The glucose‐responsive behavior of a block copolymer featuring boronic acid and glycine

Glucose responsive block copolymer featuring boronic acid as a glucose responsive moiety and glycine are reported. The first block is polymerized through reversible addition–fragmentation chain transfer (RAFT) polymerization and the resulting poly(N‐acryloylmorpholine)₁₁₃ (PAcM) is employed as a macro‐chain transfer agent for chain extension with pentafluorophenyl acrylate (PFPA) yielding a well‐defined PAcM₁₁₃‐block‐poly(pentafluorophenyl acrylate)₈₄ (PPFPA). The PPFPA block is then reacted with functional (3‐aminomethyl) phenyl boronic acid and glycine via post‐polymerization modification and the structure of the block copolymer is confirmed by proton nuclear magnetic resonance (NMR), ¹⁹F NMR, Fourier transform infrared, and gel permeation chromatography. By copolymerizing glycine into the polymer backbone, the relative pK_a of the block copolymer is significantly lowered. The block copolymer can self‐assemble into core–shell micelles in aqueous solution and disassemble in response to glucose at the physiological pH. Furthermore, the encapsulation and release of Nile red (NR) as a hydrophobic model drug is studied under the physiological pH. The influence of the glucose concentration on the NR release from the polymeric micelles is demonstrated. These results suggested that the glucose‐responsive poly[(AcM)₁₁₃‐b‐(3‐(aminomethyl)phenylboronic acid hydrochloride(‐co‐Gly)₈₄] block copolymer has potential applications as a glucose‐responsive polymer for insulin delivery. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 422–431     

聚(丙烯腈-甲氧基聚乙二醇单丙烯酸酯-丙烯酸锂)的制备与表征

采用乳液聚合方法制备了锂离子电池凝胶电解质用丙烯腈-甲氧基聚乙二醇(350)单丙烯酸酯-丙烯酸锂共聚物. 利用红外光谱(IR), 差示扫描量热法(DSC)对共聚物结构进行了表征. 利用倒相法制备了共聚物微孔膜, 使聚(丙烯腈-甲氧基聚乙二醇(350)单丙烯酸酯)共聚物的溶解性能得到了显著提高, 同时, 还改善了膜的收缩性. 采用交流阻抗方法测试了凝胶电解质膜在室温下的电导率, 结果表明, 该凝胶电解质具有较高的离子电导率, 能满足现有锂离子电池使用要求.     

Poly(glyceryl glycerol): A multi‐functional hydrophilic polymer for labeling with boronic acids

The synthesis of poly(glyceryl glycerol) (PGG), a polymer featuring a polyethylene oxide backbone and 1,2‐diol groups in every repeating unit, is presented. PGG was prepared by monomer‐activated ring‐opening polymerization of (dl ?1,2‐isopropylidene glyceryl) glycidyl ether, introducing a functional azido‐ or bromo‐head group to each chain. The 1,2‐diol groups, which were released by acidic deprotection, readily reacted with boronic acid derivatives, enabling the attachment of functional moieties under mild aqueous conditions. PGG was conjugated to poly(l ‐lactide) (PLLA) via azide‐alkyne cycloaddition and the resulting copolymer assembled into nanoparticles of 70 nm diameter in aqueous solution. Labeling of the PGG–PLLA particles was achieved by simple mixing with a boronic acid‐functional fluorophore. The labeling efficiency was determined by fluorescence spectroscopy to be 85.5% for boronic acid‐functional rhodamine B compared with 0.2% for plain rhodamine B. The strong interaction of PGG with boronic acids is ascribed to its polyol structure. This study demonstrates the usefulness and versatility of PGG as a hydrophilic polymer for possible biomedical applications. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55 , 1822–1830     

Synthesis of ferrocene boronic acid-based block copolymers via RAFT polymerization and their micellization,redox responsive and glucose sensing properties

Current study is focused on the synthesis of three novel diblock copolymers poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polymethyl vinyl amido phenyl boronic acid, poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-poly vinylamido phenyl boronic acid and poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polystyrene boronic acid using S-methoxycarbonylphenylmethyl dithiobenzoate as reversible addition–fragmentation chain transfer polymerization agent. The synthesized block copolymers were characterized by gel permeation chromatography, fourier transform infrared spectroscopy, ¹H nuclear magnetic resonance spectroscopy, dynamic light scattering, scanning electron microscopy and transmission electron microscopy. Detailed micellization behaviour of poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polymethyl vinyl amido phenyl boronic acid (in binary organic solvents mixture and aqueous solution) was studied. Comparative studies of micellization showed that the larger aggregates were obtained in binary organic solvents system than during dialysis in aqueous medium. The redox responsive behaviour of poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polymethyl vinyl amido phenyl boronic acid was investigated by water soluble oxidizing (Ammonium cerium nitrate) and reducing (Sodium hydrogen sulphite) agents. Glucose binding/sensing properties of poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polymethyl vinyl amido phenyl boronic acid were also explored by micellization. It was found that the increase in polarity and swelling of poly(2-methacryloyloxy)ethyl ferrocene carboxylate-b-polymethyl vinyl amidophenyl boronic acid micelles was due to the redox behaviour of ferrocene, while binding of glucose with boronic acids hydroxyls appears as unimers or small aggregates.     

Cyclodextrin solubilization of celecoxib: solid and solution state characterization

The low aqueous solubility of celecoxib (CCB) hampers its oral bioavailability and permeation from aqueous environment through biological membranes. The aim of this study was to enhance the aqueous solubility of CCB by complexation with cyclodextrin (CD) in the presence of water-soluble polymer. The effects of different CDs (αCD, βCD, γCD, 2-hydroxypropyl-β-cyclodextrin and randomly methylated β-cyclodextrin (RMβCD)) and mucoadhesive, water-soluble polymers (hydroxypropyl methylcellulose (HPMC), chitosan and hyaluronic acid) were investigated. The phase solubility profiles and CCB/CD complex characteristics were determined. RMβCD exhibited the greatest solubilizing effect of the two CDs tested. However, γCD was also selected for further investigations due to its safety profile. Addition of polymer to the aqueous CD solutions enhanced the CD solubilization. Formation of CCB/RMβCD/HPMC and CCB/γCD/HPMC ternary complexes resulted in 11 and 19-fold enhancement in the apparent complexation efficiency in comparison to their CCB/CD binary complex, respectively. The size of ternary complex aggregates in solution were determined to be from about 250 to about 350 nm. The data obtained from Fourier transform infra-red, differential scanning calorimetry and powder X-ray diffraction indicated presence of CCB/CD inclusion complexes in the solid state. Proton nuclear magnetic resonance data demonstrated that CCB was partially and totally inserted into the hydrophobic central cavities of RMβCD and γCD.     

Glucose‐Responsive Trehalose Hydrogel for Insulin Stabilization and Delivery

Effective delivery of therapeutic proteins is important for many biomedical applications. Yet, the stabilization of proteins during delivery and long‐term storage remains a significant challenge. Herein, a trehalose‐based hydrogel is reported that stabilizes insulin to elevated temperatures prior to glucose‐triggered release. The hydrogel is synthesized using a polymer with trehalose side chains and a phenylboronic acid end‐functionalized 8‐arm poly(ethylene glycol) (PEG). The hydroxyls of the trehalose side chains form boronate ester linkages with the PEG boronic acid cross‐linker to yield hydrogels without any further modification of the original trehalose polymer. Dissolution of the hydrogel is triggered upon addition of glucose as a stronger binder to boronic acid (K_b = 2.57 vs 0.48 m ⁻¹ for trehalose), allowing the insulin that is entrapped during gelation to be released in a glucose‐responsive manner. Moreover, the trehalose hydrogel stabilizes the insulin as determined by immunobinding after heating up to 90 °C. After 30 min heating, 74% of insulin is detected by enzyme‐linked immunosorbent assay in the presence of the trehalose hydrogel, whereas only 2% is detected without any additives.     

Properties of low temperature swelling hydrogels prepared with partially saponified PVA and drug release using the hydrogels

The hydrogels prepared by the crosslinking of partially saponified poly(vinyl alcohol) (PVA) which has low critical solution temperature (LCST) in water showed characteristics of swelling at low temperature and shrinkage at high temperature. The hydrogels showed repeatable swelling–shrinking behavior. The hydrogels containing release substances such as cyanocobalamin, p‐acetamidophenol, insulin and ovalbumin were prepared by dipping these aqueous solutions and the release substances were studied. Insulin and ovalbumin were not absorbed by the hydrogels when the use of partially PVA with the degrees of polymerization (DPs) of 540 were prepared, but absorbed by the hydrogels with DPs of 1860. The size of the polymer network prepared with a higher DP was suitable for the absorption of insulin and ovalbumin. In accordance with release substances, the release patterns were different. In this way, the polymer network sizes and their swelling behaviors of partially saponified PVAs were estimated. Copyright © 2003 John Wiley & Sons, Ltd.     

Encapsulation and sustained release of a model drug, indomethacin, using CO(2)-based microencapsulation

A carbon dioxide (CO(2))-based microencapsulation technique was used to impregnate indomethacin, a model drug, into biodegradable polymer nanoparticles. Compressed CO(2) was emulsified into aqueous suspensions of biodegradable particles. The CO(2) plasticizes the biodegradable polymers, increasing the drug diffusion rate in the particles so that drug loading is enhanced. Four types of biodegradable polymers were investigated, including poly(d,l-lactic acid) (PLA), poly(d,l-lactic acid-co-glycolic acid) (PLGA) with two different molar ratios of LA to GA, and a poly(d,l-lactic acid-b-ethylene glycol) (PLA-PEG) block copolymer. Biodegradable nanoparticles were prepared from polymer solutions through nonsolvent-induced precipitation in the presence of surfactants. Indomethacin was incorporated into biodegradable nanoparticles with no change of the particle size and morphology. The effects of a variety of experimental variables on the drug loadings were investigated. It was found that the drug loading was the highest for PLA homopolymer and decreased in PLGA copolymers as the fraction of glycolic acid increased. Indomethacin was predicted to have higher solubility in PLA than in PLGA based on the calculated solubility parameters. The drug loading in PLA increased markedly as the temperature for impregnation was increased from 35 to 45 degrees C. Drug release from the particles is a diffusion-controlled process, and sustained release can be maintained over 10 h. A simple Fickian diffusion model was used to estimate the diffusion coefficients of indomethacin in the biodegradable polymers. The diffusion coefficients are consistent with previous studies, suggesting that the polymer properties are unchanged by supercritical fluid processing. Supercritical CO(2) is nontoxic, easily separated from the polymers, can extract residual organic solvent, and can sterilize biodegradable polymers. The CO(2)-based microencapsulation technique is promising for the production of drug delivery devices without the use of harmful solvents.     

高选择性透过SO_2气体分离膜研究 Ⅰ.丙基乙烯基亚砜改性聚乙烯醇功能高分子的合成

本文研究聚乙烯醇与丙基乙烯基亚砜经Michael加成反应合成含亚砜基的改性聚乙烯醇功能高分子.用IR、~1H-NMR、X-射线衍射等鉴定反应产物.结果表明,随着亚砜基含量的增加聚合物的结晶性降低,而在冷水,DMSO,CH_3OH,C_2H_5OH和CH_2Cl_2中的溶解性提高.     

高选择性透过SO2气体分离膜研究 Ⅰ.丙基乙烯基亚砜改性聚乙烯醇功能高分子的合成

 本文研究聚乙烯醇与丙基乙烯基亚砜经Michael加成反应合成含亚砜基的改性聚乙烯醇功能高分子.用IR、¹H-NMR、X-射线衍射等鉴定反应产物.结果表明,随着亚砜基含量的增加聚合物的结晶性降低,而在冷水,DMSO,CH₃OH,C₂H₅OH和CH₂Cl₂中的溶解性提高.     

Oxidation of Hydroquinone By (N-Vinylpyrrolidone)-(4-Vinylpyridine) Block and Graft Copolymers

ABSTRACT

A-B Type block copolymer of N-vinylpyrrolidone (NVP) and 4-vinylpyridine (VPy) [poly(NVP-b-VPy) and graft copolymers of VPy onto copolymers of NVP with 4-vinylbenzyl N,N-diethyldithiocarbamate (VBDC) [poly(NVP-g-VPy) were synthesized by the iniferter method. the compatibility between NVP and VPy units in the copolymers was evaluated from the glass transition temperature of these copolymers. Hydroquinone was then oxidized by the synthesized NVP-VPy copolymers-Cu(II) complex catalysts. the influence of the distribution of each monomer unit in copolymers on the catalytic activity was studied by comparing the activity of these copolymers. the catalytic activity of these copolymers increased in the order: NVP-VPy blend polymer, poly(NVP-b-VPy), poly(NVP-g-VPy), random copolymer [poly(NVP-ran-VPy)]. This order parallels the compatibility between NVP units and VPy units in these copolymers.     

Substitution and condensation reactions with poly(anilineboronic acid): reactivity and characterization of thin films

Poly(anilineboronic acid) thin films are treated under various conditions to achieve substitution or condensation reactions involving the boronic acid moiety. These reactions are studied with polarization modulated infrared reflection absorption spectroscopy, cyclic voltammetry, and UV-vis spectroscopy. The results suggest the single-step formation of substituted polyanilines, such as poly(hydroxyaniline), halogenated polyanilines, and mercury chloride-substituted polyaniline. A condensation reaction of poly(anilineboronic acid) with cis-diol compounds in aqueous solution, as well as with phenylenebisboronic acid and salycilamide in THF, indicates the formation of boronic esters. The latter reactions appear to be a good entry point for the formation of complex or supramolecular polymer structures.     

Synthesis of Molecularly Imprinted Polymers for Nevirapine by Dummy Template Imprinting Approach

Nevirapine (NVP) and its structurally related analogs including nicotinamide (NAM), benzamide (BZM) and benzophenone (BZP) were used as templates in the synthesis of molecularly imprinted polymers for NVP. Molecular modeling was used to estimate binding energy of the complex formation between methacrylic acid (MAA) monomer and the selected templates, while equilibrium binding studies were applied to evaluate the polymer binding efficiency. The data indicated that NAM is the best candidate to prepare MIPs for retaining NVP due to a relatively similar binding energy between the NVP–MAA and NAM–MAA complex. The NAM-imprinted polymer showed a high binding affinity and selectivity toward NVP. When the polymer was applied as a sorbent in solid-phase extraction of NVP from human plasma, high recovery and reproducibility were obtained.     

Spherical phospholipid polymer hydrogels for cell encapsulation prepared with a flow-focusing microfluidic channel device

To prepare spherical polymer hydrogels, we used a flow-focusing microfluidic channel device for mixing aqueous solutions of two water-soluble polymers. Continuous encapsulation of cells in the hydrogels was also examined. The polymers were bioinspired 2-methacryloyloxyethyl phosphorylcholine polymer bearing phenyl boronic acid groups (PMBV) and poly(vinyl alcohol) (PVA), which spontaneously form a hydrogel in aqueous medium via specific molecular complexation upon mixing, even when they were in cell culture medium. The microfluidic device was prepared with polydimethylsiloxan, and the surface of the channel was treated with fluoroalkyl compound to prevent sticking of the polymers on the surface. The microfluidic channel process could control the diameter of the spherical hydrogels in the range of 30-90 μm and generated highly monodispersed diameter spherical hydrogels. We found that the polymer distribution in the hydrogel was influenced by the PVA concentration and that the hydrogel could be dissociated by the addition of d-sorbitol to the suspension. The single cells could be encapsulated and remain viable in the hydrogels. The localized distribution of polymers in the hydrogel may provide an environment for modulating cell function. It is concluded that the spontaneous hydrogel formation between PMBV and PVA in the flow-focusing microfluidic channel device is applicable for continuous preparation of a spherical hydrogel-encapsulating living cell.     

Mesoscopic and microscopic investigation on poly(vinyl alcohol) hydrogels in the presence of sodium decylsulfate

The structure of poly(vinyl alcohol) (PVA) hydrogels formed as a result of freeze/thaw treatments of aqueous solutions of the polymer (11 wt % PVA) in the freshly prepared state is analyzed through the combined use of small (SANS) and ultrasmall (USANS) angle neutron scattering techniques. The structure of these hydrogels may be described in terms of polymer rich regions, with dimensions of the order of 1-2 microm, dispersed in a water rich phase, forming two bicontinuous phases. The PVA chains in the polymer rich phase form a network where the cross-linking points are mainly crystalline aggregates of PVA having average dimensions of approximately 45 A. The structural organization of freeze/thaw PVA hydrogel membranes does not change either after rehydration of dried gels or in the presence of a tensile force. Finally, addition of surfactant micelles inside the gel provides a formulation with both hydrophobic and hydrophilic regions, which demonstrates the potential of the system for drug delivery. Both SANS and EPR measurements show that sodium decylsulfate (C10OS) micelles do not significantly interact with the PVA gel. Variation of the gel structure by the number of freeze/thaw cycles should modulate the rate of release of an active constituent, for example, in a dermal patch.     

Synthesis of Molecularly Imprinted Polymers for Nevirapine by Dummy Template Imprinting Approach

Nevirapine (NVP) and its structurally related analogs including nicotinamide (NAM), benzamide (BZM) and benzophenone (BZP) were used as templates in the synthesis of molecularly imprinted polymers for NVP. Molecular modeling was used to estimate binding energy of the complex formation between methacrylic acid (MAA) monomer and the selected templates, while equilibrium binding studies were applied to evaluate the polymer binding efficiency. The data indicated that NAM is the best candidate to prepare MIPs for retaining NVP due to a relatively similar binding energy between the NVP–MAA and NAM–MAA complex. The NAM-imprinted polymer showed a high binding affinity and selectivity toward NVP. When the polymer was applied as a sorbent in solid-phase extraction of NVP from human plasma, high recovery and reproducibility were obtained.

     

Unusual salt stability in highly charged diblock co-polypeptide hydrogels

The stability and properties of dilute solution hydrogels, synthesized by transition metal mediated polymerization of amino acid N-carboxyanhydrides (NCAs), have been studied in deionized (DI) water as well as various ionic media. These hydrogels are diblock amphiphilic copolymers of hydrophilic, charged segments of poly(l-lysine HBr) or poly(l-glutamic acid sodium salt), and helical, hydrophobic segments of poly(l-leucine). While many of these samples are able to form strong gels in deionized water at polymer concentrations as low as 0.25 wt %, stability in salt or buffer solutions was found to be only achieved at moderately higher polymer concentrations ( approximately 3.0 wt %). We have adjusted relative copolymer compositions and molecular weights to optimize hydrogel strength and polymer solubility in salt concentrations up to 0.5 M NaCl, as well as in cell growth media and aqueous buffers of varying pH. These materials are unique since they do not collapse in high ionic strength media, even though gel formation is contingent upon the presence of highly charged polyelectrolyte segments. The remarkable properties of these hydrogels make them excellent candidates for use as scaffolds in biomedical applications, such as tissue regeneration.     

顺丁烯二酸β-环糊精酯-N-乙烯基吡咯烷酮水溶性聚合物的合成及其吸附疏水性药物的研究

以γ射线引发顺丁烯二酸β-环糊精酯(CDM)和N-乙烯基吡咯烷酮(NVP)发生自由基链式反应,制备了顺丁烯二酸β-环糊精酯-N-乙烯基吡咯烷酮聚合物(CDM-NVP).优化后的CDM-NVP聚合物的合成条件为: CDM∶NVP为1∶0.7(w/w, CDM 3.6 g 和 NVP 2.52 g),辐照剂量4 kGy,DMF溶液用量为20 mL.在此条件下制备聚合物的产率为84%,重均分子量为20 kDa.结果表明,此聚合物可以同纳他霉素(NM)和多菌灵(MBC)形成稳定复合物.研究了复合物抑菌活性,测定了其表观稳定常数.利用紫外光谱、核磁图谱和相溶解度对药物复合物进行结构表征.303 K下,NM-CDM-NVP和 MBC-CDM-NVP复合物的表观稳定系数分别为12988.54和865.94 L/mol.抑菌实验结果表明,NM-CDM-NVP和 MBC-CDM-NVP复合物可以显著提高NM和MBC的溶解性和抑菌活性.     

Gold nanoparticles as structurizing agents for the formation of hybrid nanocomposites

Two types of transparent gold-containing organo-inorganic hybrid gels (polymer nanocomposites) in which gold nanoparticles (nano-Au) are efficient species were synthesized. The stage of hybrid gel formation is preceded by the in situ chemical reduction of chloroauric acid in an aqueous solution of the synthetic linear polymer (polyvinyl alcohol or poly(N-vinylpyrrolidone)) affording a nano-Au. The presence of ultradispersed gold particles in the obtained nanocomposites was confirmed by UV-Vis spectroscopy and electron microscopy. The loss of solubility of the films in water confirms the formation of a gel network. The size of the gold particles and characteristics of the hybrid gel change depending on the molecular weight of the polymer. The interaction of the macromolecules and growing particles mainly determines the diameter and number of particles of the inorganic phase, whereas the content of chloroauric acid affects these parameters to a less extent. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 329–336, February, 2008.     

Thermally reversible polymer gels for biohybrid artificial pancreas

As an approach to replacing islets of Langerhans in an implanted biohybrid artificial pancreas, thermally reversible polymers based on N-isopropylacrylamide were synthesized and then evaluated as an extracellular matrix for islets in an immunoprotecting membrane pouch. A high molecular weight poly(N-isopropylacrylamide-co-acrylic acid (2 mole % in feed)) demonstrated gelation at 37°C and became a solution below 30°C. This polymer exhibited minimum syneresis (water separation) upon gelation from a solution state when the temperature was raised from room temperature to 37°C, while poly(N-isopropylacrylamide) exhibited considerable syneresis under the same conditions. These properties influence the efficiency of islet entrapment. The copolymer was able to entrap rat islets almost 100%, but the homopolymer entrapped less than 50%. The static insulin secretion of the islets in the copolymer matrix at high glucose concentration (16.5 mM) was comparable to that of control islets, however, the entrapped islets showed prolonged viability in vitro. These results indicate the potential of developing a rechargeable biohybrid pancreas using thermally reversible polymer gels.