Molecular Weight Threshold Research Articles

Concentration polarization on surface patterned membranes

AbstractSurface pattern is a promising approach to enhance membrane performance while contradictory results have been reported on its impact on concentration polarization. Here, we provide an experimental and modeling study of the concentration polarization on patterned membranes by varying pattern size, solute size, surface hydrophilicity, and membrane orientation. Interesting trends were observed when comparing different membrane orientations, where relative concentration polarization degree (CPD) was found depend on molecular weight. Salts and small organic molecules encountered more severe CPD in the transverse mode, while molecules larger than a threshold value showed a different trend. Such threshold molecular weight increased at larger pattern size. Simulation results were consistent with experimental observations, and revealed the critical role of diffusivity on such phenomena. Results also showed more severe concentration polarization on patterned membranes in both parallel and transverse modes in most cases, compared to smooth membrane.

Allergy evaluation of messenger RNA vaccine reactions is crucial, with a specific role for polyethylene glycol testing

Allergy evaluation of messenger RNA vaccine reactions is crucial, with a specific role for polyethylene glycol testing

Challenges in solving structures from radiation-damaged tomograms of protein nanocrystals assessed by simulation.

Structure-determination methods are needed to resolve the atomic details that underlie protein function. X-ray crystallography has provided most of our knowledge of protein structure, but is constrained by the need for large, well ordered crystals and the loss of phase information. The rapidly developing methods of serial femtosecond crystallography, micro-electron diffraction and single-particle reconstruction circumvent the first of these limitations by enabling data collection from nanocrystals or purified proteins. However, the first two methods also suffer from the phase problem, while many proteins fall below the molecular-weight threshold required for single-particle reconstruction. Cryo-electron tomography of protein nanocrystals has the potential to overcome these obstacles of mainstream structure-determination methods. Here, a data-processing scheme is presented that combines routines from X-ray crystallography and new algorithms that have been developed to solve structures from tomograms of nanocrystals. This pipeline handles image-processing challenges specific to tomographic sampling of periodic specimens and is validated using simulated crystals. The tolerance of this workflow to the effects of radiation damage is also assessed. The simulations indicate a trade-off between a wider tilt range to facilitate merging data from multiple tomograms and a smaller tilt increment to improve phase accuracy. Since phase errors, but not merging errors, can be overcome with additional data sets, these results recommend distributing the dose over a wide angular range rather than using a finer sampling interval to solve the protein structure.

Molecular-weight and cooling-rate dependence of polymer thermodynamics in molecular dynamics simulation

Molecular dynamics (MD) simulations are conducted to systematically benchmark the effects of molecular weight, chain number, and cooling rate on the glass transition temperature (Tg) and coefficient of thermal expansion (CTE) of poly(ethylene oxide) (PEO). Hyperbolic regression as an objective identified method is used to extract Tg and CTE. The results show that for a cooling rate higher than 5 × 1013 K/min, Tg and CTE are both strongly affected by rapid quenching. For a cooling rate lower than 5 × 1013 K/min, Tg and CTE in the high-temperature domain still slightly depend on the cooling rate. Eventually, to eliminate the finite size effect of the model, a threshold molecular weight of 11,240 g/mol should be satisfied in the system. In addition, the chain number must be more than 10, at least for an oligomer system (50 monomers). This study comprehensively reveal the critical parameters of poly(ethylene oxide) (PEO) in the MD simulation that causes the numerical effect on polymer simulation and the variation of thermodynamics property. The threshold value of total molecular weight of 11,240 g/mol must be satisfied, which leads the polymer that exhibits its steady state bulk properties. For the oligomer system (Mw < 2248 g/mol per chain (50 monomers)), the total chain number must be more than 10 at least. The cooling rate must be lower than 5 × 1013 K/min for the structural equilibrium.

Regulating Heterogeneous Catalysis of Gold Nanoparticles with Polymer Mechanochemistry.

Polymer mechanochemistry has emerged as a unique approach to regulate homogeneous catalysis in chemical transformations. The utilization of polymer mechanochemistry to regulate heterogeneous catalysis, however, still remains to be investigated. In this study, using polymer-grafted gold nanoparticles as the model heterogeneous catalysts, we show that polymer chains can be mechanically ruptured from the surface of gold nanoparticles, and thus, the catalytic activity of gold nanoparticles can be accelerated under sonication. The mechanical activation of polymer-grafted gold nanoparticles only occurs when the grafted polymer chains exceed a threshold molecular weight. This mechanical behavior is similar to those mechanophore-linked polymers. More importantly, further characterizations reveal that the Au-Au bonds instead of the Au-S bonds are broken at the heterointerfaces of polymer chains and gold nanoparticles. Our study unveils an unprecedented characteristic of polymer-grafted metallic nanoparticles in response to external mechanical stress.

Coloring of PLGA implants to better understand the underlying drug release mechanisms.

Different dyes and a colored vitamin (riboflavin) were used to better understand the underlying drug release mechanisms in poly(lactic-co-glycolic acid) (PLGA)-based implants. The latter were prepared by hot melt extrusion (HME) or formed in-situ, upon solvent exchange when injecting a PLGA solution in N-methyl-pyrrolidone (NMP) into phosphate buffer pH 7.4. Methylene blue was used as water-soluble dye to stain the release medium, riboflavin as a yellow, water-soluble "model drug", and Sudan-III-red as poorly water-soluble dye, incorporated in the implant. In the case of pre-formed HME implants, the "orchestrating" role of polymer swelling for the control of drug release could be visualized: At early time points, only limited amounts of water penetrate into the system, insufficient for noteworthy drug dissolution and diffusion. However, bulk erosion starts, and once a critical polymer molecular weight threshold value is reached, substantial implant swelling sets on: Large amounts of water come in and allow for significant drug dissolution and diffusion. In the case of in-situ forming implants, the importance of the composition of the liquid formulation for the resulting inner implant structure could be visualized. The latter affects the rate and extent at which water penetrates into the system and, thus, the resulting drug release rate.

Often neglected: PLGA/PLA swelling orchestrates drug release: HME implants

Different types of poly(lactic-co-glycolic acid) (PLGA)- and poly(lactic acid) (PLA)-based implants for controlled dexamethasone release were prepared by hot melt extrusion (HME). The lactic acid:glycolic acid ratio was varied (50:50, 75:25, 100:0) as well as the drug loading (1–15%). Resomer RG 502H, RG 752H and R 202H (all with –COOH end groups) were studied. The implants were characterized before and after exposure to phosphate buffer pH 7.4 at 37 °C. Interestingly, in all cases polymer swelling seems to play an “orchestrating” role for drug release: At early time points, the amounts of water penetrating into the systems are limited (since the macromolecules are hydrophobic and highly entangled). Consequently, only small amounts of drug can dissolve and the dissolved drug molecules are not sufficiently mobile to diffuse out to a noteworthy extent (negligible dexamethasone release for up to 6 weeks). However, the water that is able to enter the implants at early time points cleaves the polyesters right from the beginning. Due to the newly generated –COOH end groups and decreased chain length, the macromolecules become more and more hydrophilic and less entangled. In addition, water-soluble polymer degradation products build up a steadily increasing osmotic pressure, attracting water into the system. Once a critical polymer molecular weight threshold range (around 8 kDa) is reached, substantial implant swelling starts: The systems' volume increases up to 600–1700% and the water contents exceeds 80–90% (partially approaching 100%). Under these fundamentally altered conditions, significant drug amounts can dissolve and the dissolved drug molecules are sufficiently mobile to diffuse out of the implants: Drug release sets on. In brief, polymer swelling “orchestrates” the involved mass transport phenomena: It enables drug release after a certain lag time by fundamentally changing the conditions for drug dissolution and diffusion. Note that in other types of implants, additional mass transport phenomena might be involved, e.g. no burst release was observed from the investigated, initially non-porous implants.

Viscoelastic Properties of Thixotropic Semisolid Alloy Relating the Microstructure

The subject of this work is to investigate viscoelastic properties such as loss modulus (G ́ ́), storage modulus (G ́), complex shear modulus (G*), complex viscosity (η*) and loss angle () at different temperatures by means of a small-amplitude oscillatory test. These properties allow to provide information about materials structure. For this purpose, we employed a tin-lead alloy (Sn-15%Pb) which exhibits a similar microstructure to aluminum alloys and is the classic alloy for semisolid thixotropic studies. It is interesting to note that the Sn-15%Pb alloy exhibits a slightly decrease in storage modulus (G ́) over the entire frequency (0.01-10Hz) at high temperatures, showing its viscoelastic behavior. In addition, a detailed analysis of master curves (oscillatory tests) was made to relate the semisolid microstructure (solid fraction) with the plateau modulus (GN0) which is directly related with both molecular weight or percolation threshold in polymer and gels science respectively.

Multiscale modelling for the heterogeneous strength of biodegradable polyesters

A heterogeneous method of coupled multiscale strength model is presented in this paper for calculating the strength of medical polyesters such as polylactide (PLA), polyglycolide (PGA) and their copolymers during degradation by bulk erosion. The macroscopic device is discretized into an array of mesoscopic cells. A polymer chain is assumed to stay in one cell. With the polymer chain scission, it is found that the molecular weight, chain recrystallization induced by polymer chain scissions, and the cavities formation due to polymer cell collapse play different roles in the composition of mechanical strength of the polymer. Therefore, three types of strength phases were proposed to display the heterogeneous strength structures and to represent different strength contribution to polymers, which are amorphous phase, crystallinity phase and strength vacancy phase, respectively. The strength of the amorphous phase is related to the molecular weight; strength of the crystallinity phase is related to molecular weight and degree of crystallization; and the strength vacancy phase has negligible strength. The vacancy strength phase includes not only the cells with cavity status but also those with an amorphous status, but a molecular weight value below a threshold molecular weight. This heterogeneous strength model is coupled with micro chain scission, chain recrystallization and a macro oligomer diffusion equation to form a multiscale strength model which can simulate the strength phase evolution, cells status evolution, molecular weight, degree of crystallinity, weight loss and device strength during degradation. Different example cases are used to verify this model. The results demonstrate a good fit to experimental data.

Rainfastness of Poly(vinyl alcohol) Deposits on Vicia faba Leaf Surfaces: From Laboratory-Scale Washing to Simulated Rain

Rainfastness is the ability of agrochemical deposits to resist wash-off by rain and other related environmental phenomena. This work reports laboratory-scale and raintower studies of the rainfastness of fluorescently labeled poly(vinyl alcohol) (PVA) using fluorescent microscopy combined with image analysis. Samples of hydrolyzed PVA exhibit improved rainfastness over a threshold molecular weight, which correlates with PVA film dissolution, swelling, and crystalline properties. It was also established that the rainfastness of PVA scaled with the molecular weight over this threshold. These PVA samples were further characterized in order to determine the effect of the crystallinity on rainfastness. The quantification of rainfastness is of great interest to the field of agrochemical formulation development in order to improve the efficacy of pesticides and their adjuvants.

Conformation of the Poly(ethylene Glycol) Chains in DiPEGylated Hemoglobin Specifically Probed by SANS: Correlation with PEG Length and in Vivo Efficiency.

Cell-free hemoglobin (Hb)-based oxygen carriers have long been proposed as blood substitutes but their clinical use remains tricky due to problems of inefficiency and/or toxicity. Conjugation of Hb with the biocompatible polymer poly(ethylene glycol) (PEG) greatly improved their performance. However, physiological data suggested a polymer molecular weight (Mw) threshold of about 10 kDa, beyond which the grafting of two PEG chains no longer improves efficiency and nontoxicity of diPEG/Hb conjugates. We used small-angle neutron scattering and contrast variation, which are the only techniques able to probe separately the conformation of PEG chains and Hb protein within the complex, to investigate the role of PEG chain conformation in diPEGylated Hb conjugates as a function of the polymer Mw. We found out that the structure of Hb tetramer is not modified by the polymer grafting. Similarly, with a constant grafting of two chains per protein, there is no significant change of the Gaussian conformation between free and grafted PEG below ∼10 kDa, the complex being well described by the "dumbbell" model. However, beyond that threshold, the radius of gyration of grafted PEG is significantly smaller than that of the free polymer, showing a compaction of the PEG chains, either in the "dumbbell" model or in the "shroud" one. In the latter model, the polymer may be wrapped on the surface of the protein spreading a protective "shielding" effect over a larger fraction of the protein. Both proposed models are in good agreement with the physiological data reported in the literature.

The effect of molecular weight on the separation of semiconducting single‐walled carbon nanotubes using poly(2,7‐carbazole)s

ABSTRACTThe use of selective interactions between conjugated polymers and single‐walled carbon nanotubes has emerged as a promising method for the separation of nanotubes by electronic type. Although much attention has been devoted to investigating polyfluorenes and their ability to disperse semiconducting carbon nanotubes under specific conditions, other polymer families, such as poly(2,7‐carbazole)s, have been relatively overlooked. Poly(2,7‐carbazole)s have been shown to also preferentially interact with semiconducting carbon nanotubes, however a detailed investigation of polymer parameters, such as molecular weight, has not been performed. We have prepared seven different molecular weights of a poly(2,7‐carbazole), from short chain oligomers to high molecular weight polymers, and have investigated their effectiveness at dispersing semiconducting single‐walled carbon nanotubes. Although all polymer chain lengths were able to efficiently exfoliate carbon nanotube bundles using a mild dispersion protocol, only polymers above a certain threshold molecular weight (Mn ∼ 27 kDa) were found to exhibit complete selectivity for semiconducting nanotubes, with no observable signals from metallic species. Additionally, we found the quality of separation to be strongly dependent on the ratio of polymer to carbon nanotube. Contrary to previous reports, we have found that an excess of poly(2,7‐carbazole) leads to incomplete removal of metallic carbon nanotubes. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2510–2516

Mechanophore activation at heterointerfaces.

Silica nanoparticles grafted with poly(methyl acrylate) (PMA) chains anchored by a maleimide-anthracene cycloadduct were synthesized to demonstrate mechanochemically selective activation of mechanophores at heterogeneous interfaces. By quantifying the anthracene-containing cleaved PMA polymers, which are generated via retro-[4 + 2] cycloaddition reactions, the first-order kinetic coefficient was determined. Activation characteristics of mechanophores anchored to a nanoparticle exhibit behavior similar to mechanophore-linked polymers, e.g., threshold molecular weight and linear increase in rate coefficient with molecular weight above the threshold. This model system is thus valuable as a probe to test stress activation of interfacially bonded mechanophores relevant to the design of fiber-reinforced polymer composites.

Synthesis and phase behavior of a new 2-vinylbiphenyl-based mesogen-jacketed liquid crystalline polymer with a high glass transition temperature and low threshold molecular weight

A new mesogen-jacketed liquid crystalline (LC) polymer was synthesized by NMP. It has a high Tg and a relatively low threshold MW for LC formation.

Estimation of biliary excretion of foreign compounds using properties of molecular structure.

Biliary excretion is one of the main elimination pathways for drugs and/or their metabolites. Therefore, an insight into the structural profile of cholephilic compounds through accurate modelling of the biliary excretion is important for the estimation of clinical pharmacokinetics in early stages of drug discovery. The aim of this study was to develop quantitative structure-activity relationships as computational tools for the estimation of biliary excretion and identification of the molecular properties controlling this process. The study used percentage of dose excreted intact into bile measured in vivo in rat for a diverse dataset of 217 compounds. Statistical techniques were multiple linear regression analysis, regression trees, random forest and boosted trees. A simple regression tree model generated using the CART algorithm was the most accurate in the estimation of the percentage of bile excretion of compounds, and this outperformed the more sophisticated boosted trees and random forest techniques. Analysis of the outliers indicated that the models perform best when lipophilicity is not too extreme (log P < 5.35) and for compounds with molecular weight above 280 Da. Molecular descriptors selected by all these models including the top ten incorporated in boosted trees and random forest indicated a higher biliary excretion for relatively hydrophilic compounds especially if they are anionic or cationic, and have a large molecular size. A statistically validated molecular weight threshold for potentially significant biliary excretion was above 348 Da.

Nano-domain behaviour in P3HT:PCBM nanoparticles, relating material properties to morphological changes

In this article we report a morphological study of the poly(3-hexylthiophene) (P3HT): phenyl-C61-butyric acid methyl ester (PCBM) material system in nanoparticle organic thin films. The morphology and chemical composition of unannealed and annealed P3HT:PCBM nanoparticles has been investigated using scanning transmission X-ray microscopy (STXM) for a range of P3HT molecular weights (Mw=5–72kgmol−1). Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) have been used to support the STXM data. We find that unannealed P3HT:PCBM nanoparticles (NPs) exhibit a common core–shell morphology, with a PCBM-rich core and P3HT-rich shell. The morphology of the thermally annealed NP films is highly dependent upon the molecular weight of the P3HT and is determined by PCBM diffusion through the P3HT matrix. Two PCBM diffusion mechanisms operate within this system: (1) at high molecular weights diffusion of molecular PCBM dominates whilst, (2) at low molecular weights diffusion of the PCBM cores is significant. The Stokes–Einstein continuum model for diffusion has been used to determine a threshold molecular weight at which the diffusion of PCBM cores is activated in these films. The calculated value (Mw~38–25kgmol−1) is shown to agree very well with experimental observations. Finally, a model for the morphological evolution of annealed P3HT:PCBM NP films is developed.

Increased Affinity to Canalicular P-gp via Formation of Lipophilic Ion-Pair Complexes with Endogenous Bile Salts is Associated with Mw Threshold in Hepatobiliary Excretion of Quaternary Ammonium Compounds

We intended to elucidate the mechanism of the molecular weight (Mw) threshold (i.e., 200 +/- 50) for appreciable hepatobiliary excretion of quaternary ammonium compounds (QACs) in rats. We measured the effect of ion-pair complexation of QACs with taurodeoxycholate (TDC), an endogenous anionic bile salt, on the apparent partition coefficients (APC) of QACs between n-octanol and phosphate buffer, and the inhibition of organic cation transporter1 (OCT1)- and P-glycoprotein (P-gp)-mediated transport of representative substrates. By measuring the APC, we demonstrated that there is a Mw threshold of 200 +/- 50 in the ion-pair complexation of QACs with an endogenous bile salt, TDC. We also demonstrated, by measuring the inhibition of relevant transports, that a Mw threshold of 200 +/- 50 exists for the binding of QACs to canalicular P-gp, but not for sinusoidal OCT1. The Mw threshold values for ion-pair formation and P-gp binding were identical and consistent with the reported Mw threshold value for appreciable biliary excretion of QACs in rats. Mw-dependent binding of QACs to canalicular P-gp contributes in part to the mechanism of the Mw threshold of 200 +/- 50. The formation of lipophilic ion-pair complexes with bile salts, followed by stronger binding to canalicular P-gp, appears to accelerate biliary excretion of QACs with a high Mw.

Biliary excretion in dogs: Evidence for a molecular weight threshold

Molecular weight (MW) is known as an important factor of biliary excretion in rats, guinea pigs, rabbits and humans. The objective of this study was to evaluate the relationship between the biliary excretion and MW of drugs in dogs. Data on the percentage of dose excreted into bile as parent drug (PD b) in dogs were collected from the literature for 134 compounds. Receiver operating characteristic (ROC) curve analysis was utilized to determine whether a MW threshold exists for PD b. A MW threshold of 375–400 Da was established for anions in dogs, which is similar with the cutoff value observed in rats (400 Da) but lower than the one in humans (475 Da). No MW threshold was found for cations or cations/neutral compounds. A molecular volume threshold of 300 Å 3 was also determined for anions in dogs, which corresponds to a MW of 394 Da. In conclusion, our analysis suggested the presence of a MW cutoff for anions in dogs, which may be related with the molecular size of a compound. This represents the first report of the influence of MW or molecular volume as a determinant of biliary excretion for a structurally diverse set of compounds in dogs.

Prediction of human pharmacokinetics—biliary and intestinal clearance and enterohepatic circulation

The main objective was to evaluate and propose methods for predicting biliary clearance (CL(bile)) and enterohepatic circulation (EHC) of intact drugs in man. Another aim was to evaluate to role of intestinal drug secretion and propose a method for prediction of intestinal secretion CL (CL(i)). Animal data poorly predict the CL and CL(bile) of biliary excreted drugs, and the suggested molecular weight threshold for bile excretion as the dominant elimination route does not seem to hold. Active transport, low metabolic intrinsic CL (CL(int)) and, as an approximation, permeability (P(e)) less than that of metoprolol is required for substantial CL(bile) to occur. The typical EHC plasma concentration vs time profile (multiple peaks) is demonstrated for many low metabolic CL(int)-compounds with efflux and moderate to high intestinal P(e) and fraction absorbed. Physiologically-based in-vitro to in-vivo (PB-IVIV) methodology with in-vitro intrinsic CL(bile)-data obtained with sandwich-cultured human hepatocytes has generated 2- and 5-fold underpredictions for two compounds with intermediate to high CL(bile). This is despite not considering the unbound fraction. Possible explanations include low transporter activity and diffusion limitations in the in-vitro experiments. Intestinal reabsorption and EHC were also neglected in these predictions and in-vivo CL(bile) estimations. The sandwich model and these reference data are still very useful. Consideration of an empirical scaling factor and a newly developed approach that accounts for intestinal reabsorption and EHC could potentially lead to improved PB-IVIV predictions of CL(bile). Apparently, no attempts have been made to predict CL(i). Elimination via the intestinal route does not appear to be of great importance for the few compounds with available data, but could be equally as important as bile excretion. Net secretion in-vitro P(e) and newly estimated in-vivo intrinsic CL(i) data for digoxin and rosuvastatin could be useful for approximation of CL(i) of other compounds.

Prediction of Biliary Excretion in Rats and Humans Using Molecular Weight and Quantitative Structure–Pharmacokinetic Relationships

The aims were (1) to evaluate the molecular weight (MW) dependence of biliary excretion and (2) to develop quantitative structure-pharmacokinetic relationships (QSPKR) to predict biliary clearance (CL(b)) and percentage of administered dose excreted in bile as parent drug (PD(b)) in rats and humans. CL(b) and PD(b) data were collected from the literature for rats and humans. Receiver operating characteristic curve analysis was utilized to determine whether a MW threshold exists for PD(b). Stepwise multiple linear regression (MLR) was used to derive QSPKR models. The predictive performance of the models was evaluated by internal validation using the leave-one-out method and external test groups. A MW threshold of 400 Da was determined for PD(b) for anions in rats, while 475 Da was the cutoff for anions in humans. MW thresholds were not present for cations or cations/neutral compounds in either rats or humans. The QSPKR model for human CL(b) showed a significant correlation (R (2) = 0.819) with good prediction performance (Q (2) = 0.722). The model was further assessed using a test group, yielding a geometric mean fold-error of 2.68. QSPKR models with significant correlation and good predictability were also developed for CL(b) in rats and PD(b) data for anions or cation/neutral compounds in rats and humans. Both CL(b) and PD(b) data were further evaluated for subsets of MRP2 or P-glycoprotein substrates, and significant relationships were derived. QSPKR models were successfully developed for biliary excretion of non-congeneric compounds in rats and humans, providing a quantitative prediction of biliary clearance of compounds.