factor for the inner filter effect in spectrofluorimetry was proposed, and the data obtained were compared to those commonly used in the literature. Mucins deeply interact with AuNP1, perturbing their core, whereas they remain at the periphery of AuNP2. The quantitative method suggests that a larger number of mucins interact with AuNP2. The establishment of this protocol could be applied to assess the mucoadhesive properties of other stable molecules. This mucoadhesive property of gold nanoparticles could be combined with their drug delivery ability in order to improve the medication administered on mucosa.

Hydroxymethyl Salicylaldehyde Auxiliary for a Glycine-Dependent Amide-Forming Ligation.

A new amide-forming ligation that requires a glycine or a primary amine at the linkage site is described herein. The distinguishing feature of this ligation is its reliance on an O-hydroxymethyl salicylaldehyde ester at the C-terminus which allows, via an N,O-acetal intermediate, the formation of a native peptide bond.