Hydrophilic Copolymers Research Articles

ThermosensitivePMMAcore/oligo(ethylene glycol)‐based shell microgels as drug carriers in detoxification treatment

AbstractThe core‐shell structured polymer microgels were synthesized by coating the hydrophobic poly(methyl methacrylate) (PMMA) sphere cores with hydrophilic nonlinear poly(ethylene glycol)‐based gel shell layer. The uniqueness of these core‐shell microgels lies in the integration of the PMMA core microsphere with strong hydrophobicity and the novel oligo(ethylene glycol)‐based gel layer with well‐defined thermosensitivity for improving loading/release efficacy of two detoxification drugs (chlorpromazine and diltiazem). The hydrophilic shell is composed of hydrophilic copolymer of 2‐(2‐methoxyethoxy)ethyl methacrylate (MEO2MA) with oligo(ethylene glycol) methyl ether methacrylates (MEO5MA). It was found that the molar ratio of two shell monomersn(MEO2MA)/n(MEO5MA) of 1:6 was an ideal matching value for production of the P(MEO2MA)/P(MEO2MA‐co‐MEO5MA) core‐shell microgels with tunable volume phase transition temperature and excellent colloidal stability across the physiologically important temperature range. Moreover, chlorpromazine‐ and diltiazem‐loaded microgels can show an obvious thermosensitive release and in vitro sustained‐release characteristic up to 80 h.

Poly (vinyl alcohol-co-ethylene) (EVOH) modified polymer inclusion membrane in heavy rare earths separation with advanced hydrophilicity and separation property

Efficient separation of adjacent rare earths is an interesting and challenging job for membrane separation scientists. In this article, a novel polymer inclusion membrane (PIM) incorporating the hydrophilic additive random copolymer poly (vinyl alcohol-co-ethylene) (EVOH) was synthesized. Due to the polarity of P = O and P-OH groups in Cyanex272 and hydrophilicity of –OH groups in EVOH, the membranes exhibited much smaller water contact angles than pure PVDF membranes. And FT-IR results indicated that the addition of EVOH made no difference on the coordination between P = O, P-OH in Cyanex272 and Lu3+. SEM and AFM results indicated that the addition of appropriate amount of EVOH could generate more and larger surface pores and internal channels. Optimum membrane compositions and permeation conditions were fixed via static adsorption and dynamics permeation experiments. Separation factor was calculated as high as 3.78, which was much higher than previous studies no matter in solvent extraction or membrane separation. It is worth noting that it’s the first time an obvious carrier’s leakage was observed via characterizations which implied Cyanex272 may be not a perfect carrier in terms of PIM’s stability. All these results proved that this novel PIM with EVOH serving as hydrophilic additive could be further testified in heavy rare earths separation and purification process.

A Method for Characterizing the Chemical Heterogeneity of Comb-Copolymers and Its Dependence on Synthesis Routes.

The heterogeneity in chemical structure of polymers is difficult to characterize and consequently remains an often-overlooked factor in mechanistic studies of functional polymers, as well as in their industrial scale optimization. In this study, we present a method to characterize chemical heterogeneity and apply it to illustrate how it can be affected differently in different synthesis routes. The polymers used are comb-copolymer dispersants used in particulate suspensions which are composed of a polycarboxylate backbone onto which PEG side chains are grafted. The largest use of these polymers concerns concrete, where they are referred to as poly(carboxylate ether) (PCE) superplasticizers and produced at a very large industrial scale. Apart from their practical relevance, PCEs provide a good test case for studying the means and benefits of characterizing chemical heterogeneity. Indeed, the simple addition of a UV detector to a traditional SEC setup with RI detection allowed us to monitor variations in the grafting ratio in dependence on the molecular size. We show that the synthesis pathway significantly impacts the chemical heterogeneity. The suggested method is versatile and can be adapted for a wide range of hydrophilic copolymers. Thus, we present a tool to comprehensively analyze the molecular heterogeneity of dispersants and give a deep insight into their chemical dispersity.

Development and characterization of poloxamine 908-hydrogels for potential pharmaceutical applications

Poloxamine 908 (P908) is a highly hydrophilic copolymer that is in wide use as a biomaterial. The aim of this investigation was to evaluate the suitability of P908 for the development of in situ-forming injectable hydrogels, as well as the influence of the copolymer concentration and temperature on their rheological properties. P908 formed thermally reversible gels at a polymer concentration equal to or greater than 25% w/w, showing a useful shear thinning behaviour at 37 °C, which makes the formulations easily injectable. Moreover, the use of different aqueous media as well as autoclave sterilization did not modify the rheological properties of the resulting systems. In vitro drug release studies demonstrated a constant and sustained release of various model compounds (rhodamine B and ovalbumin) for up to 120 h. The evaluation of in vitro cytotoxicity performed on human keratinocytes showed a slight decrease of cell viability only after 72 h incubation. The results demonstrated the potential application of P908-hydrogels as thermosensitive systems to be used in various applications.

New Aldehyde-Functional Methacrylic Water-Soluble Polymers.

Aldehyde groups enable facile conjugation to proteins, enzymes, oligonucleotides or fluorescent dyes, yet there are no literature examples of water‐soluble aldehyde‐functional vinyl monomers. We report the synthesis of a new hydrophilic cis‐diol‐based methacrylic monomer (GEO5MA) by transesterification of isopropylideneglycerol penta(ethylene glycol) using methyl methacrylate followed by acetone deprotection via acid hydrolysis. The corresponding water‐soluble aldehyde monomer, AGEO5MA, is prepared by aqueous periodate oxidation of GEO5MA at 22 °C. RAFT polymerization of GEO5MA yields the water‐soluble homopolymer, PGEO5MA. Aqueous periodate oxidation of the terminal cis‐diol units on PGEO5MA at 22 °C affords a water‐soluble aldehyde‐functional homopolymer (PAGEO5MA). Moreover, a library of hydrophilic statistical copolymers bearing cis‐diol and aldehyde groups was prepared using sub‐stoichiometric periodate/cis‐diol molar ratios. The aldehyde groups on PAGEO5MA homopolymer were reacted in turn with three amino acids to demonstrate synthetic utility.

New Aldehyde‐Functional Methacrylic Water‐Soluble Polymers

AbstractAldehyde groups enable facile conjugation to proteins, enzymes, oligonucleotides or fluorescent dyes, yet there are no literature examples of water‐soluble aldehyde‐functional vinyl monomers. We report the synthesis of a new hydrophilic cis‐diol‐based methacrylic monomer (GEO5MA) by transesterification of isopropylideneglycerol penta(ethylene glycol) using methyl methacrylate followed by acetone deprotection via acid hydrolysis. The corresponding water‐soluble aldehyde monomer, AGEO5MA, is prepared by aqueous periodate oxidation of GEO5MA at 22 °C. RAFT polymerization of GEO5MA yields the water‐soluble homopolymer, PGEO5MA. Aqueous periodate oxidation of the terminal cis‐diol units on PGEO5MA at 22 °C affords a water‐soluble aldehyde‐functional homopolymer (PAGEO5MA). Moreover, a library of hydrophilic statistical copolymers bearing cis‐diol and aldehyde groups was prepared using sub‐stoichiometric periodate/cis‐diol molar ratios. The aldehyde groups on PAGEO5MA homopolymer were reacted in turn with three amino acids to demonstrate synthetic utility.

Self-assembly of polymer-doxorubicin conjugates to form polyprodrug micelles for pH/enzyme dual-responsive drug delivery

Functionality of polymers is crucially fundamental to polymers. However, the application of polymers faces great challenges due to the insufficient function of hydrophobic chain, especially in drug delivery. One novel approach to solve this dilemma involves the use of medicated hydrophobic chains. Herein, the polymer-doxorubicin conjugates are synthesized from hydrophilic copolymer and hydrophobic chain composed of doxorubicin (DOX). DOX, a common hydrophobic anticancer drug, is used to serve as a hydrophobic pendant for inducing self-assembly of polymer-doxorubicin conjugates. The self-assembly of polymer-drug conjugates is employed to encapsulate the unreacted drug for the first time and form drug-loaded polyprodrug micelles that possess a low critical micelle concentration (CMC), which improves the use efficiency of expensive drug. The detachment of DOX moieties from polymer-doxorubicin conjugates caused by amidase facilitates the disintegration of DOX-loaded polyprodrug micelles to trigger the enhanced release of DOX in a slightly acidic medium. It is demonstrated that the DOX-loaded polyprodrug micelles have a higher suppression against cancer cells in in vitro investigations. This work thus proposes a strategy to modify the poor functionality of polymer-based nanostructures, through designing the medicated hydrophobic chains. This strategy facilitates the potential application of polymer-drug conjugates and provides profound insights into the effect of medicated polymer on drug delivery system.

Water dynamics within nanostructured amphiphilic statistical copolymers from quasielastic neutron scattering.

Understanding the properties of water under either soft or hard confinement has been an area of great interest, but nanostructured amphiphilic polymers that provide a secondary confinement have garnered significantly less attention. Here, a series of statistical copolymers of 2-hydroxyethyl acrylate (HEA) and 2-(N-ethylperfluorooctane sulfonamido)ethyl methacrylate (FOSM) are swollen to equilibrium in water to form nanostructured physically cross-linked hydrogels to probe the effect of soft confinement on the dynamics of water. Changing the composition of the copolymer from 10 to 21 mol. % FOSM decreases the average size of the assembled FOSM cross-link, but also the spacing between the cross-links in the hydrogels with the mean distance between the FOSM aggregates decreasing from 3.9 to 2.7 nm. The dynamics of water within the hydrogels were assessed with quasielastic neutron scattering. These hydrogels exhibit superior performance for inhibition of water crystallization on supercooling in comparison to analogous hydrogels with different hydrophilic copolymer chemistries. Despite the lower water crystallinity, the self-diffusion coefficient for these hydrogels from the copolymers of HEA and FOSM decreases precipitously below 260 K, which is a counter to the nearly temperature invariant water dynamics reported previously with an analogous hydrogel [Wiener et al., J. Phys. Chem. B 120, 5543 (2016)] that exhibits nearly temperature invariant dynamics to 220 K. These results point to chemistry dependent dynamics of water that is confined within amphiphilic hydrogels, where the interactions of water with the hydrophilic segments can qualitatively alter the temperature dependent dynamics of water in the supercooled state.

Revisiting the salt-triggered self-assembly in very hydrophilic triblock copolymer Pluronic® F88 using multitechnique approach

An insight scrutiny into the micellization behavior of a linear triblock copolymer Pluronic® F88 in aqueous potassium chloride (KCl) solutions is put forth through various physicochemical techniques, viz. cloud point, tensiometric, microcalorimetry, fluorescence life-time decay, spectral, and scattering. Phase transitions of 5% w/v F88 in KCl electrolyte environment demonstrated the dehydration of copolymer coil; a decrease in the micellization temperature with increase in [KCl] due to salting out effect was configured with high sensitivity differential scanning calorimetry (HSDSC) and fluorescence spectroscopy conduct. Salting out effect exhibited by PEO and PPO blocks of F88 in the presence of KCl was measured by the variations in the bond stretching, intensity of vibrations, and change in chemical shifts using spectral (Fourier-transfer infrared (FT-IR) and 1H-nuclear magnetic resonance (1H-NMR) spectroscopy) techniques. The micellization that followed the double-relaxation process is further validated, employing ultrasonic absorption spectroscopy. The plausible unimers to spherical micelles transition induced by KCl are confirmed with the measured hydrodynamic diameter (Dh) of micelles using dynamic light scattering (DLS). Furthermore, UV-vis spectroscopy findings depicted the successive solubilization of water-insoluble organic dye (orange-OT) in the examined micellar solution which revealed the salient role of salt-water interaction in emboldening the micellization of F88.

Synthesis and self-assembly of polyzwitterionic phenylboronic acid-containing double hydrophilic block copolymers

Double hydrophilic block copolymers self-assemble into smart materials with promising applications in nanomedicine. However, such practical applications require thoroughly understanding the underlying mechanisms of this self-assembly process and the effects of external stimuli on the resulting materials. Thus, we report the post-polymerization modification of a pH-responsive double hydrophilic diblock copolymer (poly(ethylene oxide)-b-poly(4-vinyl pyridine)) by stimuli-responsive, diol-binding 2-bromomethyl-4-fluorophenylboronic acid and the comprehensive study of the self-assembly properties of this polyzwitterionic polymer for potential applications in the delivery of functional diols, including pharmaceutical drugs, steroids and sugars. For this purpose, we performed simple, robust and reproducible quaternization reactions at three different degrees (25, 50 and 100%) by varying the composition of the initial mixture and confirmed full control over the degree of quaternization by proton nuclear magnetic and infrared spectroscopy. Our results show that the degree of quaternization strongly affects the solubility of these polymers in basic solutions because PBA adopts a tetragonal conformation with a negative charge on boron at pH values higher than the pKA of PBA. Nevertheless, the specific PBA (anionic vs neutral) form of these polymers can be differentiated by 11B NMR, regardless of the degree of quaternization. In turn, the pH of the solvent affected the intensity of the NMR signals, thus suggesting the formation of kinetically frozen nanoparticles, in line with the results from both static and dynamic light scattering, with no indication of particle dissociation at low concentrations. Moreover, electrophoretic light scattering showed linear, albeit opposite (direct and inverse) correlations between the degree of quaternization and the zeta potential in water and 0.1 M HCl, respectively. When adsorbed to a mica surface, these nanoparticles predominantly displayed globular shapes under atomic force microscopy. Therefore, our high-throughput and low-cost nanofabrication method combining the stimuli-responsive behavior of a double hydrophilic block copolymer with the unique chemical properties of pH-responsive diol-binding phenylboronic acid functional groups establishes an experimental paradigm for preparing nanocarriers for biomedical applications, such as targeted drug delivery.

Hydrophilic Cross-Linked Aliphatic Hydrocarbon Diblock Copolymer as Proton Exchange Membrane for Fuel Cells.

This study proposes a hydrophobic and hydrophilic aliphatic diblock copolymer wherein the hydrophobic block contains glycidyl methacrylate (GMA) units that are distanced by poly(acrylonitrile) (PAN) segments to fabricate a proton exchange membrane (PEM). This diblock copolymer also known as ionomer due to the hydrophilic block comprising 3-sulfopropyl methacrylate potassium salt (SPM) block. The diblock copolymer was synthesized in the one-pot atom transfer radical polymerization (ATRP) synthesis. Subsequently, the membrane was fabricated by means of solution casting in which an organic diamine, e.g., ethylene diamine (EDA), was introduced to crosslink the diblock copolymer chains via the addition of amine to the epoxide group of GMA. As a result, the PEM attained possesses dual continuous phases, in which the hydrophobic domains are either agglomerated or bridged by the EDA-derived crosslinks, whereas the hydrophilic domains constitute the primary proton conducting channels. The in-situ crosslinking hydrophobic block by using a hydrophilic cross-linker represents the merit aspect since it leads to both improved proton conductivity and dimensional stability in alcohol fuel. To characterize the above properties, Nafion® 117 and random copolymer of P(AN-co-GMA-co-SPM) were used as control samples. The PEM with the optimized composition demonstrates slightly better fuel cell performance than Nafion 117. Lastly, this diblock ionomer is nonfluorinated and hence favors lowering down both material and environmental costs.

Effects of Ionic Strength and Ion Specificity on the Interface Behavior of Poly(dimethylaminoethyl methacrylate)-Poly(lauryl methacrylate).

The ion specificity effect on the water solubility of poly(N-isopropylacrylamide)-containing copolymers complies with the Hofmeister series, which is applicable to other copolymers or not need to be explored. In this work, effects of ionic strength under acidic conditions and ion specificity under alkaline conditions on the air/water interface behavior of two amphiphilic diblock copolymers poly(dimethylaminoethyl methacrylate)-poly(lauryl methacrylate) (PDMAEMA-PLMA) were systematically studied. Under acidic conditions, the surface pressure-area isotherms of a predominantly hydrophilic copolymer are insensitive to ionic strength. In contrast, the isotherms of a predominantly hydrophobic copolymer successively shift to the large, small, and large molecular area with the increase of ionic strength. Under alkaline conditions, the interfacial stretch degrees of PDMAEMA chains of two copolymers change with salt species and concentrations, which do not comply with the Hofmeister series. All of the Langmuir-Blodgett films of the former copolymer exhibit separate circular micelles. Nevertheless, those of the latter copolymer obtained under alkaline conditions exhibit various distinctive morphologies such as separate circular micelles, large separate PLMA cores within large PDMAEMA domains, and large PLMA domains/aggregates surrounded by short PDMAEMA shells. It can be attributed to the high deformability of PLMA chains, the ion specificity effect on the stretch degree of PDMAEMA blocks, and their underwater solubility upon compression.

Micellization through complexation of oppositely charged diblock copolymers: Effects of composition, polymer architecture, salt of different valency, and thermoresponsive block

AbstractThe structural and electrical characteristics of polyelectrolyte complex micelles (PCMs) formed by mixing of oppositely charged double hydrophilic copolymers are studied by means of molecular dynamics simulations. In mixtures of linear diblock copolymers we found that the preferential aggregation number Np of PCMs is a universal function of the ratio γ± of the total positive to total negative charges of the mixture. The addition of divalent salts ions induces a secondary micellization. In mixtures of copolymers bearing a common neutral thermoresponsive block, micelles with contracted corona consisting of thermoresponsive blocks and complex polyelectrolyte core are formed at low salt concentration and temperature far away the biphasic regime. At high salt concentration and temperature in the biphasic regime, reversed micelles are obtained. In equimolar mixtures of linear copolymers with miktoarm stars we found that Np of PCMs decreases as the number of charged branches of miktoarm copolymer increases. The shape of micelles progressively changes from spherical to worm‐like with the increase of number of branches of miktoarm copolymers. Our findings are in full agreement with existing experimental and theoretical predictions and provides new and additional insights.

Synthesis and self-assembly of optically active random copolymers bearing L-alanine and L-glutamic acid moieties in aqueous medium

This study reports the synthesis by free radical polymerization and aggregation behavior of two new optically active hydrophilic random copolymers comprising glutamic acid or alanine-derived acrylamides and N-[3-(dimethylamino)propyl] methacrylamide (DMAPMA) taken in a 3:1 molar ratios. Their structures, chemical composition and optical activity are confirmed by spectral analysis (FTIR, 1H/13C NMR), thermal methods (TGA, DSC), molecular weight measurements (GPC) and specific rotation measurements. In addition, surface tension, fluorescence spectroscopy, dynamic light scattering (DLS), atomic force microscopy (AFM) and transmission electron microscopy (TEM) are utilized for the characterization of the self-assemblies in solution and/or thin films. The critical aggregation concentration (CAC) determined by surface tension and fluorescence spectroscopy shows similar values of 6 × 10−2 and 5 × 10−2 g∙L−1, respectively. Steady-state fluorescence measurements using 1-pyrene-methanol as molecular probe suggest the tendency of micro-domain formation as a result of interpolymer hydrophobic interactions, while their hydrodynamic sizes are determined by DLS technique. Moreover, the micrographs from AFM technique evidence a combination of comb and brush-shaped orderly structures for the L-glutamic acid-based copolymer, and a star-type structure with four arms, in which each arm presents in turn a brush structure for the L-alanine-based copolymer.

Development and Evaluation of HILIC-type Sorbents Modified with Hydrophilic Copolymers for Solid-phase Extraction.

Hydrophilic interaction chromatography (HILIC) has attractive attention for the separation of water-soluble compounds via HPLC. There are, however, few studies on the pretreatment of the HILIC-type solid-phase extraction (SPE) due to the difficulty of obtaining the HILIC-type sorbent. Therefore, the development of HILIC-type sorbents for SPE is essential. In this study, four different hydrophilic copolymers, namely diallylamine-maleic acid copolymer (DAM), diallylamine-acrylamide copolymer (DAA), allylamine-maleic acid copolymer (MAM), and partly methylcarbonylated allylamine acetate copolymer (MAC), were immobilized on glycidyl methacrylate (GMA)-base resin, and their adsorptive properties were evaluated. The results of the physical and adsorptive properties indicated that a balance between the water content of the water-enriched layer on sorbent and the amount of hydrophilic copolymer immobilized on the GMA-base resin was vital for the adsorption in HILIC-type sorbent for SPE.

Structure and Physical Properties of Hydrophilic Polyamide Copolymers Fiber Based on Nylon 6 and Nylon 4,6

Recently, hydrophilic synthetic fiber products have been sought to substitute natural fibers. This paper investigates the structure and properties of spined copolymer of nylon 6, nylon 4,6 and polyethylene oxide (PEO) — polypropylene oxide (PPO) diamine according to contents of PEO-PPO diamine (15–40%). The structure of new polyamide (NPA) were analyzed by X-ray diffraction (XRD), differential scanning calorimeter (DSC), dynamic mechanical analysis (DMA), gradient density column and gas pycnometry. Through XRD and DSC analysis, it was confirmed that the structure of NPA was similar to nylon 6 regardless of the content of PEO-PPO diamine. The DMA results show that the mobility of polymer chain in non-crystalline structure increases. It was considered that PEO-PPO diamine provides flexible segments and hydrophilic moieties to NPA. The analysis of moisture regain and tenacity was revealed that NPA exhibited 7.38% moisture regain and 2.85 g/denier tenacity.

Optimized polymer-based glucose release in microtiter plates for small-scale E. coli fed-batch cultivations

BackgroundSmall-scale cultivation vessels, which allow fed-batch operation mode, become more and more important for fast and reliable early process development. Recently, the polymer-based feeding system was introduced to allow fed-batch conditions in microtiter plates. Maximum glucose release rates of 0.35 mg/h per well (48-well-plate) at 37 °C can be achieved with these plates, depending on the media properties. The fed-batch cultivation of fluorescent protein-expressing E. coli at oxygen transfer rate levels of 5 mmol/L/h proved to be superior compared to simple batch cultivations. However, literature suggests that higher glucose release rates than achieved with the currently available fed-batch microtiter plate are beneficial, especially for fast-growing microorganisms. During the fed-batch phase of the cultivation, a resulting oxygen transfer rate level of 28 mmol/L/h should be achieved.ResultsCustomization of the polymer matrix enabled a considerable increase in the glucose release rate of more than 250% to up to 0.90 mg/h per well. Therefore, the molecular weight of the prepolymer and the addition of a hydrophilic PDMS-PEG copolymer allowed for the individual adjustment of a targeted glucose release rate. The newly developed polymer matrix was additionally invariant to medium properties like the osmotic concentration or the pH-value. The glucose release rate of the optimized matrix was constant in various synthetic and complex media. Fed-batch cultivations of E. coli in microtiter plates with the optimized matrix revealed elevated oxygen transfer rates during the fed-batch phase of approximately 28 mmol/L/h. However, these increased glucose release rates resulted in a prolonged initial batch phase and oxygen limitations. The newly developed polymer-based feeding system provides options to manufacture individual feed rates in a range from 0.24–0.90 mg/h per well.ConclusionsThe optimized polymer-based fed-batch microtiter plate allows higher reproducibility of fed-batch experiments since cultivation media properties have almost no influence on the release rate. The adjustment of individual feeding rates in a wide range supports the early process development for slow, average and fast-growing microorganisms in microtiter plates. The study underlines the importance of a detailed understanding of the metabolic behavior (through online monitoring techniques) to identify optimal feed rates.

Amphiphilic Polymeric Nanoparticles Modified with a Retro-Enantio Peptide Shuttle Target the Brain of Mice

The blood–brain barrier (BBB) is a challenge for the treatment of diseases of the central nervous system (CNS) from the systemic circulation. The design of novel strategies to increase drug bioavailability in the CNS is called for. In this work, we synthesized amphiphilic polymeric nanoparticles by the self-assembly of graft copolymers of chitosan (CS, hydrophilic copolymer backbone) hydrophobized in the side-chain with poly­(methyl methacrylate) (PMMA)/poly­(acrylic acid) (PAAc) blocks and surface-decorated with a biologically stable retro-enantio peptide shuttle that improves brain transport. Nanoparticles showed one size population in the 190–210 nm range (intensity distribution) and a relatively small polydispersity index, as measured by dynamic light scattering. The surface charge estimated by the zeta-potential decreased from +35 mV in the unmodified nanoparticles to +14 mV in the modified ones, confirming the exposure of the peptide shuttle at the nanoparticle surface. The cell compatibility and uptake were assayed in hCMEC/D3 cells, a model of BBB endothelium, by a metabolic assay, confocal laser scanning fluorescence microscopy, and imaging flow cytometry in the absence and the presence of endocytosis inhibitors. Results indicated that the peptide shuttle modification improves their cell compatibility and that they are internalized by a clathrin-mediated pathway. In vitro permeability studies conducted in hCMEC/D3 cell monolayers showed that peptide shuttle-modified nanoparticles increase the apparent permeability with respect to the unmodified ones by 3.4 times. Finally, the brain accumulation was investigated upon i.v. administration to Hsd:ICR mice by using fluorescently labeled nanoparticles in an in vivo imaging system and light sheet fluorescence microscopy. Unmodified nanoparticles could be hardly detected in the brain blood vessels and parenchyma. Conversely, nanoparticles modified with the peptide shuttle could be detected after 10 min, with a maximum accumulation at 30 min and a slow concentration decline later on. Calculation of the area under the curve confirmed a 4-fold statistically significant increase in the accumulation of the modified nanoparticles with respect to the unmodified counterparts. These findings demonstrate the promise of this strategy to improve the delivery of nanoencapsulated cargos to the CNS.

Interfacial dilatational rheology as a bridge to connect amphiphilic heterografted bottlebrush copolymer architecture to emulsifying efficiency

HypothesisMolecular architecture and composition of amphiphilic bottlebrush copolymers will dictate the dominant interfacial relaxation modes and the corresponding dilatational rheology for adsorbed layers at oil/water interfaces in a way that will correlate with the emulsifying efficiency of different bottlebrush copolymers. ExperimentsAmphiphilic, xylene-soluble poly(ethylene oxide)-poly(n-butyl acrylate) (PEO-PBA) heterografted bottlebrush copolymers with controlled differences in backbone length, hydrophilicity and arm length were synthesized by atom transfer radical polymerization. Dilatational rheology of adsorbed layers at the xylene/water interface was probed via pendant drop tensiometry by measuring the interfacial stress response to either large-amplitude strain cycling or small-amplitude strain oscillation. The rheological response was recorded as a function of interfacial pressure for adsorbed layers under different compression states. Emulsifying efficiency was determined as the lowest copolymer concentration that yielded water-in-xylene emulsions with at least one-month stability against coalescence. FindingsThe more hydrophilic copolymers with longer PEO arms exhibited non-hysteretic stress-strain response curves in large-amplitude strain cycling and a tendency for the modulus to increase with increasing interfacial pressure. These were more efficient emulsifiers than less hydrophilic copolymers that exhibited hysteretic interfacial rheology. Mere existence of significant moduli did not correlate with high emulsifying efficiency, while an increase in modulus with increasing interfacial pressure did so.

The In Vitro, Ex Vivo, and In Vivo Effect of Polymer Hydrophobicity on Charge-Reversible Vectors for Self-Amplifying RNA.

RNA technology has the potential to revolutionize vaccination. However, the lack of clear structure-property relationships in relevant biological models mean there is no clear consensus on the chemical motifs necessary to improve RNA delivery. In this work, we describe the synthesis of a series of copolymers based on the self-hydrolyzing charge-reversible polycation poly(dimethylaminoethyl acrylate) (pDMAEA), varying the lipophilicity of the additional co-monomers. All copolymers formed stable polyplexes, showing efficient complexation with model nucleic acids from nitrogen/phosphate (N/P) ratios of N/P = 5, with more hydrophobic complexes exhibiting slower charge reversal and disassembly compared to hydrophilic analogues. The more hydrophobic copolymers outperformed hydrophilic versions, homopolymer controls and the reference standard polymer (polyethylenimine), in transfection assays on 2D cell monolayers, albeit with significantly higher toxicities. Similarly, hydrophobic derivatives displayed up to a 4-fold higher efficacy in terms of the numbers of cells expressing green fluorescent protein (GFP+) cells in ex vivo human skin (10%) compared to free RNA (2%), attributed to transfection enrichment in epithelial cells. In contrast, in a mouse model, we observed the reverse trend in terms of RNA transfection, with no observable protein production in more hydrophobic analogues, whereas hydrophilic copolymers induced the highest transfection in vivo. Overall, our results suggest an important relationship between the vector lipophilicity and RNA transfection in vaccine settings, with polymer biocompatibility potentially a key parameter in effective in vivo protein production.