Co-block Polymer Research Articles

Molecular insight into sequence-defined polyelectrolytes for energy storage devices

Polyelectrolyte (PE) adsorption on charged surfaces is a complex phenomenon that has an array of applications ranging from healthcare to designing energy storage devices. PE adsorption on surfaces involves surface charge polarization effects which arise due to the dielectric dissimilarities between the PE and the charged surface. PEs owing to their high potential window, and leakage-resistant behavior are used as supercapacitor electrolytes. Recent experimental evidence suggests co-block polymers as potential design materials for energy storage devices (ESDs). It is imperative to mention that the structural variation of the co-block polymers under spatial confinements will have a key role in designing electrodes and electrolytes for ESDs which demands a detailed investigation. This study reveals that the spatial orientations of the charged groups have an impressive impact on the changes in PE charge density peaks, charge amplification peaks, PE adsorption, counter-ion adsorption, and differential and integral capacitance while confined by graphene electrodes. It is startling to observe that the counter-ion distribution within the electrical double layer of the positively charged surface significantly depends on the orientation of the PEs. However, with increasing solvent dielectric constant the variations in the above-mentioned properties subside due to reduced electrostatic interactions. The differential capacitance and the integral capacitance are also found to be dependent on the dielectric constants of the solvent. These findings will be immensely useful in determining the key factors needed to describe the preferred spatial configuration of a PE suitable for various ESDs and applications involving PEs in a confined system.

Assessment of Modern Excipients in Controlled Delivery of Proteins and Peptides

Polymeric micelles are highly proficient of modulating the function, distribution of drugs in the body, and can overcome biological barriers hence provoked as novel nanomedicine via various formulations. Current review emphasis on application of several polymers, biomaterials, lipids for the preparation of polymeric micelles formed by several molecular interactions between the block co-polymers and encapsulated molecules. Micellar carriers will be selected on basis of the type of polymer/payload interaction, which includes biological interface focused on the internal chemistry and fabrication of block-co polymers. Several features of these carriers can be manipulated to catering a broad range of drugs through active sensing of body targets. The fine-tuning of their properties in response to particular stimuli, modulating the activity of the loaded drugs at the targeted sites, even at the subcellular level. To end with, the future perspective and impending challenges for polymeric micelles as nanomedicine are elaborated, anticipating prompting further innovations. 
 Keywords: Proteins, Peptides, Co-block Polymers, Lipids, Controlled, Drug Delivery.

Novel thymoquinone loaded chitosan-lecithin micelles for effective wound healing: Development, characterization, and preclinical evaluation

While the wound healing activity of thymoquinone (TQ) is well known, its clinical effectiveness remains limited due to the inherently low aqueous solubility, resulting in suboptimal TQ exposure in the wound sites. To address these problems, TQ loaded chitosan-lecithin micelles for wound healing were prepared and its efficacy was determined in vivo in the excision wound model. Firstly, the co-block polymer of chitosan and soya lecithin was synthesized which has low critical micelle concentration (CMC). Its employment in the development of TQ loaded polymeric micelles by Self-assembly method resulted in the stable polymeric micelle composition having requisite small particle size (<100 nm), narrow size distribution (close to zero) and high entrapment efficiency (98.77 %) of TQ. The designed nano-carriers not only substantially entrapped the drug but also controlled the release rate of TQ. The TQ-polymeric micelle hydrogel exhibited superior wound healing efficacy to the native TQ and Silver Sulphadiazine.

Assessment of the Effect of PLGA Co-polymers and PEG on the Formation and Characteristics of PLGA-PEG-PLGA Co-block Polymer Using Statistical Approach.

Purpose: To assess the effect of the lactic acid (LA)-to-glycolic acid (GA) molar ratio and polyethylene glycol (PEG) concentration on the formation of poly-lactide co-glycolide acid (PLGA)-PEG-PLGA co-block polymers simultaneously using statistical approach. Methods: A 22 full factorial design with the addition of a point in the center of the design, namely curvature, was applied. Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR) were performed to confirm the formation of the co-block polymer. Simvastatin (SMV), a drug model was incorporated into the nano-polymeric micellar (NpM) of PLGA-PEG-PLGA followed by solubility phase, particle size, zeta potential, and entrapment efficiency characterizations. Results: FTIR, DSC, and NMR successfully confirmed the formation of co-block polymers. Solubility of SMV increased from 2 to 44-folds depending on co-block concentration with entrapment efficiency of 59%-80%. The NpM had size in the range of 206 to 402 nm with negative zeta potential. LA to GA ratio had greater effect on particle size reduction and increasing of co-polymer length. In addition, it had higher contributions on increasing of solubility and entrapment efficiency of SMV than PEG. Conclusion: According to these findings, the LA to GA ratio and PEG concentration gained a great consideration in order to prepare the PLGA-PEG-PLGA co-block which fulfilled the quality target product profile of NpM delivery system.

Solubility and bioavailability improvement of pazopanib hydrochloride

The anti-cancer drug pazopanib hydrochloride (PZH) has a very low aqueous solubility and a variable oral bioavailability. A new pharmaceutical formulation with an improved solubility may enhance the bioavailability and reduce the variability. A broad selection of polymer excipients was tested for their compatibility and solubilizing properties by conventional microscopic, thermal and spectrometric techniques. A wet milling and mixing technique was used to produce homogenous powder mixtures. The dissolution properties of the formulation were tested by a pH-switch dissolution model. The final formulation was tested in vivo in cancer patient following a dose escalation design. Of the tested mixture formulations, the one containing the co-block polymer Soluplus® in a 8:1 ratio with PZH performed best in terms of in vitro dissolution properties. The in vivo results indicated that 300 mg of the developed formulation yields similar exposure and a lower variability (379 μg/mL∗h (36.7% CV)) than previously reported values for the standard PZH formulation (Votrient®) at the approved dose of 800 mg. Furthermore, the expected plasma-Cthrough levels (27.2 μg/mL) exceeds the defined therapeutic efficacy threshold of 20 μg/mL.

Fabrication of poly (butadiene-block-ethylene oxide) based amphiphilic polymersomes: An approach for improved oral pharmacokinetics of Sorafenib

Sorafenib (SFN), a hydrophobic anticancer drug, has several limitations predominantly poor aqueous solubility and hepatic first-pass effect, limiting its oral delivery that results into several other complications. Present study aims to develop Sorafenib loaded polymersomes using poly butadiene block poly ethylene oxide (PB-b-PEO), an amphiphilic co-block polymer. Prior to drug loading, critical aggregate concentration (CAC) of polymer was calculated for stable formulation synthesis. The developed SFN loaded PB-b-PEO polymersomes (SFN-PB-b-PEO, test formulation) characterized by DLS and cryo-TEM showed particle size 282 nm, polydispersity (PDI) of less than 0.29 and membrane thickness of about 20 nm. SFN-PB-b-PEO polymersomes demonstrated encapsulation efficiency of 71% and showed sustained drug release up to 144 h. Formulation remained stable for 3 months in suspension form. In vitro cytotoxicity against HepG2 cells showed 1.7 folds improved toxicity compared to SFN suspension. In addition, oral administration of SFN-PB-b-PEO polymersomes in BALB/c mice showed increased Cmax and AUC0–96 by 1.7 and 2.77-fold respectively (p < 0.05) compared to those of SFN suspension (reference formulation). Findings suggest that the SFN-PB-b-PEO polymersomes can be a potential candidate for oral delivery of SFN.

Improving the solubility of nilotinib through novel spray-dried solid dispersions

The tyrosine kinase inhibitor nilotinib has a very low aqueous solubility and a low and variable oral bioavailability. A pharmaceutical formulation with an improved solubility may enhance the bioavailability and reduce the variability thereof and of the pharmacokinetics. The aim of this study was to enhance the solubility of nilotinib by developing a spray dried solid dispersion. A broad selection of polymer excipients were tested for solubilizing properties. The spray drying technique was used to produce solid dispersions of nilotinib hydrochloride (NH) in matrices of the best performing polymers. Both the dissolution and physicochemical characteristics of the formulations were studied using a pH-switch dissolution model and conventional microscopic, thermal and spectrometric techniques. Of the tested spray dried solid dispersions, the ones containing the co-block polymer Soluplus® performed best in terms of in vitro dissolution properties. Further testing led to an optimized weight ratio of 1:7 (NH:Soluplus®) that improved the solubility up to 630-fold compared to crystalline NH (1.5μg/mL) in simulated intestinal fluid. This effect can be attributed to the amorphization of NH and the solubilization of the drug due to micelle formation. A spray dried solid dispersion formulation of NH with Soluplus® in a ratio of 1:7 was developed that showed a significant increase in solubility.

Compartmentalization and Transport in Synthetic Vesicles.

Nanoscale vesicles have become a popular tool in life sciences. Besides liposomes that are generated from phospholipids of natural origin, polymersomes fabricated of synthetic block copolymers enjoy increasing popularity, as they represent more versatile membrane building blocks that can be selected based on their specific physicochemical properties, such as permeability, stability, or chemical reactivity. In this review, we focus on the application of simple and nested artificial vesicles in synthetic biology. First, we provide an introduction into the utilization of multicompartmented vesosomes as compartmentalized nanoscale bioreactors. In the bottom-up development of protocells from vesicular nanoreactors, the specific exchange of pathway intermediates across compartment boundaries represents a bottleneck for future studies. To date, most compartmented bioreactors rely on unspecific exchange of substrates and products. This is either based on changes in permeability of the coblock polymer shell by physicochemical triggers or by the incorporation of unspecific porin proteins into the vesicle membrane. Since the incorporation of membrane transport proteins into simple and nested artificial vesicles offers the potential for specific exchange of substances between subcompartments, it opens new vistas in the design of protocells. Therefore, we devote the main part of the review to summarize the technical advances in the use of phospholipids and block copolymers for the reconstitution of membrane proteins.

Real Time, in vivo Photoacoustic Potassium Imaging and Monitoring

Potassium ions are of physiological interest due to the role they play in the action potential, electrochemically balancing biological ions, and maintaining a healthy heart. Traditionally, in vivo potassium-sensing has been performed using ion-specific electrodes. However, these electrodes are limited by their inherently intrusive application and inability to generate diagnostic images. Using the thin film rehydration method, we have developed a potassium sensor suitable for real-time in vivo potassium sensing and monitoring. Nanoscale micelles synthesized from pluronic coblock polymers were loaded with a potassium ionophore and a highly absorbent, ratiometric pH dye. Due to hydrogen abstraction from the bulk solution, changes in potassium concentration induce a measurable pH change within the micelle. By exciting this dye at its protonated wavelength, we are able to use of the photoacoustic effect, and non-invasively measure ultrasonic, potassium-dependent frequencies produced from the dye in real time. Furthermore, the acoustic signal allows us to generate ultrasonic images of the target area, enhancing the diagnostic benefit. The micelle boasts a wide sensitivity range spanning three orders of magnitude, which includes typical intra- and extracellular potassium concentrations. Additionally, our approach is robust in that one need only switch the ionophore to probe a different cation of interest. These micelles represent the first demonstration of cationic-analyte imaging and will contribute positively to diagnostic efforts.

Pluronic Coblock Polymer L10 Demonstrates Promise As Novel Radiosensitizing Agent for Human Colorectal Cancer

Pluronic Coblock Polymer L10 Demonstrates Promise As Novel Radiosensitizing Agent for Human Colorectal Cancer

Nanoparticle system for the local delivery of disease modifying osteoarthritic drugs

Purpose: The purpose of this study is to develop the nanoparticles that i) can be injected intra-articularly ii) target to cartilage due to an opposite charge difference with the extracellular cartilaginous matrix and iii) due to their small size can penetrate into the cartilage. In this way retention time in the joint can be prolonged. By releasing disease modifying OA drugs (DMOAD) in the vicinity of chondrocytes such materials may be beneficial for restoring cartilage tissue homeostasis. Here we demonstrate the generation of drug-containing nanoparticles for intra-articular joint therapy. Methods: We have prepared nanoparticles of biodegradable poly ethylene glycol- poly lactic acid PEG-PLA co-block polymers. The hydrophilic PEG and hydrophobic PLA ends of this polymer make it possible to generate micelles that contain drugs. The polymers are functionalized with UV-sensitive acrylate groups that can be stabilized by UV-crosslinking. These drug containing nanoparticles will be used for intra-articular joint injection and release of DMOADs. We have also established co-culture systems in vitro using MSCs and chondrocytes where the effect of these molecules and nanocarriers can be tested. Results: Micelle type nanoparticles using PEG-PLA co-block polymers were prepared. The obtained dexamethasone loaded nanoparticles had diameters of 20-80 nm. These nanoparticles are photo-crosslinked at their hydrophobic cores which provides stability to the structure and resulted in a slight decrease in average particle size . Dexamethasone was successfully encapsulated in these nanoparticles. The current release profiles show initial burst release in the first 8 hours followed by a sustained release over at least 3 days. Conclusions: We have generated nanoparticles that can serve as a carrier system to deliver clinically relevant disease modifying osteoarthritic drugs in a more effective way after intra-articular injection. We are currently investigating the retention of nanoparticles in the joint and are developing strategies to target these particles to cartilage.

Highly Stabilized Curcumin Nanoparticles Tested in an In Vitro Blood–Brain Barrier Model and in Alzheimer’s Disease Tg2576 Mice

The therapeutic effects of curcumin in treating Alzheimer's disease (AD) depend on the ability to penetrate the blood-brain barrier. The latest nanoparticle technology can help to improve the bioavailability of curcumin, which is affected by the final particle size and stability. We developed a stable curcumin nanoparticle formulation to test in vitro and in AD model Tg2576 mice. Flash nanoprecipitation of curcumin, polyethylene glycol-polylactic acid co-block polymer, and polyvinylpyrrolidone in a multi-inlet vortex mixer, followed by freeze drying with β-cyclodextrin, produced dry nanocurcumin with mean particle size <80 nm. Nanocurcumin powder, unformulated curcumin, or placebo was orally administered to Tg2576 mice for 3 months. Before and after treatment, memory was measured by radial arm maze and contextual fear conditioning tests. Nanocurcumin produced significantly (p=0.04) better cue memory in the contextual fear conditioning test than placebo and tendencies toward better working memory in the radial arm maze test than ordinary curcumin (p=0.14) or placebo (p=0.12). Amyloid plaque density, pharmacokinetics, and Madin-Darby canine kidney cell monolayer penetration were measured to further understand in vivo and in vitro mechanisms. Nanocurcumin produced significantly higher curcumin concentration in plasma and six times higher area under the curve and mean residence time in brain than ordinary curcumin. The P(app) of curcumin and tetrahydrocurcumin were 1.8×10(-6) and 1.6×10(-5)cm/s, respectively, for nanocurcumin. Our novel nanocurcumin formulation produced highly stabilized nanoparticles with positive treatment effects in Tg2576 mice.

A New Angle on Pluronic Additives: Advancing Droplets and Understanding in Digital Microfluidics

Biofouling in microfluidic devices limits the type of samples which can be handled and the duration for which samples can be manipulated. Despite the cost of disposing fouled devices, relatively few strategies have been developed to tackle this problem. Here, we have analyzed a series of eight amphiphilic droplet additives, Pluronic coblock polymers of poly(propylene oxide) (PPO) and poly(ethylene oxide) (PEO), as a solution to biofouling in digital microfluidics using serum-containing cell culture media as a model fluid. Our analysis shows that species with longer PPO chains are superior for enabling droplet motion and reducing biofouling. Two of the tested species, L92 and P105, were found to lengthen device lifetimes by 2-3 times relative to additives used previously when used at optimal concentrations. Pluronics with low PEO content such as L92 were found to be cytotoxic to an immortalized mammalian cell line, and therefore we recommend that Pluronic additives with greater or equal to 50% PEO composition, such as P105, be used for digital microfluidic applications involving cells. Finally, contact angle measurements were used to probe the interaction between Pluronic-containing droplets and device surfaces. Strong correlations were found between various types of contact angle measurements and the capacity of additives to reduce biofouling, which suggests that contact angle measurements may be useful as a tool for rapidly screening new candidates for the potential to reduce biofouling. We propose that this study will be useful for scientists and engineers who are developing digital microfluidic platforms for a wide range of applications involving protein-containing solutions, and in particular, for applications involving cells.

Linear Viscoelastic and Fatigue Characteristics of Styrene–Butadiene–Styrene Modified Asphalt Mixtures

Three styrene–butadiene–styrene coblock polymer modified asphalt concrete mixtures (70/100M5, 160/220M5, and 160/220M10) are characterized using complex modulus and fatigue testing. The compositions of the materials investigated are identical (aggregate size distribution, binder, and void contents) and differ solely regarding binder characteristics. The modified binders are manufactured using two base bitumens (70/100 and 160/220) modified by a styrene–butadiene–styrene coblock polymer. The fatigue tests are carried out at three different temperatures (0, 10, and 20°C) using both stress- and strain-controlled modes. A continuum damage model is used to investigate its ability to characterize fatigue of polymer modified mixtures. The results indicate that the continuum damage model is suitable for characterizing the materials at the test conditions used (mode of loading, excitation amplitude, and testing temperature) in that visually similar material functions are obtained. Using statistical analysis, it was indicated that strain amplitude does not significantly influence the model parameters of the characteristic material functions. However, even though different loading conditions lead to apparently similar material functions, the model parameter values were actually significantly affected by the testing temperature used. Predictions of fatigue path, including number of cycles to failure, based on the material functions indicate reasonable accuracy.