pH-responsive Polyelectrolyte Research Articles

Monte Carlo simulation of the ionization and uptake behavior of cationic oligomers into pH-responsive polyelectrolyte microgels of opposite charge - a model for oligopeptide uptake and release.

External stimuli can tune the uptake and release of guest molecules in microgels. Especially their pH responsiveness makes microgels exciting candidates for drug delivery systems. When both microgel and guest molecules are pH-responsive, predicting the electrostatically driven uptake can be complex since the ionization depends on many parameters. In this work, we performed Metropolis Monte Carlo simulations while systematically varying the pK of the monomers, the concentrations of microgel and guest molecules to obtain a better understanding of the uptake of weak cationic oligomers as a model for oligopeptides into a weak anionic polyelectrolyte microgel. Further, we varied the chain length of the oligomers. The polyelectrolyte networks can take up oligomers when both the network and the oligomers are charged. The presence of both species in the system leads to a mutual enhancement of their ionization. The uptake induces a release of counterions and results in complex formation between the oligomers and the network, leading to the collapse of the networks. Longer oligomers enhance the ionization of the network and, therefore, the complexation. A higher microgel concentration increases the uptake only around the isoelectric point but prevents the uptake due to lower entropy gain at counterion release at higher pH. The results give an insight into the uptake of cationic oligomers into oppositely charged polyelectrolyte microgels and provide hints for the design of anionic microgels as carriers for guest molecules e.g. antimicrobial peptides.

Chitosan–Sesbania Gum Mediated pH-Responsive Polyelectrolyte Complexes for Targeted Delivery of Diclofenac Sodium: Preparation and Spectroscopical Evaluation

Chitosan–Sesbania Gum Mediated pH-Responsive Polyelectrolyte Complexes for Targeted Delivery of Diclofenac Sodium: Preparation and Spectroscopical Evaluation

Formulation of pH-Responsive Methacrylate-Based Polyelectrolyte-Stabilized Nanoparticles for Applications in Drug Delivery.

pH-responsive polyelectrolytes, including methacrylate-based anionic copolymers (MACs), are widely used as enteric coatings and matrices in oral drug delivery. Despite their widespread use in these macroscopic applications, the molecular understanding of their use as stabilizers for nanoparticles (NPs) is lacking. Here, we investigate how MACs can be used to create NPs for therapeutic drug delivery and the role of MAC molecular properties on the assembly of NPs via flash nanoprecipitation. The NP size is tuned from 59 to 454 nm by changing the degree of neutralization, ionic strength, total mass concentration, and the core-to-MAC ratio. The NP size is determined by the volume of hydrophilic domains on the surface relative to the volume of hydrophobic domains in the core. We calculate the dimensions of the hydrophobic NP core relative to the thickness of the polyelectrolyte layer over a range of ionizations. Importantly, the results are shown to apply to both high-molecular-weight polymers as core materials and small-molecule drugs. The pH responsiveness of MAC-stabilized NPs is also demonstrated. Future development of polyelectrolyte copolymer-stabilized nanomedicines will benefit from the guiding principles established in this study.

PH-Responsive Polyelectrolyte Coatings that Enable Catheter-Mediated Transfer of DNA to the Arterial Wall in Short and Clinically Relevant Inflation Times.

We report the design and characterization of pH-responsive polymer coatings that enable catheter balloon-mediated transfer of DNA to arterial tissue in short, clinically relevant inflation times. Our approach exploits the pH-dependent ionization of poly(acrylic acid) (PAA) to promote disassembly and release of plasmid DNA from polyelectrolyte multilayers. We characterized the contact transfer of multilayers composed of PAA, plasmid DNA, and linear poly(ethyleneimine) (LPEI) identified as promising in prior studies on the delivery of DNA to arterial tissue. In contrast to thinner films evaluated previously, we found thicker coatings composed of 32 repeating (LPEI/PAA/LPEI/DNA)x tetralayers to swell substantially in physiologically relevant media (in PBS; pH = 7.4). In some cases, these coatings also disintegrated or delaminated rapidly from their underlying substrates, suggesting the potential for enhanced balloon-mediated transfer. We developed a technically straightforward agarose gel-based hole-insertion model to characterize factors (inflation time, lumen size, etc.) that influence contact transfer of DNA when film-coated balloons are inflated into contact with soft surfaces. Those studies and the results of in vivo experiments using small animal (rat) and large animal (pig) models of peripheral arterial injury revealed catheters coated with these materials to promote robust contact transfer of DNA to soft hydrogel surfaces and the luminal surfaces of arterial tissue using inflation times as short as 30 s. These short inflation times are relevant in the context of clinical vascular interventions in peripheral arteries. Additional studies demonstrated that contact transfer of DNA using these short times can promote subsequent dissemination and transport of DNA to the medial tissue layer, suggesting the potential for use in therapeutically relevant applications of balloon-mediated gene transfer.

Electric double layer of spherical pH-responsive polyelectrolyte brushes in an electrolyte solution: A strong stretching theory accounting for excluded volume interaction and mass action law

In this paper, we study the electrostatics of pH-responsive polyelectrolyte-grafted spherical particles by using a strong stretching theory that takes into account the excluded volume interaction and the density of chargeable sites on the polyelectrolyte molecules. Based on free energy formalism, we obtain self-consistent field equations for determining the structure and electrostatics of spherical polyelectrolyte brushes. First, we find that the smaller the radius of the inner core, the longer the height of the polyelectrolyte brush. Then, we also prove that an increase in the excluded volume interaction yields a swelling of the polyelectrolyte brush height. In addition, we demonstrate how the effect of pH, bulk ionic concentration, and lateral separation between adjacent polyelectrolyte chains on the electrostatic properties of a spherical polyelectrolyte brush is affected by the radius of the inner core, the excluded volume interaction, and the chargeable site density.

Structural and electrostatic properties between pH-responsive polyelectrolyte brushes studied by augmented strong stretching theory.

In this paper, we study electrostatic and structural properties between pH-responsive polyelectrolyte brushes by using a strong stretching theory accounting for excluded volume interactions, the density of polyelectrolyte chargeable sites, and the Born energy difference between the inside and outside of the brush layer. In a free energy framework, we obtain self-consistent field equations to determine electrostatic properties between two pH-responsive polyelectrolyte brushes. We elucidate that in the region between two pH-responsive polyelectrolyte brushes, electrostatic potential at the centerline and osmotic pressure increase not only with excluded volume interaction but also with the density of chargeable sites on a polyelectrolyte molecule. Importantly, we clarify that when two pH-responsive polyelectrolyte brushes approach each other, the brush thickness becomes short and that a large excluded volume interaction and a large density of chargeable sites yield the enhanced contract of polyelectrolyte brushes. In addition, we also demonstrate how the influence of such quantities as pH, the number of Kuhn monomers, the density of charged sites, the lateral separation between adjacent polyelectrolyte brushes, and Kuhn length on the electrostatic and structural properties between the two polyelectrolyte brushes is affected by the exclusion volume interaction. Finally, we investigate the influence of the Born energy difference on the thickness of polyelectrolyte brushes and the osmotic pressure between two pH-responsive polyelectrolyte brushes.

Chemoattractant releasing microneedles for enhanced DNA vaccination

Transcutaneous delivery of a DNA vaccine using microneedle (MN) has attracted much attention since there are a variety of immune cells underneath the skin. However, the clinical use of DNA vaccine is limited due to its poor cellular uptake of naked plasmid DNA (pDNA) and suboptimal presentation of an antigen by antigen presenting cells (APC). Herein, we designed a MN system for delivering polyplex-based DNA vaccine and recruiting APCs by a chemoattractant N-formyl-methionyl-leucyl-phenylalanine peptide (fMLP)-releasing microspheres (fMLP-MS) using MN coated with pH-responsive polyelectrolyte multilayer assembly (PMA). The PMA can be rapidly disrupted upon the application of MN to the skin, leading to the release of polyplex and fMLP-MS. The polyplex would be taken up by the epidermal cells and resident APCs to express and secrete the antigen (amyloid beta monomer, Aβ1-42) encoded in the DNA vaccine. fMLP released from fMLP-MS could recruit APCs to the site of MN administration by chemotactic effects. The MN-based vaccination system was able to induce robust antigen-specific antibody production.

PH-responsive polyelectrolyte complexation on upconversion nanoparticles: a multifunctional nanocarrier for protection, delivery, and 3D-imaging of therapeutic protein.

The delicate tertiary structure of proteins, their susceptibility to heat- and enzyme-induced irreversible denaturation, and their tendency to get accumulated at the cell membrane during uptake are daunting challenges in proteinaceous therapeutic delivery. Herein, a polyelectrolyte complex having encapsulated therapeutic protein has been designed on the surface of upconverting luminescent nanoparticles (NaYF4:20%Yb3+,2%Er3+). This nanosized complex system has been found to overcome the challenges of protein aggregation at the cell membrane. It has also defended the cargo from denaturation against (a) enzymatic action of proteinase K and (b) heat (up to 60 °C). Additionally, the nanoparticles at the core of the loaded carrier served as near-infrared (980 nm) responsive probe to accomplish extended-duration 3D imaging during protein delivery. The outer layer of polymer played pivotal role to protect/retrieve the protein structure from denaturation as investigated by circular dichroism studies. Both the masked surface-charges of protein and the nanoscale size of the loaded carrier have facilitated their efficient passage through the cell membrane as observed through 3D images/videos. This nanocarrier is the first of its kind for direct delivery of protein. Thus, the findings can be useful to protect and transport various proteinaceous materials to overcome challenges of accumulation at the cell-membrane and low-temperature storage, as nature does.

Cytocompatible drug delivery hydrogels based on carboxymethylagarose/chitosan pH-responsive polyelectrolyte complexes

Several drugs are chemically unstable in the gastric environment and have low bioavailability restricted by intestinal absorption, which motivates the development of alternative routes for drug release, such as transdermal drug carriers for drug delivery to specific areas of the skin. Herein, novel polyelectrolyte complexes (PEC) consisting of carboxymethylagarose (CMA) and chitosan (CS) were prepared. pH-responsive CMA/CS hydrogels were obtained by mixing CMA and CS at various weight ratios. Swelling ratio was modulated by varying the CMA and CS weight ratio, and the highest swelling values were achieved for 2:1 wt% hydrogels at 25 °C and pH 6.0. PEC films were characterized by ATR-FTIR spectroscopy, TGA, DSC, and SEM. Results indicated that CMA and CS were successfully crosslinked by ionic complexation. As a model drug, diclofenac sodium (DS) was loaded in CMA/CS PECs. Association efficiency and loading capacity were ca. 69% and 79%, respectively, exhibiting 67% cumulative release after 72 h at 37 °C and pH 6.0 through Fickian diffusion mechanism. Viability assay of immortalized human keratinocyte (HaCat) cells showed ca. 100% survival in the presence of hydrogels and DS. Therefore, this work suggests that CMA/CS PECs can be applied as pH-responsive carriers for dermal drug delivery.

Thermo-osmotic transport in nanochannels grafted with pH-responsive polyelectrolyte brushes modelled using augmented strong stretching theory

Abstract

A pH-responsive polyelectrolyte multilayer film with tunable interfacial properties

We report a facile and versatile approach to fabricate polyelectrolyte multilayer (PEM) films with a chemically modifiable outer surface. A PEM film was prepared by layer-by-layer assembly of poly (2-aminoethyl methacrylate) (PAMA) and polymethacrylic acid (PMAA), terminated with a partially tert-butyloxycarbonyl (Boc)-protected random copolymer (PAMA-co-PBocAMA) as the final layer. The obtained PEM film was then cross-linked and the free amino groups in the PEM film were quenched using EDC/NHS chemistry. The outer layer of the film was then treated via a deprotection reaction, affording free amino groups selectively located at the film surface. As a proof of concept study, these functional groups were used to modify the film surface with two model hydrophilic and hydrophobic compounds, which tuned the wettability of the PEM.

Benefits of pH-responsive polyelectrolyte coatings for carboxymethyl cellulose-based microparticles in the controlled release of esculin.

Moderate and prolonged payload release in response to a particular factor is highly demanded for efficient carriers of low-molecular-weight, chemically unstable phytopharmaceuticals. Thus, the objective of our contribution was to establish the effect of pH-responsive polyelectrolyte coatings on the release properties of carboxymethyl cellulose-based microparticles designed to deliver phytopharmaceuticals through the gastrointestinal tract. Microparticles were fabricated via extrusion coupled with external gelation and further coated with polyelectrolytes (PEs) (chitosan, gelatin, or PAH and PSS) involving electrostatic interactions. Successful deposition of PEs was confirmed by FTIR, and their thickness and viscosity were characterized in terms of QCM-D and ellipsometric techniques. The encapsulation efficiency of esculin, used as a model phytopharmaceutical, as proven by UV-Vis studies, was over 57%. SEM and fluorescence microscopy revealed a micrometric size, a mostly spherical shape and an altered topography of the investigated microcapsules. The physical stability of the microcapsules in media of various pH values was confirmed with CLSM and gravimetric studies. Studies on human gingival fibroblasts in vitro revealed that the obtained microparticles did not induce any cytotoxic effects. Payload release was monitored in situ by means of CLSM and ex situ under gastrointestinal conditions in vitro. Mathematical evaluation of the microparticle release profiles using classical models led to the establishment of a new hybrid model that revealed the mechanism behind esculin release. We demonstrated that the application of a polyelectrolyte shell onto CMC-based microspheres may provide controlled delivery of the payload, with its release triggered by the pH and ionic strength of the medium. These observations suggest that the release manner of small-molecule glycosides under gastrointestinal conditions can be tailored by careful selection of suitable materials to obtain biocompatible and functional hydrogel microparticles.

Tuning Electrokinetic Flow, Ionic Conductance, and Selectivity in a Solid-State Nanopore Modified with a pH-Responsive Polyelectrolyte Brush: A Molecular Theory Approach

We use an efficient molecular theory approach to study electrokinetic flow within a pH-responsive nanopore grafted with a polyelectrolyte (PE) brush. The flow rate, migration and convective conduct...

Theoretical study on the massively augmented electro-osmotic water transport in polyelectrolyte brush functionalized nanoslits.

We demonstrate that functionalizing nanoslits with pH-responsive polyelectrolyte brushes can lead to extremely fast electro-osmotic (EOS) water transport, where the maximum centreline velocity and the volume flow rate can be an order of magnitude larger than these quantities in identically charged brush-free nanochannels for a wide range of system parameters. Such an enhancement is most remarkable given that the brushes have been known to retard the transport by imparting additional drag on the fluid flow. We argue that this enhancement stems from the localization of the charge density of the brush-induced electric double layer (and, hence, the EOS body force) away from the nanochannel wall (or the location of the wall-induced drag force). This ensures a much larger impact of the EOS body force triggering such fast water transport. Finally, the calculated flux values for the present brush-grafted nanochannels are found to be significantly larger than those for a wide range of nanofluidic membranes and channels, suggesting that the brush functionalization can be considered as a mechanism for enabling such superfast nanofluidic transport.

Ionic diffusioosmotic transport in nanochannels grafted with pH-responsive polyelectrolyte brushes modeled using augmented strong stretching theory

In this paper, we study the diffusioosmotic (DOS) transport in a nanochannel grafted with pH-responsive polyelectrolyte (PE) brushes and establish brush-functionalization-driven enhancement in induced nanofluidic electric field and electrokinetic transport. The PE brushes are modeled using our recently developed augmented strong stretching theory. We consider the generation of the DOS transport due to the imposition of a salt concentration gradient along the length of the nanochannel. The presence of the salt concentration gradient induces an electric field that has an osmotic (associated with the flow-driven migration of the ions in the induced electric double layer) and an ionic (associated with the conduction current) component. These two components evolve in a manner such that the electric field in the brush-grafted nanochannel is larger (smaller) in magnitude than that in the brush-less nanochannels for the case where the electric field is positive (negative). Furthermore, we quantify the DOS flow velocity and establish that for most of the parameter choices, the DOS velocity, which is a combination of the induced pressure-gradient-driven chemiosmotic component and the induced electric field driven electroosmotic transport, is significantly larger for the nanochannels grafted with backbone-charged PE brushes (i.e., brushes where the charge is distributed along the entire length of the brushes) as compared to brush-free nanochannels or nanochannels grafted with PE brushes containing charges on their non-grafted ends.

Low-salt dyeing of cotton fabric grafted with pH-responsive cationic polymer of polyelectrolyte 2-(N,N-dimethylamino)ethyl methacrylate

In this work, a pH-responsive polyelectrolyte 2-(N, N-dimethylamino) ethyl methacrylate (PDMAEMA) was grafted onto the cotton fabric by surface-initiated atom transfer radical polymerization by activator regenerated electron transfer (SI-ARGET ATRP). Then, the grafted cotton fabric was dyed by reactive dyes. SEM, XRD, FT-IR, TGA and whiteness test were investigated to characterize the PDMAEMA grafted cotton fabric. Meanwhile, the dyeing temperature, fixed temperature and pH value in the dye bath were carried out to explore the optimum dyeing process. Finally, the mechanism of salt-free dyeing of PDMAEMA grafted cotton fabric is proposed. The results showed that the cotton fabric was successfully grafted by PDMAEMA, which presents excellent dye up-take, fixation yield, K/S value and dyeing uniformity and color fastness under the dyeing temperature of 30 °C, the fixed temperature of 60 °C,and the pH value of 6. Moreover, the pH-responsive process not only realizes salt-free dyeing, but also increases the dye up-take, fixation yield and the dye levelness due to the migration dyeing process. This work provides a promising route to realize the salt-free dyeing of reactive dye on cotton fabric, which is beneficial to environment protection for the significant reduced content of dye and salt in waste water.

Strong stretching theory for pH-responsive polyelectrolyte brushes in large salt concentrations

In this paper, we develop a theory for describing the thermodynamics, configuration, and electrostatics of strongly-stretched, pH-responsive polyelectrolyte (PE) brushes in the presence of large salt concentrations. The aim of the paper, therefore, is to study the properties of a PE brush in a salt concentration regime (namely, large concentrations of several molars) that has been hitherto unexplored theoretically in the context of PE brushes but can be routinely encountered in molecular scale simulations of the problem. The brushes are modelled using our recently developed augmented Strong Stretching Theory (SST), while the effect of the presence of the large salt concentration is accounted for by including the contributions of three different types of non-Poisson-Boltzmann (non-PB) effects to the free energy description of the PE brush induced electric double layer (EDL). These non-PB effects are ionic non-mean-field ion-ion correlations, solvent polarization, and the finite size effect of the ions and water dipoles. We study the individual influences of these different effects and show that the ion-ion correlations and solvent polarization effect reduce the brush height which consequently enhances the monomer density and leads to an electrostatic potential distribution of the brush induced EDL that has a larger magnitude at near-wall locations and becomes zero at shorter distances from the wall. The finite size effect, on the other hand, increases the brush height and therefore, weakens the monomer density and leads to a smaller near-wall magnitude of the EDL potential that becomes zero at larger distances from the wall. Eventually, we consider the impact of all the three non-PB effects simultaneously and show that the ion-ion correlations and solvent polarization effect dominate the size effects and dictate the overall brush configuration and the EDL electrostatics. We also point out that the influence of all the three non-PB effects becomes the largest for a larger salt concentration and a smaller bulk pH. Finally, we compare our theoretical predictions with those obtained from our recently developed all-atom MD simulation model and obtain an excellent match.

Cutaneous microenvironment responsive microneedle patch for rapid gene release to treat subdermal tumor

Transdermal gene therapy is a useful treatment for many skin lesions. By penetrating stratum corneum directly, microneedle patch (MNP) has been widely investigated to improve transdermal gene delivery. However, considering the operability and patience compliance, quick gene release was required after insertion. In this research, by utilizing acidic cutaneous environment, pH-responsive polyelectrolyte multilayers (PEM) were coated on the surface of polycaprolactone (PCL) microneedles by layer-by-layer assembly to realize rapid gene release. Dimethylmaleic anhydride-modified polylysine (PLL-DMA), a charge reversible polymer, was introduced to PEM. The PEM composed of two parts: the transition layers of (PLL-DMA/polyethyleneimine)12 and the gene-loaded layers of (p53 expression plasmid/polyethyleneimine)16. Microneedle patch modified with such PEM was marked as tr-MNP. In following experiment, Hoechst 33258 dyed model DNA was used to track modification process, fluorescent intensity of tr-MNP was obviously strengthened while the number of bilayers increased and the morphology could be maintained. Each tr-MNP could load 31μg model DNA and improve gene release. To prove this character, MNP without transition layers (ntr-MNP) was fabricated as control. Tr-MNP could release 33% of model DNA in simulative cutaneous environment (phosphate buffer saline; pH=5.5) while ntr-MNP could only release 4%. That was because PLL-DMA could achieve charge reversal in acidic cutaneous environment, leading to the collapse of transition layers and promoted the gene release. In vivo experiment showed tumor inhibit efficacy of tr-MNP treated mice could reach 90.1% while that of ntr-MNP treated mice and intravenous administration mice was only 46.4% and 30.5%. Overall, the pH-responsive gene loaded MNP could treat subcutaneous tumor efficiently and showed potential to be a platform to load many biomacromolecule.

Ionic current in nanochannels grafted with pH-responsive polyelectrolyte brushes modeled using augmented strong stretching theory.

In this paper, we provide a theory to quantify the ionic current ( ) in nanochannels grafted with pH-responsive polyelectrolyte (PE) brushes. We consider the PE brushes to be modeled by our recently proposed augmented strong stretching theory (SST) model that improves the existing SST models by incorporating the effects of excluded volume interactions and an extended mass action law. Use of such augmented SST for this problem implies that this is the first study on computing in PE brush-grafted nanochannels accounting for the appropriate coupled configuration-electrostatic description of the PE brushes. is obtained as functions of PE brush grafting density, medium pH and salt concentration ( ), and the density of polyelectrolyte chargeable sites (PECS). For large , increases linearly with (as for such , becomes independent of the PE charge and is dominated by the bulk mobility and number density of the electrolyte ions), whereas is independent of at small (where the electric double layer electrostatics and the total number of ions in the system is dominated by the hydrogen ions). We further witness an enhancement of for smaller pH and larger grafting density at low and moderate , while there is little to no effect of the PECS density on the ionic current except for weakly grafted brushes at low . We anticipate that this study will serve as a theoretical foundation for a large number of applications that are based on the brush-induced modification of the ionic current in ananochannel.

Electrokinetic energy conversion in nanochannels grafted with pH-responsive polyelectrolyte brushes modelled using augmented strong stretching theory.

In this paper, we develop a theory to quantify the electrokinetic energy conversion in electrolyte-filled nanochannels grafted with pH-responsive polyelectrolyte (PE) brushes. A pressure-driven flow drives the mobile electrolyte ions of the electric double layer (EDL) supported by the charged PE brushes leading to the generation of a streaming current, a streaming electric field and eventually an electrical energy. The salient feature of this study is that the brushes are described using our recently developed augmented Strong Stretching Theory (SST) model. In all the previous theoretical studies on liquid transport in PE-brush-grafted nanochannels, the brushes have either been assumed to be of constant height (independent of salt concentration or pH) or modelled using the Alexander-de-Gennes model that considers uniform monomer distribution along the brush height. Such simplifications have meant that the salt and the pH dependence of the brush height, the monomer distribution, and the resulting electrostatics have not been appropriately accounted for in the transport calculations. This paper addresses these limitations and provides a much more detailed description of the brushes while capturing the corresponding electrokinetic energy conversion. The results establish that the presence of the PE brushes ensures a localization of the average EDL charge density away from the grafting surface, thereby enabling the migration of the EDL ions with a larger background flow velocity; as a consequence, there is an enhancement of the streaming current, streaming electric field, and the resulting electrical energy generation under certain grafting densities of the PE brushes.