Chondroitin Sulphate-Chitosan polyelectrolyte complexes for etorocoxib transdermal delivery: in silico, in vitro and in vivo studies.

Rheumatoid arthritis (RA) is a chronic autoimmune disease which affects around 1% globally leading to joint inflammation and disability. Etorocoxib (ETR) is a potent COX-2 inhibitor traditionally used orally to alleviate RA induced inflammation, yet it causes hepatic side effects on prolonged use. This study aims for in silico optimization of ETR polyelectrolyte complex (PEC) utilizing chondroitin sulphate (CS) and chitosan (CH) for transdermal delivery to RA-inflamed joints with a synergistic anti-inflammatory action owing to CS. An artificial neural network (ANN) combined with 22 factorial design was used to optimize the PEC formula according to particle size (PS) and entrapment efficiency (%EE) by varying CS and CH concentrations. The optimum ETR PEC was incorporated in a gel and examined for its in vitro release, ex vivo permeation, in vivo inflammatory biomarkers, and histopathological evaluation in rats. The optimized formula (F3) with 0.1 CH% w/w and 0.5 CS %w/w showed a PS of 214.98 ± 17.24 nm, %EE 75.31 ± 1.67%, and enhanced in vitro release profile, ex vivo permeation and in vivo anti-inflammatory effect compared to ETR gel via suppressing the expression of IL-6, TNF-α, and TGF-ß pro-inflammatory cytokines as well as the additional anti-inflammatory effect of CS. In conclusion, ETR-PEC gel holds promise as transdermal therapy for managing RA-induced inflammation.

Polycations and polyanions in SARS-CoV-2 infection.

We hypothesize that polycations, such as nuclear histones, released by neutrophils COVID-19 aggravate COVID-19 by multiple mechanisms: (A) Neutralization of the electrostatic repulsion between the virus particles and the cell membrane, thereby enhancing receptor-mediated entry. (B) Binding to the virus particles, thereby inducing opsonin-mediated endocytosis. (C) Adding to the cytotoxicity, in conjunction with oxidants, cytokines and other pro-inflammatory substances secreted by cells of the innate immunity system. These effects may be alleviated by the administration of negatively charged polyanions such as heparins and heparinoids.

Efficient near-infrared anionic conjugated polyelectrolyte for photothermal therapy.

In this work, an anionic conjugated polyelectrolyte (PCP-SO3K), in which the backbone contains alternating 4,4-bis-alkyl-4H-cyclopenta-[2,1-b;3,4-b']-dithiophene and benzene structural units and the charges are provided by pendant sulfonate groups, was synthesized. The ionic nature of PCP-SO3K renders it soluble in water, and PCP-SO3K aqueous solution exhibits good photostability, with two main absorbance bands centered at 490 nm and 837 nm before and after laser irradiation. Its NIR absorption in water, negligible photoluminescence and insignificant intersystem crossing endow PCP-SO3K with efficient photothermal therapy performance, and an effective photothermal conversion efficiency of 56.7% was realized. Thus, PCP-SO3K aqueous solution can be used as an effective photothermal agent for in vivo applications as its photoactivity can be triggered by NIR light and can convert laser energy into thermal energy in a water environment. Of particular importance is the fact that complete tumor remission without recurrence in 4T1 tumor-bearing mice was realized after intravenous injection of PCP-SO3K aqueous solution and laser irradiation (2.0 W cm-2, 808 nm). The results indicate that the application of anionic conjugated polyelectrolytes as photothermal agents in photothermal therapy provides a new platform for the design of photothermal agents for clinical cancer treatment.

Recent advances of polyoxometalates in multi-functional imaging and photothermal therapy.

Polyoxometalates (POMs) as a kind of molecular metal-oxide cluster with precise chemical composition and architecture have been demonstrated to show potential in multidisciplinary materials. Accompanied by their bioactivities, POM clusters have also been shown to be capable of sensing diseases and allowing synergistic therapy based on their redox and near infrared absorption. In parallel with metal nanoparticles and organic materials, these inorganic clusters have also displayed unique photothermal imaging and therapeutic properties over recent years. In this review, we outlined the main achievements of POMs in the fields of bio-detecting probes and the photothermal effect. Fluorescence detection, magnetic resonance, computed tomography, and photothermal property-supported photoacoustic imaging acting as a multifunction platform that integrates photothermal therapy (PTT) were discussed at the same time. The comparison of nanocomposites to POMs alone in imaging-guided PTT, multi-modal imaging, and the combination of PTT with controlled chemotherapy and gas therapy were described in detail. The advantages and possible drawbacks of POMs as well as perspectives in related areas were analyzed, which ascertained such clusters to be a type of promising agent in biomedical applications.

Curcumin Nanocrystal/pH-Responsive Polyelectrolyte Multilayer Core-Shell Nanoparticles for Inflammation-Targeted Alleviation of Ulcerative Colitis.

In this study, we developed oral core-shell nanoparticles composed of curcumin nanocrystals in the core and chitosan/alginate multilayers in the shell for inflammation-targeted alleviation of ulcerative colitis (UC). The release rate of curcumin from the core-shell nanoparticles was low at a pH mimicking the stomach and small intestine, whereas it was higher at a pH mimicking the colon. Further, biodistribution studies in the gastrointestinal tract of mice showed that distribution of nanoparticles was significantly higher in the colon than that in the stomach and small intestine. Quantitative analysis of drugs in colonic tissues and confocal imaging of colons revealed preferential accumulation of nanoparticles in inflamed tissues than that in healthy tissues. In vivo anti-inflammatory studies revealed that nanoparticles exhibit enhanced efficacy in alleviating inflammation-related symptoms in a mouse colitis model. The results suggest that the core-shell nanoparticles presented here can be exploited as efficient colon-targeted drug delivery systems for UC therapy.

Influence of cross-linking in loading/release applications of polyelectrolyte multilayer assemblies. A review.

Design of polymeric matrices for loading/release purposes is of great interest in various applications, such as drug delivery systems, antimicrobial surfaces, biosensors, water purification. Compared with other strategies to fabricate materials for such applications, the Layer-by-Layer (LbL) assembly remarked itself by the countless possibilities to tailor the organic architectures at nanoscale owing to the structural diversity of "nano-bricks" suitable for assembly and easiness to control the deposition features. LbL assembled systems have been extensively used as matrices to load/release low molecular compounds such as drugs and dyes, proteins and enzymes, or DNA (RNA). In many studies, cross-linking the layers was investigated as a mean to stabilize and to induce new functionalities in the obtained architectures, as well as to tune their loading/release properties. In this review we discuss recent progress in the use of LbL constructions in loading/release of bioactive species, with a main focus on the role of cross-linking on such features. Overviews of the LbL assembly strategy describing the parameters which influence the build-up process and of the main synthetic routes used to cross-link the obtained architectures are briefly presented. The use of LbL systems (either as thin films deposited on solid surfaces or as hollow capsules) to load/release low molecular compounds and proteins/enzymes, highlighting the role of cross-linking in such processes (construction of porous architectures capable to load high molecular compounds or decreasing the assemblies permeability to delay the release of encapsulated compounds) was thoroughly discussed.

Precisely Defined Conjugated Oligoelectrolytes for Biosensing and Therapeutics.

Conjugated oligoelectrolytes (COEs) are a relatively new class of synthetic organic molecules with, as of yet, untapped potential for use in organic optoelectronic devices and bioelectronic systems. COEs also offer a novel molecular approach to biosensing, bioimaging, and disease therapy. Substantial progress has been made in the past decade at the intersection of chemistry, materials science, and the biological sciences developing COEs and their polymer analogues, namely, conjugated polyelectrolytes (CPEs), into synthetic systems with biological and biomedical utility. CPEs have traditionally attracted more attention in arenas of sensing, imaging, and therapy. However, the precisely defined molecular structures and interactions of COEs offer potential key advantages over CPEs, including higher reliability and fluorescence quantum efficiency, larger diversity of subcellular targeting strategies, and improved selectivity to biomolecules. Here, the unique-and sometimes overlooked-properties of COEs are discussed and the noticeable progress in their use for biological sensing, imaging, and therapy is reviewed.

Evaluation of hemostatic effect of polyelectrolyte complex-based dressings.

The aim of this work was to develop a polyelectrolyte complex-based hemostatic dressing made from chitosan and polygalacturonic acid. Porous dressings were fabricated by ultrasonication of chitosan and alginate solutions followed by freeze-drying. Since chitosan has inherent hemostatic properties, and polygalacturonic acid is anti-inflammatory in nature, it was desired to combine these two polymers to develop an effective hemostatic dressing, which may also promote wound healing. Porous structure of the bandages was observed using field-emission scanning electron microscope. Blood clotting behavior was studied using whole blood clotting assay. Plasma recalcification time, prothrombin time, and activated partial thromboplastin time were also determined to study the mechanism of clotting. The dressings were found to accelerate clotting rates and showed increased thrombin activity with an increase in chitosan concentration.

Washless Method Enables Multilayer Coating of an Aggregation-Prone Nanoparticulate Drug Delivery System with Enhanced Yields, Colloidal Stability, and Scalability.

Aggregation is frequently encountered during coating nanoparticles, especially when the core is not solid and the coating polyelectrolytes are weak. Here, the coating of a nanoliposome with two weak polyelectrolytes, alginate and chitosan, is investigated. First, quartz crystal microbalance with dissipation, atomic force microscopy, scanning electron microscopy, and energy dispersive spectroscopy analyses confirm the feasibility of firm adsorption of up to 16 layers of weak polyelectrolytes to the liposomal surface. Titrations are then performed to identify the lowest amounts of polyelectrolytes required to make eight saturated coating layers using the washless method. Significantly improved yields and reproducibility (almost 100%) are achieved, in addition to control over layer thickness. Attenuated total reflectance Fourier transform infrared spectroscopy studies confirm the success of layering. This is special since scientists always attempt to reduce nanoparticle aggregation by substituting the soft core, using one strong polyelectrolyte, or contending with lower yields or numbers of coating layers.

Patchy Layersomes Formed by Layer-by-Layer Coating of Liposomes with Strong Biopolyelectrolytes.

Layer-by-layer deposition of polyelectrolytes (PEs) onto self-assembled liposomes represents an alternative to PE deposition on solid particles for the formation of hollow nanoscale capsules. This work examines how competition between PE-liposome and inter-PE interactions drives the structure and colloidal stability of layersomes. Unlike solid particles, liposomes respond to adsorbed material through lipid reorganization and changes in size and shape. This responsive nature could yield new types of layered PE structures. We show that sequential deposition of strong biopolyelectrolytes, dextran sulfate-sodium salt (DxS-) and poly-l-arginine (PA+), onto cationic liposomes in water yields the expected charge inversion behavior commonly observed for dispersed particles. However, cryogenic transmission electron microscopy results show that the layersomes formed and their PE coatings were heterogeneous. The PE coatings contained PE complexes (PECs) that were formed when an even number of layers (2 or 4) was deposited. PECs remained attached as patches that were spatially distinguishable. This behavior was confirmed through fluorescence anisotropy measurements of liposome bilayer fluidity, where PA+ counteracted the ordering effects of DxS- on the lipid bilayer through charge neutralization and local PEC desorption. With increased charge screening, DxS- desorbed from the layersomes, whereas the patchy layersomes terminating in PA+ retained their PE coatings and colloidal stability at higher salt concentrations. To our knowledge, this is the first time such patchy layersome structures have been observed.

Dermatan sulfate/chitosan polyelectrolyte complex with potential application in the treatment and diagnosis of vascular disease.

Cardiovascular disease is the largest single cause of morbid-mortality in the world. However, there is still no pharmaceutical treatment that directly targets the blood vessel wall instead of just controlling the risk factors. Here, we produced polyelectrolyte complexes (PECs) by a simple and reproducible polyelectrolyte complexation method between low molecular mass dermatan sulfate (polyanionic polysaccharide) and chitosan (polycationic polysaccharide), and evaluated the cellular uptake by vascular endothelial cells. The composition and the composition homogeneity of PECs were confirmed by (13)C-CP-MAS spectroscopy and by polyacrylamide gel electrophoresis, respectively. The hydrodynamic radius, determined by dynamic light scattering, was 729±11nm. PECs were not cytotoxic for a murine heart endothelium-derived cell line. Fluorescent confocal microscopy showed the specific uptake of fluorescently-labeled PECs by endothelial cells when they were cultured alone or in the presence of macrophages. Overall, these findings confirmed the potential of these PECs for targeting different agents to the vessel wall in the prevention, diagnosis, and therapy of vascular disease.

Potassium-Binding Agents to Facilitate Renin-Angiotensin-Aldosterone System Inhibitor Therapy.

OBJECTIVE: To evaluate safety and efficacy data for potassium-binding resins in renin-angiotensin-aldosterone system (RAAS)-associated hyperkalemia. DATA SOURCES: A search of MEDLINE (EBSCOhost; 1946 to February 2016) was conducted using the terms hyperkalemia, rennin-angiotensin-aldosterone system, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, aldosterone antagonists, resin, and binder Results were limited to human trials in English language journals. References of identified articles were reviewed to identify other relevant articles. STUDY SELECTION AND DATA EXTRACTION: Concurrent potassium-binding agents and RAAS inhibitor use literature were reviewed. Inclusion criteria a 2-week minimum therapy duration with hyperkalemia or high-risk patients receiving concurrent RAAS-inhibiting agents. Seven articles met inclusion criteria: 1 retrospective case series for sodium polystyrene sulfonate (SPS), 1 noncontrolled study using patiromer, and 5 randomized, placebo-controlled trials using 3 different agents-2 patiromer, 2 sodium zirconium cyclosilicate (SZC), and 1 cross-linked polyelectrolyte (CLP). DATA SYNTHESIS: SPS efficacy data are limited to a mean potassium reduction of 1.8 mEq/L in a 14-patient uncontrolled case series. CLP did not reduce hyperkalemia incidence compared with placebo. Patiromer effectively maintained potassium at 0.45 to 0.72 mmol/L lower than placebo while allowing spironolactone dose titration in more patients (91% vs 74%, P = 0.019). SZC also safely and effectively normalized and maintained potassium levels in patients receiving RAAS inhibitors (71%-85% vs 48% for placebo, P < 0.01). CONCLUSIONS: Currently, the literature does not support SPS and CLP for preventing RAAS inhibitor-associated hyperkalemia. Patiromer and SZC safely and effectively lower serum potassium and prevent hyperkalemia redevelopment in patients receiving RAAS inhibitors for up to 4 and 8 weeks,0 respectively.

How Leucocyte Cell Membrane Modified Janus Microcapsules are Phagocytosed by Cancer Cells.

Modern drug delivery systems rely on either antibody-based single-surface recognition or on surface-hydrophobicity-based approaches. For a tumor showing various surface mutations, both approaches fail. This publication hereby presents Janus capsules based on polyelectrolyte multilayer microcapsules exhibiting human leucocyte (THP-1 cell line) cell membranes for discriminating HUVEC cells from three different cancer cell lines. Despite destroying the cellular integrity of leucocyte cells, the modified Janus capsules are able to adhere to cancer cells. Leucocyte cell-membrane-coated Janus capsules are phagocytosed with the cellular membrane part pointing to the cells.