End-group functionalization of poly(2-oxazoline)s using methyl bromoacetate as initiator followed by direct amidation

Poly(2-alkyl/aryl-2-oxazoline)s (PAOx) are an alluring class of polymers for many applications due to the broad chemical diversity that is accessible for these polymers by simply changing the initiator, terminating agent and the monomer(s) used in their synthesis. Additional functionalities (that are not compatible with the cationic ring-opening polymerization) can be introduced to the polymers via orthogonal post-polymerization modifications. In this work, we expand this chemical diversity and demonstrate an easy and straightforward way to introduce a wide variety of functional end-groups to the PAOx, by making use of methyl bromoacetate (MeBrAc) as a functional initiator. A kinetic study for the polymerization of 2-ethyl-2-oxazoline (EtOx) in acetonitrile (CH3CN) at 140 degrees C revealed relatively slow initiation and slower polymerization than the commonly used initiator, methyl tosylate (MeOTs). Nonetheless, well-defined polymers could be obtained with MeBrAc as initiator, yielding polymers with near-quantitative methyl ester end-group functionality. Next, the post-polymerization modification of the methyl ester end-group with different amines was explored by introducing a range of functionalities, i.e. hydroxyl, amino, allyl and propargyl end-groups. The lower critical solution temperature (LCST) behavior of the resulting poly(2-ethyl-2-oxazoline)s was found to vary substantially in function of the end-group introduced, whereby the hydroxyl group resulted in a large reduction of the cloud point transition temperature of poly(2-ethyl-2-oxazoline), ascribed to hydrogen bonding with the polymer amide groups. In conclusion, this paper describes an easy and fast modular approach for the preparation of end-group functionalized PAOx

Comparative study of the potential of poly(2-ethyl-2-oxazoline) as carrier in the formulation of amorphous solid dispersions of poorly soluble drugs

Despite the fact that solid dispersions are gaining momentum, the number of polymers that have been used as a carrier during the past 50 years is rather limited. Recently, the poly(2-alkyl-2-oxazoline) (PAOx) polymer class profiled itself as a versatile platform for a wide variety of applications in drug delivery, including their use as amorphous solid dispersion (ASD) carrier. The aim of this study was to investigate the potential of poly(2-ethyl-2-oxazoline) (PEtOx) by applying a benchmark approach with well-known, commercially available carriers (ie. polyvinylpyrrolidone (PVP) K30, poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) 64 and hydro-xypropylmethylcellulose (HPMC)). For this purpose, itraconazole (ITC) and fenofibrate (FFB) were selected as poorly water-soluble model drugs. The four polymers were compared by establishing their supersaturation maintaining potential and by investigating their capability as carrier for ASDs with high drug loadings. Spray drying, as well as hot melt extrusion and cryo-milling were implemented as ASD manufacturing technologies for comparative evaluation. For each manufacturing technique, the formulations with the highest possible drug loadings were tested with respect to in vitro drug release kinetics. This study indicates that PEtOx is able to maintain supersaturation of the drugs to a similar extent as the commercially available polymers and that ASDs with comparable drug loadings can be manufactured. The results of the in vitro dissolution tests reveal that high drug release can be obtained for PEtOx formulations. Overall, proof-of-concept is provided for the potential of PEtOx for drug formulation purposes

Experiments and data for model evaluation and application

Crop models and decision support systems can be very useful tools for scientists, extension educators, teachers, planners and policy makers to help with the evaluation of alternative management practices. Many of the current crop ­models respond to differences in local weather conditions, soil characteristics, crop management practices and genetics. However, computer-based tools require inputs in order to provide reliable results. Especially for those new to crop modeling, the data requirements are sometimes somewhat overwhelming. In this chapter we provide a clear and concise summary of the input data requirements for crop modeling. We differentiate between requirements for model evaluation, model application and model development and improvement. For model inputs we define daily weather data, soil surface and profile characteristics, and crop management. For model evaluation and improvement we define crop performance data as it relates to growth, development, yield and yield components, as well as additional observations. We expect that this chapter will make the use and application of crop models and ­decision support systems easier for beginning modelers as well as for the more advanced user

Synthesis of novel boronic acid-decorated poly(2-oxazoline)s showing triple-stimuli responsive behavior

Boronic acid-functionalized (co)polymers have gained increasing attention in the field of responsive polymers and polymeric materials due to their unique characteristics and responsiveness towards both changes in pH and sugar concentrations. This makes these (co)polymers excellently suited for various applications including responsive membranes, drug delivery applications and sensor materials. Unfortunately, boronic acid-based polymer research is also notorious for its challenging monomer synthesis and polymerization and its overall difficult polymer purification and manipulation. In light of this, many research groups have focused their attention on the optimization of various polymerization techniques in order to expand the field of BA-research including previously unexplored monomers and polymerization techniques. In this paper, a new post-polymerization modification methodology was developed allowing for the synthesis of novel boronic acid-decorated poly(2-alkyl-2-oxazoline) (PAOx) copolymers, utilizing the recently published PAOx methyl ester reaction platform. The developed synthetic pathway provides a straightforward method for the introduction of pH- and glucose-responsiveness, adding this to the already wide variety of possible responsive PAOx-based systems. The synthesized BA-decorated PAOx are based on the thermoresponsive poly(2-n-propyl-2-oxazoline) (PnPropOx). This introduces a pH and glucose dependence on both cloud and clearance point temperatures of the copolymer in aqueous and pH-buffered conditions, yielding a triply-responsive (co)polymer that highlights the wide variety of obtainable properties using this pathway

Thermoresponsive laterally-branched polythiophene phenylene derivative as water-soluble temperature sensor

Polymers with thermoresponsive properties have received a strong interest due to their potential applications. Here we report the synthesis and characterisation of a water soluble and thermoresponsive polythiophene derivative. Firstly, a polythiophene phenylene (PThP) functionalised with an initiator for atom transfer radical polymerization (ATRP) and azide groups on the side chains was synthesised. Secondly, ATRP was employed to graft poly(ethylene glycol) methacrylate (PEGMA) from the PThP to create a permanently water soluble conjugated polymer. Further functionalisation was then conducted through the `click' reaction with propargyl functionalised poly(2-n-propyl-2-oxazoline) to introduce thermoresponsivness. The polymer displayed lower critical solution temperature (LCST) behavior, as revealed by fluorescence and UV-Vis spectroscopy with potential use as soluble polymeric thermometer

Recognition-mediated hydrogel swelling controlled by interaction with a negative thermoresponsive LCST polymer

Most polymeric thermoresponsive hydrogels contract upon heating beyond the lower critical solution temperature (LCST) of the polymers used. Herein, we report a supramolecular hydrogel system that shows the opposite temperature dependence. When the non-thermosesponsive hydrogel NaphtGel, containing dialkoxynaphthalene guest molecules, becomes complexed with the tetra cationic macrocyclic host CBPQT4+, swelling occurred as a result of host–guest complex formation leading to charge repulsion between the host units, as well as an osmotic contribution of chloride counter-ions embedded in the network. The immersion of NaphtGel in a solution of poly(N-isopropylacrylamide) with tetrathiafulvalene (TTF) end groups complexed with CBPQT4+ induced positive thermoresponsive behaviour. The LCST-induced dethreading of the polymer-based pseudorotaxane upon heating led to transfer of the CBPQT4+ host and a concomitant swelling of NaphtGel. Subsequent cooling led to reformation of the TTF-based host–guest complexes in solution and contraction of the hydrogel

Judging enzyme-responsive micelles by their covers : direct comparison of dendritic amphiphiles with different hydrophilic blocks

Enzymatically degradable polymeric micelles have great potential as drug delivery systems, allowing the selective release of their active cargo at the site of disease. Furthermore, enzymatic degradation of the polymeric nanocarriers facilitates clearance of the delivery system after it has completed its task. While extensive research is dedicated toward the design and study of the enzymatically degradable hydrophobic block, there is limited understanding on how the hydrophilic shell of the micelle can affect the properties of such enzymatically degradable micelles. In this work, we report a systematic head-to-head comparison of well-defined polymeric micelles with different polymeric shells and two types of enzymatically degradable hydrophobic cores. To carry out this direct comparison, we developed a highly modular approach for preparing clickable, spectrally active enzyme-responsive dendrons with adjustable degree of hydrophobicity. The dendrons were linked with three different widely used hydrophilic polymers-poly(ethylene glycol), poly(2-ethyl-2-oxazoline), and poly(acrylic acid) using the CuAAC click reaction. The high modularity and molecular precision of the synthetic methodology enabled us to easily prepare well-defined amphiphiles that differ either in their hydrophilic block composition or in their hydrophobic dendron. The micelles of the different amphiphiles were thoroughly characterized and their sizes, critical micelle concentrations, drug loading, stability, and cell internalization were compared. We found that the micelle diameter was almost solely dependent on the hydrophobicity of the dendritic hydrophobic block, whereas the enzymatic degradation rate was strongly dependent on the composition of both blocks. Drug encapsulation capacity was very sensitive to the type of the hydrophilic block, indicating that, in addition to the hydrophobic core, the micellar shell also has a significant role in drug encapsulation. Incubation of the spectrally active micelles in the presence of cells showed that the hydrophilic shell significantly affects the micellar stability, localization, cell internalization kinetics, and the cargo release mechanism. Overall, the high molecular precision and the ability of these amphiphiles to report their disassembly, even in complex biological media, allowed us to directly compare the different types of micelles, providing striking insights into how the composition of the micelle shells and cores can affect their properties and potential to serve as nanocarriers

Reaching the Tumor:Mobility of Polymeric Micelles Inside an In Vitro Tumor-on-a-Chip Model with Dual ECM

Degradable polymeric micelles are promising drug delivery systems due to their hydrophobic core and responsive design. When applying micellar nanocarriers for tumor delivery, one of the bottlenecks encountered in vivo is the tumor tissue barrier: crossing the dense mesh of cells and the extracellular matrix (ECM). Sometimes overlooked, the extracellular matrix can trap nanoformulations based on charge, size, and hydrophobicity. Here, we used a simple design of a microfluidic chip with two types of ECM and MCF7 spheroids to allow “high-throughput” screening of the interactions between biological interfaces and polymeric micelles. To demonstrate the applicability of the chip, a small library of fluorescently labeled polymeric micelles varying in their hydrophilic shell and hydrophobic core forming blocks was studied. Three widely used hydrophilic shells were tested and compared, namely, poly(ethylene glycol), poly(2-ethyl-2-oxazoline), and poly(acrylic acid), along with two enzymatically degradable dendritic hydrophobic cores (based on hexyl or nonyl end groups). Using ratiometric imaging of unimer:micelle fluorescence and FRAP inside the chip model, we obtained the local assembly state and dynamics inside the chip. Notably, we observed different micelle behaviors in the basal lamina ECM, from avoidance of the ECM structure to binding of the poly(acrylic acid) formulations. Binding to the basal lamina correlated with higher uptake into MCF7 spheroids. Overall, we proposed a simple microfluidic chip containing dual ECM and spheroids for the assessment of the interactions of polymeric nanocarriers with biological interfaces and evaluating nanoformulations’ capacity to cross the tumor tissue barrier.</p

Seasonal change in the daily timing of behaviour of the common vole, Microtus arvalis

1. Seasonal effects on daily activity patterns in the common vole were established by periodic trapping in the field and continuous year round recording of running wheel and freeding activity in cages exposed to natural meteorological conditions. 2. Trapping revealed decreased nocturnality in winter as compared to summer. This was paralelled by a winter reduction in both nocturnal wheel running and feeding time in cages. 3. Frequent trap checks revealed a 2 h rhythm in daytime catches in winter, not in summer. Cage feeding activity in daytime was always organized in c. 2 h intervals, but day-to-day variations in phase blurred the rhythm in summer in a summation of individual daily records. Thus both seasonal and short-term temporal patterns are consistent between field trappings and cage feeding records. 4. Variables associated with the seasonal change in daily pattern were: reproductive state (sexually active voles more nocturnal), age (juveniles more nocturnal), temperature (cold days: less nocturnal), food (indicated by feeding experiments), habitat structure (more nocturnal in habitat with underground tunnels). 5. Minor discrepancies between field trappings and cage feeding activity can be explained by assuming increased trappability of voles in winter. Cage wheel running is not predictive of field trapping patterns and is thought to reflect behavioral motivations not associated with feeding but with other activities (e.g., exploratory, escape, interactive behaviour) undetected by current methods, including radiotelemetry and passage-counting. 6. Winter decrease in nocturnality appears to involve a reduction in nocturnal non-feeding and feeding behaviour and is interpreted primarily as an adaptation to reduce energy expenditure in adverse but socially stable winter conditions.