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The delivery of therapeutics to the brain in an efficient, noninvasive manner continues to be a major unmet need in the field of drug delivery. One significant impediment to brain delivery results from the existence of the physical yet dynamic blood-brain barrier (BBB). Despite the many, often complex strategies that currently exist to breach the BBB, adequate delivery of effective therapeutics from the bloodstream continues to remain quite low. Nanotechnology has emerged as a promising tool for brain delivery, but little is known about the important particle parameters that influence delivery. Here, we synthesized and characterized a library of nanoparticles with distinct properties ranging from size, shape, stiffness, and composition to investigate and identify the key attributes influencing particle uptake and transport for brain delivery. To accomplish this task, an in vitro human BBB model was developed and validated using human cerebral microvascular endothelial cells (hCMEC/D3). Particle uptake and apparent permeability coefficients (Papp) were then determined for each particle group. To elucidate the roles of different parameters on particle uptake and transport across the BBB, the predominant mechanisms of endocytosis were also investigated. Our results show that particle composition yielded the greatest impact on penetration across the BBB model. This work lays the foundation and provides new insights into the role of particle parameters on penetration across the BBB.

Protein nanoparticles are a promising approach for nanotherapeutics, as proteins combine versatile chemical and biological function with controlled biodegradability. In this work, the development of an adaptable synthesis method is presented for synthetic protein nanoparticles (SPNPs) based on reactive electrojetting. In contrast to past work with electrohydrodynamic cojetting using inert polymers, the jetting solutions are comprised of proteins and chemically activated macromers, designed to react with each other during the processing step, to form insoluble nanogel particles. SPNPs made from a variety of different proteins, such as transferrin, insulin, or hemoglobin, are stable and uniform under physiological conditions and maintain monodisperse sizes of around 200 nm. SPNPs comprised of transferrin and a disulfide containing macromer are stimuli-responsive, and serve as markers of oxidative stress within HeLa cells. Beyond isotropic SPNPs, bicompartmental nanoparticles containing human serum albumin and transferrin in two distinct hemispheres are prepared via reactive electrojetting. This novel platform provides access to a novel class of versatile protein particles with nanoscale architectures that i) can be made from a variety of proteins and macromers, ii) have tunable biological responses, and iii) can be multicompartmental, a prerequisite for controlled release of multiple drugs.

Nanoparticle‐based therapeutic formulations are being increasingly explored for the treatment of various ailments. Despite numerous advances, the success of nanoparticle‐based technologies in treating brain diseases has been limited. Translational hurdles of nanoparticle therapies are attributed primarily to their limited ability to cross the blood–brain barrier (BBB), which is one of the body's most exclusive barriers. Several efforts have been focused on developing affinity‐based agents and using them to increase nanoparticle accumulation at the brain endothelium. Very little is known about the role of fundamental physical parameters of nanoparticles such as size, shape, and flexibility in determining their interactions with and penetration across the BBB. Using a three‐dimensional human BBB microfluidic model (μHuB), we investigate the impact of these physical parameters on nanoparticle penetration across the BBB. To gain insights into the dependence of transport on nanoparticle properties, two separate parameters were measured: the number of nanoparticles that fully cross the BBB and the number that remain associated with the endothelium. Association of nanoparticles with the brain endothelium was substantially impacted by their physical characteristics. Hard particles associate more with the endothelium compared to soft particles, as do small particles compared to large particles, and spherical particles compared to rod‐shaped particles. Transport across the BBB also exhibited a dependence on nanoparticle properties. A nonmonotonic dependence on size was observed, where 200 nm particles exhibited higher BBB transport compared to 100 and 500 nm spheres. Rod‐shaped particles exhibited higher BBB transport when normalized by endothelial association and soft particles exhibited comparable transport to hard particles when normalized by endothelial association. Tuning nanoparticles' physical parameters could potentially enhance their ability to cross the BBB for therapeutic applications.

Herein, for the first time to our knowledge, we experimentally demonstrate Fano resonant all-dielectric metasurfaces comprising of high- and median-index nanopillars (HfO2, TiO2 and ZrO2) with zero loss in visible range for polarization-sensitive structural coloration.

Histone methylation plays an important regulatory role in chromatin restructuring and RNA transcription. Arginine methylation that is enzymatically catalyzed by the family of protein arginine methyltransferases (PRMTs) can either activate or repress gene expression depending on cellular contexts. Given the strong correlation of PRMTs with pathophysiology, great interest is seen in understanding molecular mechanisms of PRMTs in diseases and in developing potent PRMT inhibitors. Herein, we reviewed key research advances in the study of biochemical mechanisms of PRMT catalysis and their relevance to cell biology. We highlighted how a random binary, ordered ternary kinetic model for PRMT1 catalysis reconciles the literature reports and endorses a distributive mechanism that the enzyme active site utilizes for multiple turnovers of arginine methylation. We discussed the impacts of histone arginine methylation and its biochemical interplays with other key epigenetic marks. Challenges in developing small-molecule PRMT inhibitors were also discussed.

Endothelial cells represent the first biological barrier for compounds, including nanoparticles, administered via the intravascular route. In the case of ischemic stroke and other vascular diseases, the endothelium overexpresses specific markers, which can be used as molecular targets to facilitate drug delivery and imaging. However, targeting these markers can be quite challenging due to the presence of blood flow and the associated hydrodynamic forces, reducing the likelihood of adhesion to the vessel wall. To overcome these challenges, various parameters including size, shape, charge or ligand coating have been explored to increase the targeting efficiency. Geometric shape can modulate nanoparticle binding to the cell, especially by counteracting part of the hydrodynamic forces of the bloodstream encountered by the classical spherical shape. In this study, the binding affinity of polystyrene nanoparticles with two different shapes, spherical and rod-shaped, were compared. First, vascular adhesion molecule-1 (VCAM-1) was evaluated as a vascular target of inflammation, induced by lipopolysaccharide (LPS) stimulation. To evaluate the effect of nanoparticle shape on particle adhesion, nanoparticles were coated with anti-VCAM-1 and tested under static conditions in cell culture dishes coated with cerebral microvasculature cells (bEnd.3) and under dynamic flow conditions in microfluidic channels lined with hCMEC/D3 cells. Effect of particle shape on accumulation was also assessed in two in vivo models including systemic inflammation and local brain inflammation. The elongated rod-shaped particles demonstrated greater binding ability in vitro, reaching a 2.5-fold increase in the accumulation for static cultures and 1.5-fold for flow conditions. Anti-VCAM-1 coated rods exhibited a 3.5-fold increase in the brain accumulation compared to control rods. These results suggest shape offers a useful parameter in future design of drug delivery nanosystems or contrast agents for neurovascular pathologies. This study has been partially supported by grants from Instituto de Salud Carlos III (PI13/00292 and PI17/0054), Spanish ResearchNetwork on Cerebrovascular Diseases RETICS-INVICTUS (RD12/0014),Fundación Mutua Madrileña. The Ministry of Economy and Competitiveness of Spain (SAF2017-84267-R). The European Union program FEDER and the European Regional Development Fund–ERDF, MADIA project No. 732678 to FC. Furthermore, F. Campos (CP14/00154) recipients a research contract from Miguel Servet Program of Instituto de Salud Carlos III. National Science Foundation Graduate Research Fellowship under Grant DGE-1745303 SI

Regarding classification of materials as ionic liquids (ILs) and deep eutectic solvents (DESs), Rogers and coworkers elegantly stated in their previous article (1) that the current definitions are based on extreme behaviors and the reality is somewhere in the middle. By definition, the behavior of ILs is dominated by ionic interactions, whereas DESs exhibit a strong contribution from hydrogen bonding. Our choline and geranate (CAGE) compound fits the definition of an IL since it comprises largely ionic species, cholinium and geranate, and has a melting point below 100 °C. At the same time, CAGE is not a classical IL since it also contains neutral geranic acid. … [↵][1]1To whom correspondence should be addressed. Email: mitragotri{at}seas.harvard.edu. [1]: #xref-corresp-1-1

The large-scale deployment of geologic carbon storage will require minimizing the risk of CO2 leakage. Here we report on a novel strategy to seal leakage pathways by injecting functionalized reactive calcium silicate (CaSiO3) particles. The particles consist of a mineral silicate core within a temperature-sensitive Poly(N,N-dimethylaminoethyl methacrylate) coating that limits contact between the core and the surrounding CO2(aq) above a switching temperature making them relatively unreactive deep in the subsurface. If the CO2 leaks to shallower depths and cooler temperatures, the coatings would extend and enable the silicate core to react with CO2(aq) to form solid carbonate precipitates that reduce the permeability of the fracture or flow path. A combined laboratory- and simulation-based investigation was conducted to explore key early-stage research questions related to the feasibility of this leakage management strategy. Sand columns were injected with either coated or uncoated CaSiO3 particles and the permeability was measured before and after exposure to CO2. Experiments were conducted at 35 °C and 70 °C, a range that spans the switching temperature for the coatings. Results show that at the cooler temperature the coating effectively enabled reaction and permeability reduction. At higher temperatures, the coated particles limited mineral carbonation and the permeability decrease was minimal compared to columns with uncoated particles. The morphology and location of the precipitates provides insight about permeability evolution. Model simulations of 2D radial particle transport from an injection point provided insight into the effects of particle size, coating properties, and concentrations of particles in several representative rock formations.

Developing selective enzyme inhibitors allows for the expansion of molecular toolboxes to investigate functions and activities of target enzymes. The histone acetyltransferase 1 (HAT1) is among the first histone acetyltransferase (HAT) enzymes that were discovered in the mid-1990s; however, it remains one of the poorly studied enzymes in comparison to the other HATs. Although HAT1 has been linked to various disease states, no inhibitors have been reported to target HAT1. Here we designed a set of peptide-CoA conjugates as bisubstrate inhibitors of HAT1 with submicromolar potency. In particular, the bisubstrate inhibitor H4K12CoA exhibited a low K(i) value of 1.1 nM for HAT1. In addition, H4K12CoA was shown to be a competitive inhibitor with respect to both AcCoA and H4 peptide, suggesting a unique kinetic mechanism of HAT1 catalysis. Creating these submicromolar inhibitors offers a mechanistic tools to better understand how HAT1 recognizes substrates and cofactors, as well as provides chemical leads to further develop therapeutic agents to target this important enzyme for disease therapy.

With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3–10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed. The formulation exhibited high biocompatibility and was stable for 2 months at room temperature and for at least 4 months under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

Microcrystalline cellulose and Bombyx mori silk blended biocomposite films were regenerated using various imidazolium-based ionic liquids. The films were characterized to understand the effect of the inter- and intra-molecular interactions upon the morphology and thermal properties. Various techniques were implemented to investigate structural, morphological and thermal properties of the biocomposite films, including Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray scattering. Results show that the type of ionic liquid has strong influence on the structure of silk-cellulose composites that can form either amorphous or semicrystalline structures. While the thermal properties are independent of the type of cation in ionic liquids, the levels of β-sheet configuration are dependent on the type of anion, which further causes changes on the biocomposite thermal properties. The topological image provided information to support morphological effects on the varying ionic liquids and X-ray scattering allowed for insight on the role of ionic liquids on the crystallinity and the spacing differences in biocomposite films. The results have demonstrated that there is a direct relationship between the intermolecular interactions in films and the anion structure of the ionic liquids.

Recent work exploring the use of high-molecular weight alcohols to treat essential tremor (ET) has identified octanoic acid as a potential novel tremor-suppressing agent. We used an established harmaline-based mouse model of ET to compare tremor suppression by 1-octanol and octanoic acid. The dose-related effect on digitized motion power within the tremor bandwidth as a fraction of overall motion power was analyzed. Both 1-octanol and octanoic acid provided significant reductions in harmaline tremor. An 8-carbon alkyl alcohol and carboxylic acid each suppress tremor in a pre-clinical mouse model of ET. Further studies are warranted to determine the safety and efficacy of such agents in humans with ET.

Naturally occurring antimicrobial peptides (AMPs) display the ability to eliminate a wide variety of bacteria, without toxicity to the host eukaryotic cells. Synthetic polymers containing moieties mimicking lysine and arginine components found in AMPs have been reported to show effectiveness against specific bacteria, with the mechanism of activity purported to depend on the nature of the amino acid mimic. In an attempt to incorporate the antimicrobial activity of both amino acids into a single water-soluble copolymer, a series of copolymers containing lysine mimicking aminopropyl methacrylamide (APMA) and arginine mimicking guanadinopropyl methacrylamide (GPMA) were prepared via aqueous RAFT polymerization. Copolymers were prepared with varying ratios of the comonomers, with degree of polymerization of 35-40 and narrow molecular weight distribution to simulate naturally occurring AMPs. Antimicrobial activity was determined against Gram-negative and Gram-positive bacteria under conditions with varying salt concentration. Toxicity to mammalian cells was assessed by hemolysis of red blood cells and MTT assays of MCF-7 cells. Antimicrobial activity was observed for APMA homopolymer and copolymers with low concentrations of GPMA against all bacteria tested, with low toxicity toward mammalian cells.

T HREE years ago I presented before this Society a paper on maximum dosage in pollen therapy.l It might be profitable at this t,ime to report my further experiences with this method of treating 1iaJ fever. Certain refinements in technic have heeu efYected since the preceding report. In the first place, my extracting fluid has been changed from a 50 per cent glycerine and buffered salt solution, to a slight modification of the Hollister-Stier? fluid. innumerable comparative skin tests have shown that a material increase in the sodium chloride content of the former extracting fluid (from 0.5 per cent to 6 per cent,), wit,11 a slight decrease in the glycerine (from 50 per cent to 46 per cent), yields more potent pollen extracts, which also have a. higher nitrogen content. Patients who hare been treated with both types of extracts report greater local reactions, with more itching:. following subcutaneous injection of doses of the new extracts. In preceding articles 1 have stressed the importance of obtainin g a satisfactory local reaction from each individual dose? and roughly speaking, the better the reactions, the better t,he results. Any theoretical ob,jection to the definitely higher salt content can be met. when we consider that Clock’s” origina. estracting fluid, which is still quite widely nsetl, containcad ti6+$ per cent glycerine and 331/! per cent saturated salt, solution, or about, I1 per cent sodium chloride. Pollen extracts with 6 per collt SOC~iUlll chloride swm to give slightly larger skin test rcact,ions than the 7 per cent sodium chloride extra& advocated by IIollister-Stier. Fort,y-six pw