Molecular Weight Of mPEG Research Articles

PEGylation of a Peptide-Based Amphiphilic Delivery Agent and Influence on Protein Delivery to Cells.

The cell membrane is a restrictive biological barrier, especially for large, charged molecules, such as proteins. The use of cell-penetrating peptides (CPPs) can facilitate the delivery of proteins, protein complexes, and peptides across the membrane by a variety of mechanisms that are all limited by endosomal sequestration. To improve CPP-mediated delivery, we previously reported the rapid and effective cytosolic delivery of proteins in vitro and in vivo by their coadministration with the peptide S10, which combines a CPP and an endosomal leakage domain. Amphiphilic peptides with hydrophobic properties, such as S10, can interact with lipids to destabilize the cell membrane, thus promoting cargo internalization or escape from endosomal entrapment. However, acute membrane destabilization can result in a dose-limiting cytotoxicity. In this context, the partial or transient deactivation of S10 by modification with methoxy poly(ethylene glycol) (mPEG; i.e., PEGylation) may provide the means to alter membrane destabilization kinetics, thereby attenuating the impact of acute permeabilization on cell viability. This study investigates the influence of PEGylation parameters (molecular weight, architecture, and conjugation chemistry) on the delivery efficiency of a green fluorescent protein tagged with a nuclear localization signal (GFP-NLS) and cytotoxicity on cells in vitro. Results suggest that PEGylation mostly interferes with adsorption and secondary structure formation of S10 at the cell membrane, and this effect is exacerbated by the mPEG molecular weight. This effect can be compensated for by increasing the concentration of conjugates prepared with lower molecular weight mPEG (5 to ∼20 kDa) but not for conjugates prepared with higher molecular weight mPEG (40 kDa). For conjugates prepared with moderate-to-high molecular weight mPEG (10 to 20 kDa), partial compensation of inactivation could be achieved by the inclusion of a reducible disulfide bond, which provides a mechanism to liberate the S10 from the polymer. Grafting multiple copies of S10 to a high-molecular-weight multiarmed PEG (40 kDa) improved GFP-NLS delivery efficiency. However, these constructs were more cytotoxic than the native peptide. Considering that PEGylation could be harnessed for altering the pharmacokinetics and biodistribution profiles of peptide-based delivery agents in vivo, the trends observed herein provide new perspectives on how to manipulate the membrane permeabilization process, which is an important variable for achieving delivery.

A new site-specific monoPEGylated β-lactoglobulin at the N-terminal: Effect of different molecular weights of mPEG on its conformation and antigenicity

A new method was investigated to decline the antigenicity of β-Lactoglobulin (β-LG) by site specifically conjugating β-LG at the N-terminus with 5 kDa and 10 kDa monomethoxy polyethylene glycol propyl aldehyde (mPEG-ALD). The optimal reaction conditions were molar ratio of 1:10 (β-LG:mPEG-ALD), reaction time for 16 h, and pH 5.0, and the content of mono-PEGylated β-LG was 51.3%. The results showed that mono-PEGylated β-LG with molecular mass of 23.2 kDa and 28.5 kDa. The peptide fragments of mPEG5kDa-ALD-β-LG produced the same sequence pattern of β-LG except for the absence of one peptides f(1–14), indicating that α-amino group at the N-terminal was selectively modified. Furthermore, the conformation of modified β-LG underwent into slight change. The antigenicity of mPEG5kDa-ALD-β-LG and mPEG10kDa-ALD-β-LG decreased from 144.4 μg/mL to 66.7 and 39.0 μg/mL respectively. It was speculated that the steric hindrance effect of PEG was the main reason for the decline of antigenicity of β-LG.

Synthesis and structure–activity relationships of nonionic surfactants with short fluorocarbon chains

The biodegradability of fluorinated surfactants can be improved by reducing the length of the fluorocarbon chain. In this study, ten new nonionic fluorinated surfactants with various hydrophilic and hydrophobic chain lengths were synthesized by means of substitution and ring-opening reactions using methoxypolyethylene glycols (mPEGs) or 2-methoxyethanol, epibromohydrin, and perfluoroalkyl alcohols as raw materials. We measured the static and dynamic surface tension of the synthesized surfactants and used the resulting data to develop structure–activity relationships. We found that mPEG molecular weight was the main determinant of minimum surface tension, and the number of fluorocarbon atoms was the main determinant of critical micelle concentration. Diffusivity decreased with increasing number of fluorocarbon atoms but increased with increasing mPEG molecular weight. Surfactant 5i showed the best performance, lowering the surface tension of water to 17.89 mN/m.

In Vitro and in Vivo Behavior of Liposomes Decorated with PEGs with Different Chemical Features.

The colloidal stability, in vitro toxicity, cell association, and in vivo pharmacokinetic behavior of liposomes decorated with monomethoxy-poly(ethylene glycol)-lipids (mPEG-lipids) with different chemical features were comparatively investigated. Structural differences of the mPEG-lipids used in the study included: (a) surface-anchoring moiety [1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), cholesterol (Chol), and cholane (Chln)]; (b) mPEG molecular weight (2 kDa mPEG45 and 5 kDa mPEG114); and (c) mPEG shape (linear and branched PEG). In vitro results demonstrated that branched (mPEG114)2-DSPE confers the highest stealth properties to liposomes (∼31-fold lower cell association than naked liposomes) with respect to all PEGylating agents tested. However, the pharmacokinetic studies showed that the use of cholesterol as anchoring group yields PEGylated liposomes with longer permeance in the circulation and higher systemic bioavailability among the tested formulations. Liposomes decorated with mPEG114-Chol had 3.2- and ∼2.1-fold higher area under curve (AUC) than naked liposomes and branched (mPEG114)2-DSPE-coated liposomes, respectively, which reflects the high stability of this coating agent. By comparing the PEGylating agents with same size, namely, linear 5 kDa PEG derivatives, linear mPEG114-DSPE yielded coated liposomes with the best in vitro stealth performance. Nevertheless, the in vivo AUC of liposomes decorated with linear mPEG114-DSPE was lower than that obtained with liposomes decorated with linear mPEG114-Chol. Computational molecular dynamics modeling provided additional insights that complement the experimental results.

Full-biodegradable polylactide-based thermoresponsive copolymer with a wide temperature range: Synthesis, characterization and thermoresponsive properties

To develop a full-biodegradable thermoresponsive polymer with a wide temperature range, a hydrophilic, biodegradable and biocompatible thermoresponsive polymer having a polylactide backbone polymer and a side chain norbornene group was synthesized by ring-opening polymerization of a norbornene-functionalized lactide, followed by graft of backbone polymer with polyethylene glycol monomethyl ether (MPEG) and modification with isopropylamide (IPA), the latter of which critically influences the phase transition temperature of the copolymer. The effects of polymerization degree (DP), molecular weight of MPEG, the proportion of MPEG and IPA, and the concentration of polymer on the behaviors of the thermoresponsive polymer solution were systematically studied. The Cp ranged from 32 to 72 °C, and it was found that higher number of the MPEG moiety led to higher Cp, whereas the longer isopropylamide group resulted in lower Cp. It is noteworthy that with the unique characteristics, thermosensitivity at body temperature, biodegradability, and a well-defined copolymer structure, the developed thermoresponsive polymer is promising for biomedical applications as an essential material.

Mechanisms of activity loss for a multi-PEGylated protein by experiment and simulation

Over the past five decades, one of the most investigated strategies to increase the circulatory half-life and to reduce the immunogenicity of non-human therapeutic proteins has been to cover their surface with multiple copies of methoxy poly(ethylene glycol) (mPEG). This multi-‘PEGylation’ strategy, however, is often associated with loss of protein activity, which is most often rationalized as direct modification of the protein's active site or to steric hindrance near its surface. While these mechanisms are generally accepted and likely valid, very few studies investigate other possible mechanisms of activity loss. To answer this question, this study investigates the mechanisms of activity loss for glutamate dehydrogenase (GDH) bearing up to 25 chains of mPEG per protein. Through a combination of experimental design and simulation, the most common proposed causes of protein inactivation (i.e. active-site PEGylation and steric hindrance near the surface of the protein) are circumvented to shed light on less characterized mechanisms such as altered protein structure, altered microenvironment at the surface of the protein, and altered protein dynamics. Experiments suggest that the secondary and tertiary structure of GDH was (sometimes significantly) affected by PEGylation, though these changes do not necessarily result in a loss of activity. Structure-activity correlations could not reconcile all trends within the library of bioconjugates tested. Moreover, by measuring catalytic activity in the presence of five different allosteric modulators, loss of activity could not be ascribed to an altered local microenvironment at the protein's surface. As such, coarse-grained simulations were exploited to reveal the effect of PEGylation on protein dynamics, which are long-ranged, cooperative, and essential for GDH catalytic activity. Normal mode analysis of native bovine GDH (i.e. not PEGylated) revealed that the lowest ranking mode displayed several features that bore similarity to movements known for the native protein. These included rotation/distortion of the ‘antenna’ regions, closure of the ‘catalytic cleft’, and constriction of the internal cavity. A reduced magnitude of this mode was observed as a function of degree of PEGylation and mPEG molecular weight and correlated well with trends observed for the library of bioconjugates tested experimentally. Overall, this study provides new insight into fundamental considerations associated with loss of activity, which will contribute to the design of future bioconjugates by providing a better understanding of possible mechanisms of loss of activity.

Effects of PEG surface density and chain length on the pharmacokinetics and biodistribution of methotrexate-loaded chitosan nanoparticles.

BackgroundOne of the most important aspects of drug delivery is extended nanoparticle (NP) residence time in vivo. Herein, we report a series of methotrexate (MTX)-loaded chito-san (CS) NPs coated with differently sized methoxy polyethylene glycol (mPEG) at different mPEG surface densities.Materials and methodsMTX was incorporated into NPs (112.8–171.2 nm in diameter) prepared from the resulting mPEG-g-CS. The NPs had a zeta potential of +7.4–35.0 mV and MTX loading efficiency of 17.1%–18.4%. MTX/mPEG-g-CS NPs showed an initial burst release of MTX followed by a sustained-release profile in PBS at pH 7.4.ResultsThe in vitro cellular uptake study showed that MTX accumulation in J774A.1 macrophage cells decreased with increasing the mPEG surface density or the mPEG molecular weight. The pharmacokinetic study on Sprague Dawley rats revealed an increase in AUC0–72 h (area under the plasma drug concentration–time curve over a period of 72 hours) with increasing the mPEG surface density or the mPEG molecular weight and a linear correlation between the mPEG surface density and AUC0–72 h.ConclusionThe biodistribution study on Institute of Cancer Research (ICR) mice revealed that MTX/mPEG-g-CS NPs significantly enhanced blood circulation time in the body and decreased accumulation in liver, spleen, and lung. These results suggest the potential of the mPEG-g-CS NPs as a promising candidate for drug delivery.

Chemoenzymatic synthesis of dual-responsive graft copolymers for drug delivery: long-term stability, high loading and cell selectivity.

A series of amphiphilic graft copolymers, poly(N-propargyldiethanolamine 4,4'-dithiodibutyionate)-graft-monomethoxy poly(ethylene glycol) (PPD-g-mPEG), were designed via a chemoenzymatic method for pH and reduced glutathione (GSH) dual-responsive drug delivery. The effects of percent grafting and molecular weights of mPEG on critical micelle concentration (CMC) values, size of micelles, drug loading and dual-response were tested. The graft copolymers could easily form homogeneous spherical micelles with appropriate sizes and zeta-potentials. The micelles of PPD-g-mPEG copolymers loaded doxorubicin (DOX) in high efficiency, and showed excellent stability under physiological conditions and synergetic dual-response to weakly acidic pH and GSH. In vitro experiments confirmed that the DOX-loaded micelles could be internalized into cancer cells efficiently and release DOX over time. Furthermore, cell cytotoxicity assays indicated that the graft copolymers were non-cytotoxic to both cancerous and normal cells while the DOX-loaded micelles greatly improved the selectivity ratios between HeLa cells and HL-7702 cells. DOX-loaded micelles also avoided hemolysis of red blood cells (RBCs) effectively compared with commercialized doxorubicin hydrochloride. All these demonstrated the potential of PPD-g-mPEG as a model to create more functional dual-responsive nanocarriers for controlled drug delivery.

Control of pH- and temperature-responsive behavior of mPEG-b-PDMAEMA copolymers through polymer composition

ABSTRACTA series of poly(ethylene glycol) monomethyl ether-block-poly(2-(dimethylamino)ethyl methacrylate) (mPEG-b-PDMAEMA) diblock copolymers were synthesized using atom transfer radical polymerization to achieve controlled polymer molecular weight and narrow molecular weight distribution. The thermoresponsive properties of the mPEG-b-PDMAEMA diblock copolymers in aqueous buffered solutions were determined using UV-Visible spectroscopy and dynamic light scattering. The cloud point, a soluble-to-insoluble transition, was observed for all mPEG-b-PDMAEMA diblock copolymer solutions. Increasing either the mPEG or PDMAEMA molecular weight resulted in a decrease in observed cloud points as a function of pH and polymer concentration. Changing the mPEG molecular weight determined whether a second, higher temperature, thermal transition was observed as a function of pH and polymer concentration. Controlling the thermoresponsive properties of mPEG-b-PDMAEMA diblock copolymers through polymer composition, concentration, and pH enables the tailoring of these copolymers for applications ranging from non-viral gene delivery to use as a strengthening agent in paper.

Chemical measurements of polyethylene glycol shells on gold nanoparticles in the presence of aggregation.

Understanding and controlling the performance of engineered nanoparticle (NP) systems is greatly assisted by quantitative characterization of their coatings. Useful measurements methods have been described for NPs in liquid environment, but NP aggregation often represents a limiting factor which impairs the accuracy of techniques such as dynamic light scattering for quantification purposes. Here, the authors show how differential centrifugal sedimentation (DCS) and x-ray photoelectron spectroscopy (XPS) can provide quantitative information on the NP coating thickness, molecular conformation, and grafting density of aggregated NP samples. The authors find that thiol-terminated methoxy polyethylene glycol (mPEG) coating thickness on gold NPs increases with increasing particle size and mPEG molecular weight. The hydration of the mPEG shell was estimated by comparing the shell thickness measured in liquid by DCS and vacuum by XPS and was found to increase with the mPEG molecular weight. Finally, the authors used XPS to measure the grafting density of the mPEG molecules. This was found to depend on the mPEG molecular volume and decreased for larger mPEG molecules, suggesting that the grafting density is determined by the conformation of the mPEG molecules in liquid. This analysis provides practical measurement methods for optimizing the design of engineered NP systems and ultimately enhance and control their performance.

Evaluation of mPEG effect on the hydrophilicity and antifouling nature of the PVDF-co-HFP flat sheet polymeric membranes for humic acid removal

In this study PVDF-co-HFP flat sheet membranes were prepared by using methoxy poly(ethylene glycol) (mPEG) of three different molecular weights (550Da, 2000Da and 5000Da) to improve hydrophilicity and antifouling characteristics of the membranes. mPEG of different molecular weights were added with Poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) in N-methyl-2-pyrrolidone (NMP) to prepare the membranes by using non solvent induced phase separation (NIPS) technique. The improvements in the membrane attributes were studied under two categories viz. morphological and permeation. Field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) were used to study the morphological properties of the prepared membranes. Presence and stability of the additive (mPEG) in the prepared membranes were confirmed by using the Fourier transform infrared spectroscopy (FTIR). Permeation studies of the prepared membranes were done in the form of pure water flux (PWF) and hydraulic permeability. Equilibrium water content (EWC) and water contact angle of the prepared membranes were calculated to analyze the increase in hydrophilicity of the prepared membranes. Antifouling studies on the prepared membranes were done by using bovine serum albumin (BSA) and humic acid (HA). The modified PVDF-co-HFP membranes have shown a 50% increase in the PWF with an increase in the molecular weight of mPEG from 550Da to 5000Da. The increase in hydrophilicity and antifouling nature leads to an increased EWC, from 36.17 to 62.62. The water contact angle also decreases from 71.32° to 59.45° with an increase in the molecular weight of mPEG. Antifouling study with BSA and HA further confirms the increased antifouling nature of the prepared membranes, due to the presence of mPEG in the membranes. The proof of the same is presented in the form of flux recovery ratio, which increases from 73.07 to 87.47. The prepared membranes have shown good rejection profiles for both BSA and HA at 95% and 99%, respectively.

Biodegradable and stimuli sensitive amphiphilic graft copolymers and their sol–gel phase transition behavior

pH and temperature‐sensitive biodegradable poly(β‐aminoester)‐graft‐poly(ε‐caprolactone)‐block‐methoxy poly(ethylene glycol) (PBAE‐g‐PCL‐b‐mPEG) amphiphilic graft copolymers with different molecular weights were synthesized. The structure of these copolymers was adjusted by varying the feed ratios of ε‐caprolactone to methoxy poly(ethylene glycol)s (mPEG), amine and diacrylate monomer amounts and the molecular weight of mPEG. Aqueous solutions of these copolymers formed micelles at lower concentrations; however, the concentrated solutions showed a reversible sol–gel transition property depending on both pH and temperature changes under representative physiological conditions (pH 7.4, 37°C). The effects of the molecular weight of pH‐sensitive poly(β‐aminoester) block and mPEG group, the hydrophobic to hydrophilic block ratio (PCL/mPEG) and the concentration of the copolymer on the sol–gel transition were investigated. Proton nuclear magnetic resonance (1H NMR) and gel permeation chromatography measurements were used to characterize the structure of the synthesized copolymers. The self‐assemble behavior and critical micelle concentration of the amphiphilic copolymers were estimated in phosphate buffer solution using fluorescence spectroscopy. The gelling behavior was measured by using tube inversion method. At pH 7.4, all copolymer solutions prepared 20 wt% concentration indicated sol–gel transition with increasing temperature. In vitro degradation experiments displayed that the synthesized graft copolymers mostly degraded hydrolytically within 20 days under physiological conditions. In order to investigate the potential application of synthesized hydrogels in drug delivery, Methylene Blue was used and approximately 70% of the loaded amount was released in 120 hr. The findings indicate that obtained graft copolymers can be used as injectable biodegradable carriers for pharmaceutical drugs. Copyright © 2015 John Wiley & Sons, Ltd.

Temperature-sensitive star-shaped block copolymers hydrogels for an injection application: phase transition behavior and biocompatibility

A series of star-shaped poly(D,L-lactic-co-glycolic acid)-b-methoxy poly(ethylene glycol) (PLGA-mPEG) block copolymers with varying PLGA/mPEG block weight ratios, mPEG block length, and arm numbers were synthesized and phase transition behaviors were investigated. Phase transition characteristics, such as critical gel concentration (CGC) and critical gel temperature (CGT), were closely related to the molecular structure of the star-shaped block copolymers. The CGC was mainly determined by the balance of hydrophobic PLGA and hydrophilic mPEG block (PLGA/mPEG block ratio). The CGTs showed a stronger dependence on mPEG block length and arm number. Also, the CGTs can be adjusted by adding mPEG homopolymer additives. The weight fraction of mPEG had a stronger influence on the CGT values than molecular weight of mPEG. In addition, the MTT assay and histological observations confirmed the acceptable biocompatibility of the star-shaped block copolymer. Hence, the star-shaped PLGA-mPEG block copolymer was a promising candidate as a novel injectable gel.

Synthesis, characterization and in vitro studies of pegylated melphalan conjugates

Melphalan, a drug used for the treatment of breast, ovaries and a certain type of cancer in the bone marrow, was conjugated to linear methoxy poly (ethylene glycol) (M-PEG) of 2000 and 5000, Da. An ester linkage between polymer and drug was used in the coupling to yield a polymeric prodrug. Purified esters were characterized by Maldi-Tof and IR spectroscopy methods. The modification allowed overcoming the known melphalan aqueous solubility problem (0.1 µg/ml) leading us to obtain a polymer-drug bioconjugate more suitable for oral and parental administration. It was found that molecular weight of M-PEG is critical for the conjugates stability, aqueous solubility (80 times and 123 times higher aqueous solubility for M-PEG 2000 and M-PEG 5000, respectively), and hemolytic activity. The melphalan caused 100% hemolysis above the concentration 3.5 µg/ml in 1 h. whereas conjugate of M-PEG 2000 and M-PEG 5000 shows 81.3 ± 0.5% and 48.8 ± 1.5% hemolysis, respectively at 32 µg/ml after1 h. Further In vitro anticancer activity of melphalan and its conjugates was performed with breast cancer MCF-7 cell lines. It shows that LD50 concentration was higher 1.14 and 2 µm for M-PEG 2000 and M-PEG 5000, respectively in comparison to pure melphalan (0.74 µm). Above studies revealed improved pharmacokinetics properties upon conjugation.

Investigation on design of stable etoposide-loaded PEG-PCL micelles: effect of molecular weight of PEG-PCL diblock copolymer on the in vitro and in vivo performance of micelles

In the present study, six different molecular weight diblock copolymer of methoxy poly (ethylene glycol)-b-poly (ϵ-caprolactone) (MPEG-PCL) were synthesized and characterized and was used for fabrication of etoposide-loaded micelles by nanoprecipitation technique. The particle size and percentage drug entrapment of prepared micelles were found to be dependent on the molecular weight of PCL block and drug to polymer ratio. The maximum drug loading of 5.32% was found in micellar formulation MPEG5000-PCL10000, while MPEG2000-PCL2000 exhibited 2.73% of maximum drug loading. A variation in the fixed aqueous layer thickness and PEG surface density of micellar formulations was attributed to difference in MPEG molecular weight and interaction of PEG and PCL block of copolymer. The MPEG2000-PCL2000 micelles demonstrated poor in vitro stability among other micellar formulations, due to its interaction with bovine serum albumin and immediate release of drug from micelles. Furthermore, plain etoposide and MPEG2000-PCL2000 micelles exhibited greater extent of hemolysis, due to presence of surfactants and faster release of drug from micelles, respectively. The biodistribution studies carried out on Ehrlich ascites tumor-bearing Balb/C mice confirmed higher accumulation of etoposide-loaded micellar formulation at tumor site compared to plain etoposide due to enhanced permeability and retention effect.

Study on Primary Reaction Kinetics of Melamine Aminated Monomethoxylpoly (ethylene Glycol)

The reaction kinetics of amination of monomethoxylpoly (ethylene glycol) (mPEG) with melamine (MA) at the molar ratio of 1:1 was studied by FTIR. This amination reaction was carried out with potassium hydroxide as reaction catalyst under high-pressure conditions at different temperature (160 °C, 170 °C, 180 °C, and 190°C) for different time (2 h, 3 h, 4 h, 5 h and 6 h). A series of melamine aminated monomethoxylpoly (ethylene glycol) (MA-mPEG) were synthesized, and the long chain of polyethylene glycol ether was grafted on the amino groups of melamine by amination. The amination kinetics parameter of reaction order and the activation energy are about 1.5 and 45 KJ/mol, respectively. In addition, the grafting amination yield increased with the number average molecular weight of mPEG at the same reaction condition.

Stable dispersions of poly(ethylene glycol) methyl ether–magnetite complexes in water

We herein describe a facile synthesis of superparamagnetic magnetite ferrofluids having long-term stability in aqueous dispersions. A single-step thermal decomposition reaction of iron (III) acetylacetonate (Fe(acac)3) was carried out in the presence of poly(ethylene glycol) methyl ether (mPEG) to serve both as a reducing agent and reaction solvent. The role of number average molecular weight () of mPEG (350 and 750 g/mol) on the size and properties of the particles was investigated. Fourier-transform infrared spectrophotometry (FTIR) indicated the presence of mPEG in the polymer–magnetite complexes. According to thermogravimetric analysis (TGA), the complexes consisted of 40–66% Fe3O4, depending on the molecular weights of mPEG used. According to the transmission electron micrographs (TEM), the particles prepared in 350 g/mol mPEG exhibited the average diameter of 7.8 ± 1.4 nm, while those in 750 g/mol mPEG were 5.3 ± 1.1 nm. From photocorrelation spectroscopy (PCS) experiments, the size of 350 g/mol mPEG–magnetite complex and 750 g/mol mPEG–magnetite complex were 37.1 ± 1.0 nm and 35.1 ± 0.4 nm, respectively. According to the calculation by the Debye–Scherrer equation, the sizes of 350 g/mol mPEG–magnetite complex and 750 g/mol mPEG–magnetite complex were 7.7 and 6.6 nm, respectively. They were highly crystalline and exhibited superparamagnetic properties. They were stable in aqueous dispersions with insignificant aggregation after 6 weeks of preparing. These stable, non-toxic dispersions might be potentially used in magnetically targeted biomedical applications.

Effect of PEGylation on the Toxicity and Permeability Enhancement of Chitosan

The aim of the present work is to investigate if conditions can be devised where PEGylation of chitosan would reduce its toxicity toward the nasal mucosa while maintaining its ability to open the cellular tight junctions and, consequently, produce an enhancement of macromolecular permeability. A series of mPEG-g-chitosan copolymers with varying levels of mPEG substitution, mPEG molecular weight, and chitosan molecular weight were synthesized by grafting carboxylic acid-terminated mPEGs (Mw 1.9 and 5.0 × 10(3) g mol(-1)) to chitosans (Mw 28.9 and 82.0 × 10(3) g mol(-1)) using a NHS/EDC coupling system. The synthesized mPEG-g-chitosans were fully characterized using a number of techniques, including FT-IR, (1)H NMR, and SEC-MALLS and their physicochemical properties were analyzed by TGA and DSC. Thereafter, the conjugates were tested for their cytotoxicity and tight junction modulating property in a relevant cell model, a mucus producing Calu-3 monolayer. mPEG-g-chitosan conjugates exhibited reduced toxicity toward cells, as compared to unmodified chitosan counterparts. Furthermore, the conjugates demonstrated a dramatic effect on cell monolayer transepithelial electrical resistance (TEER) and enhancement of permeability of model macromolecules. TEER and permeability-enhancing effects, as measurable indicators of tight junction modulation, were found to be pH-dependent and were notably more pronounced than those exhibited by unmodified chitosans. This work therefore demonstrates that conditions can be contrived where PEGylation improves the toxicity profile of chitosan, while preserving its effect on epithelial tight junctions in the nose.

Synthesis and characterization of an acrylate‐copolymer‐based antistatic agent composed of a single‐ion conductive polymer electrolyte

AbstractMonomethoxy poly(ethylene glycol) acrylate (MPEGA) was synthesized through the esterification reaction of acrylic acid and methoxy poly(ethylene glycol)s (MPEGs) of different molecular weights. Then, MPEGA was copolymerized with methyl methacrylate, butyl acrylate, and β‐carboxyethyl acrylate neutralized with potassium hydroxide via conventional solution polymerization. In this way, a single‐ion conductive polymer‐electrolyte‐based antistatic agent (PEAA), in which potassium (K) ions were used as charge carriers, was obtained. The molecular structure, coordination effects between ether oxygen (EO) groups and K cations, ionic conductivity, and crystallization ability of the copolymer were characterized with Fourier transform infrared, conductivity measurements, polarizing optical microscopy, and differential scanning calorimetry, respectively. The crystallinity of the synthesized PEAA apparently decreased with the molecular weight of MPEG and the EO/K molar ratio decreasing, and this led to a corresponding enhancement of the conductivity. The dependence of the conductivity of the copolymer on temperature could be divided into different linear parts, and each was in good agreement with the Arrhenius equation. Moreover, the dependence of the conductivity on the relative humidity (RH) revealed that the PEAA could maintain high ionic conductivity (∼10−6 S/cm) even at the low RH of 10%. This implies the potential widespread application of PEAAs for the preparation of antistatic composites and especially poly(vinyl chloride)‐ and poly(methyl methacrylate)‐related composites because of their considerable miscibility. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

Design of surface-modified poly( d, l-lactide-co-glycolide) nanoparticles for targeted drug delivery to bone

Poly( d, l-lactide-co-glycolide) (PLGA) nanoparticles, modified with both alendronate and polyethylene glycol (PEG), were prepared by dialysis method without additional surfactant to evaluate the potency of the bone-targeted drug delivery. Alendronate, a targeting moiety that has a strong affinity for bone, was conjugated to PLGA polymer via carbodiimide chemistry. Monomethoxy PEG(mPEG)–PLGA block copolymers with different molecular weights of mPEG ( M n 550, 750, and 2000) were synthesized and used for a hydrophilic layer on the surface of the nanoparticles to avoid reticuloendothelial system (RES). The surface-modified PLGA nanoparticles with various ratios of alendronate and mPEG densities on their surface were evaluated by adsorption study onto hydroxyapatite (HA). It was confirmed that alendronate-modified nanoparticles had a strong and specific adsorption to HA. The amount of nanoparticles absorbed onto HA tended to be smaller when the content of alendronate was decreased and the large block length of mPEG was found to reduce the potency of alendronate.