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Hollow hybrid nanogels were prepared first by the coassembly of the citric acid-coated superparamagnetic iron oxide nanoparticles (SPIONs, 44 wt %) with the graft copolymer (56 wt %) comprising acrylic acid and 2-methacryloylethyl acrylate units as the backbone and poly(ethylene glycol) and poly(N-isopropylacrylamide) as the grafts in the aqueous phase of pH 3.0 in the hybrid vesicle structure, followed by in situ covalent stabilization via the photoinitiated polymerization of MEA residues within vesicles. The resultant hollow nanogels, though slightly swollen, satisfactorily retain their structural integrity while the medium pH is adjusted to 7.4. Confining SPION clusters to such a high level (44 wt %) within the pH-responsive thin gel layer remarkably enhances the transverse relaxivity (r2) and renders the MR imaging highly pH-tunable. For example, with the pH being adjusted from 4.0 to 7.4, the r2 value can be dramatically increased from 138.5 to 265.5 mM(-1) s(-1). The DOX-loaded hybrid nanogels also exhibit accelerated drug release in response to both pH reduction and temperature increase as a result of the substantial disruption of the interactions between drug molecules and copolymer components. With magnetic transport guidance toward the target and subsequent exposure to an alternating magnetic field, this DOX-loaded nanogel system possessing combined capabilities of hyperthermia and stimuli-triggered drug release showed superior in vitro cytotoxicity against HeLa cells as compared to the case with only free drug or hyperthermia alone. This work demonstrates that the hollow inorganic/organic hybrid nanogels hold great potential to serve as a multimodal theranostic vehicle functionalized with such desirable features as the guidable delivery of stimuli-mediated diagnostic imaging and hyperthermia/chemotherapies.

Polymeric vesicles produced by spontaneous self-association of poly(acrylic acid-co-distearin acrylate) (poly(AAc-co-DSA)) with varying ratios of AAc and DSA units in aqueous solution of pH 5.0 exhibit the pH-regulated drug release behavior. Through the electrostatic interaction with ionized AAc residues, doxorubicin (DOX) molecules can be highly accommodated onto either the inner or outer surfaces of vesicles when the pH is adjusted from 5.0 to 7.4. The extent of DOX encapsulation is dependent largely on the structural transition of vesicles in response to the pH change. While the pH-evolved drug release profile varies to some extent with the distribution of DOX molecules within vesicles, the drug release from vesicles is accelerated significantly via the disruption of the electrostatic interaction of DOX species with ionized AAc moieties at pH 5.0. The DOX-loaded polymeric vesicles show promoted cellular uptake and cytotoxicity comparable to free DOX for HeLa cells. This indicates that they are probably taken up by the cells via the lipid raft-mediated endocytosis.

A facile approach of forming stable polymeric complexes by the two-stage phase transition of the graft copolymer comprising poly(acrylic acid) (PAAc) as the backbone and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts in water was illustrated. Rather loose and hydrated polymeric aggregates with a characteristic hydrophobic multicore structure, achieved by the first-stage thermally induced phase transition of PNIPAAm grafts, underwent the core structure rearrangement (including multicore fragmentation and fusion) upon the second-stage dehydration of mPEG grafts at 90 °C. This was followed by hydrogen-bond pairings of mPEG and PNIPAAm chain segments with unionized AAc residues acting as an effective protective shell against potential hydration of the hydrophobic inner cores during the annealing process. The polymer complexes thus obtained show surprisingly enhanced hydrophobicity of inner cores at 25 °C in water and excellent stability of the morphological structure in response to the temperature disturbance.

Shell cross-linked (SCL) assemblies are prepared from the thermally induced three-layered, onion-like micelles of graft copolymers comprising acrylic acid (AAc) and 2-methacryloylethyl acrylate (MEA) as the backbone units and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts via radical polymerization of the MEA residues within the AAc-rich interfacial layers in the aqueous phase of pH 5.0 at 60 °C. The resulting nanosized SCL assemblies exhibit versatile structural regulations in a fully reversible manner in response to changes in pH and temperature. At 20 °C, SCL assemblies retain the morphology of vesicle-like hollow microspheres with pH-controlled water influx and particle size. At pH 7.0, SCL assemblies remain invariant in both vesicular structure and size irrespective of the temperature increase beyond the coil-to-globule phase transition of PNIPAAm grafts occurring primarily in a highly individual manner. When the temperature increases from 20 to 60 °C at pH 5.0, the hollow particle size is greatly reduced, accompanied by the development of hydrophobic, impermeable PNIPAAm lumens attached to the inside surfaces of the interfacial gel layers. In addition, SCL assemblies undergo a dramatic thermally induced transformation from the vesicle-like to micelle-like morphology by virtue of yielding hydrophobic PNIPAAm inner cores at pH 3.0. The thermally evolved morphology of SCL assemblies is governed by the vesicle structure in response to the effect of pH on the AAc ionization within the interfacial gel layers at ambient temperature.

Two graft copolymers comprising acrylic acid (AAc) and 2-methacryloylethyl acrylate (MEA) units as the backbone and either poly(N-isopropylacrylamide) (PNIPAAm) alone or both PNIPAAm and monomethoxypoly(ethylene glycol) (mPEG) as the grafts were synthesized. These copolymers in the aqueous phase (pH 5.0) underwent thermally induced self-assembly into micelles. For the copolymer containing PNIPAAm grafts only, extensive interactions between un-ionized AAc residues and PNIPAAm segments occurred, thereby rendering polymer backbones partially embedded within the hydrophobic cores of thermally induced micelles. This then led to bulk (core/shell) cross-linking of micelles upon radical polymerization of the MEA units within the micellar assemblies in the aqueous phase. By contrast, with mPEG being incorporated into the copolymer, association of the backbones with PNIPAAm is greatly retarded. As a result, three-layer onion-like polymeric micelles consisting of hydrophobic PNIPAAm cores surrounded by AAc-rich shel...

Porous PMMA/Na + –montmorillonite (MMT) cation-exchange membranes were successfully prepared by entrapment method in this study. One approach (simple mixing) was to mix commercial PMMA polymer with Na + –MMT clays in solvent for membrane preparation (Membrane A). The other approach (emulsion polymerization) was to synthesize the PMMA/Na + –MMT polymer composite via emulsion polymerization first, followed by membrane casting (Membrane B for Kunipia F clays and Membrane C for PK-802 clays). Membrane morphology and properties were characterized. The thermogravimetric analysis (TGA) verified the near complete incorporation of feed Na + –MMT clays in the PMMA/Na + –MMT composite membranes, while X-ray diffractograms (WXRD) exhibited the slightly enlarged interlayer spacing of Na + –MMT. The range of cation-exchange capacity (CEC) was 9–32 μequiv./47 mm disc. For batch cationic dye adsorption, the best performance was achieved by Membrane B with feed Na + –MMT/MMA (M/P) ratio (w/w) = 0.5 and Membrane C with feed M/P = 0.6, where about 95% Methyl violet adsorption was attained in 2 h. The optimal desorption solution was 1 M KSCN in 80% methanol and its related dye desorption efficiency was 92%. In the flow process using one piece of 47 mm disc of Membrane B (M/P = 0.5), dye solution was recirculated for 6 h and ≥85% dye could be removed. Higher than 94% of dye was desorbed at 1 or 4 mL/min, and the membrane regenerability was proved by successfully performing three consecutive cycles.

The effects of SDS on the structural changes of the thermally induced polymeric micelles from a graft copolymer comprising poly(acrylic acid) (PAAc) as the backbone and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts in aqueous solution are studied. At low temperature, SDS micelles form via the hydrophobic association of SDS molecules with the PNIPAAm grafts at a critical aggregation concentration of SDS (cac(SDS)) much lower than its critical micelle concentration. Consequently, the critical aggregation temperature of the graft copolymer is elevated. The corresponding structure of the thermally induced polymeric micelles is characterized by an abrupt reduction in the particle size and an increased tendency toward formation of the monocore structure with a more compact and hydrophobic PNIPAAm microdomain being developed. On the other hand, upon the polymeric micelle formation at high temperature, the copolymer-bound SDS micelle structure is disrupted and the dissociated SDS molecules migrate to the core-shell interface with their alkyl chains residing in the liquidlike region of the hydrophobic PNIPAAm microdomain. The correlation between the polymeric particles and copolymer-bound micelles is further substantiated by showing the change of the colloidal particle size in response to changes in cac(SDS) via adjusting the pH of the aqueous copolymer/SDS solutions.

Graft copolymers comprising poly(acrylic acid) (PAAc) as the backbone and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts were prepared and characterized. These copolymers with the AAc residues in the negatively charged state underwent self-assembling into large polymeric aggregates in water in the range 32−35 °C due to the formation of the multicore structure (comprising several solidlike hydrophobic PNIPAAm cores surrounded by the liquidlike interfacial layers) and the intercore PEG connections. These rather labile intercore PEG connections were partially destroyed due to the continual dehydration and solidification of the liquidlike interfacial layers with increasing temperature, thereby leading to fragmentation of the original aggregates into smaller particles with the more distinct core/shell structure. The final particle size was virtually governed by the structure of the hydrophobic PNIPAAm microdomains in response to the effects of the PNIPAAm conce...

Amphiphilic graft copolymers comprising monomeric units of methoxy poly(ethylene glycol) (mPEG)-acrylate, 2-hydroxyethyl methacrylate (HEMA)–cholesterol conjugates and HEMA were synthesized and their properties characterized. The value of the critical micelle concentration (CMC) for these copolymers is linearly proportional to the ratio of the number of mPEG–acrylates to that of the HEMA–cholesterol conjugates per macromolecule (NPEG/Nc), which is the most important parameter which influences the formation of polymeric micelles. The latter show excellent colloidal stability and their sizes decrease with increasing CMC. Based on the quenching of pyrene fluorescence, the relatively high levels of the loading capacity of pyrene are attributed to the elevated hydrophobicity of the micelle core. The loading capacity of pyrene decreases with increasing CMC. The weight-average partition coefficient for pyrene in polymeric micelles increases with increasing polymer concentration because more micelles are available for accommodating pyrene. Copyright © 2004 Society of Chemical Industry

In this study, dextran hydrogels were obtained by free radical copolymerization of methacrylated dextran with acrylic acid (AAc) in aqueous solution. The fractions of dissociation of AAc units within hydrogel in response to changes in pH and ionic strength of external aqueous solution were determined by FTIR-ATR spectroscopy. The influence of small ion concentration within hydrogel on the dissociation constant of AAc follows the Debye–Huckel behavior. Based on the results from the FTIR-ATR measurements, the total ion concentration difference inside and outside the hydrogel was determined according to the Donnan equilibrium theory, taking account of the counterion condensation effect quantitatively. The swelling response of hydrogels to changes in external pH and ionic strength was governed mainly by the ionic osmotic pressure due to the accumulation of diffusible ions within hydrogels. The energy balance between the osmotic and elastic retractile responses indicates the non-Gaussian behavior of elastically effective subchains with increasing swelling.

In this study, pH-responsive dextran hydrogels were prepared by radical copolymerization of methacrylated dextran (MA-dextran) with acrylic acid (AAc) in aqueous solution, using ammonium peroxydisu...

Dextran hydrogels were obtained by radical copolymerization of methacrylated dextran (MA-dextran) with acrylic acid (AAc) using ammonium peroxydisulfate (APS) and N,N,N′,N′-tetramethylethylenediamine (TMEDA) as an initiation system in an aqueous solution. The AAc content in hydrogels was determined by FTIR. Copolymerization of MA-dextran with AAc increased the cross-linking density of hydrogels by the bridging effect of AAc and, to a certain extent, facilitated the formation of hydrogels from MA-dextran with a low degree of MA substitution (DS). For hydrogels with a low DS (5.9), the swelling at pH 7.4 initially decreased and then increased with increasing AAc. The swelling of hydrogels with high DS (11.4 and 22.4) increased gradually with AAc. This discrepancy was explained by the differences in the chemical potentials of water outside and inside of the hydrogels as a function of AAc. Further increases of AAc, however, led to a reduction in polymerization conversion and even incomplete formation of hydrogel. The reduction in polymerization yield was primarily a consequence of the pH reduction and salt formation of AAc with TMEDA.

pH-Sensitive dextran hydrogels were prepared by free radical polymerization of methacrylate derivatized dextran, acrylic acid and N-t-butylacrylamide. Incorporation of acrylic acid in hydrogels was confirmed by Fourier transform infrared spectroscopy. The pH-dependent swelling of hydrogels was strongly influenced by the acrylic acid content, conjugation degree of methacrylate moiety with dextran and modified dextran concentration. Intermolecular polymerization that occurred to a greater extent with a lower degree of conjugation of methacrylate and/or higher concentration of modified dextran effectively increased the network density of hydrogels. An increase of acrylic acid reduced the enzymatic degradability of pre-swollen hydrogels by dextranase, although the increased equilibrium swelling was observed.

Synthesis of Temperature/pH-Sensitive Hydrogels Containing Disulfide Linkages as Cross-Links and Their Characterization

Poly(ether sulfone) hollow fibers modified with various polysaccharides were used to immobilize Cibacron Blue 3GA for affinity adsorption. Characterization of modified hollow fibers with respect to their activation using ethylene glycol diglycidyl ether, conjugation with polysaccharides, and immobilization with Cibacron Blue 3GA indicates that the surface modification was successfully achieved. This work also studied the adsorption behavior of lysozyme onto immobilized Cibacron Blue 3GA using the polysaccharide-modified fibers as solid supports. The optimal adsorption capacity was observed from the hollow fibers conjugated with hydroxyethyl cellulose or dextran derivative and with high density of immobilized Cibacron Blue 3GA. Moreover, the effect of temperature on lysozyme adsorption was investigated. The results show that the lysozyme-ligand binding on the polysaccharide-modified hollow fibers tends to be endothermic.

By using different spacer arms to immobilize Cibacron Blue 3GA onto regenerated cellulose membrane discs, this work investigated their effects on ligand density and corresponding lysozyme adsorption. When EGDGE alone was adopted as a spacer arm, using 0.1 M EGDGE without the formation of liquid film in its reaction with the membrane disc led to higher adsorption capacities. When EGDGE was combined with another reagent with two end functional groups as a spacer arm, EGDGE + 1,4-diaminobutane performed better in both ligand density and adsorption capacity. In addition, the ligand densities using the combinations of EGDGE with another reagent were generally lower than those from EGDGE alone, whereas the ligand utilization percentages were higher. Moreover, adding a spacer arm did not affect the binding strength between lysozyme and Cibacron Blue 3GA, regardless of the type of spacer arms and their length, and the reaction condition.

Amphiphilic graft copolymers of alkyl methacrylates, methoxy poly(ethylene glycol) (PEG) acrylate, and acrylic acid were synthesized by free radical polymerization. PEG graft copolymers with respect to structure, composition, and average molecular weight were characterized by FT-IR, 1 H NMR, and GPC. The critical micelle concentration and molar mass of the polymeric micelles were determined by fluorescence spectroscopy using pyrene as the fluorescence probe and static laser light scattering, respectively. The formation of polymeric micelles was influenced by the balance of hydrophobicity and hydrophilicity and other factors such as molecular weight of the copolymer products. The molar mass of polymeric micelles increased with mole content of hydrophobic comonomers. Loading capacity and weight average partition coefficient for the pyrene molecules into polymeric micelles were estimated via fluorescence quenching by Cu 2+ . Fluorescence quenching studies of pyrene indicated that a loose structure of micelles was formed from the graft copolymer containing high content of hydrophilic monomethoxy poly(ethylene glycol) (mPEG) and acrylic acid.

pH-Sensitive dextran hydrogels were prepared by activation of dextran (T-70) with 4-nitrophenyl chloroformate, followed by conjugation of the activated dextran with 4-aminobutyric acid and cross-linking with 1,10-diaminodecane. The cross-linking efficiencies determined by mechanical measurements were in the range of 52-63%. Incorporation of carboxylpropyl groups in dextran hydrogels led to a higher equilibrium and faster swelling under high pH conditions. The swelling reversibility of hydrogels was also observed after repeated changes in buffers between pH 2.0 and 7.4. The slow rates of swelling and deswelling in response to changes in pH were attributed to the hydrophilic nature of dextran and formation of hydrogen bonds between the hydroxyl groups of dextran with water molecules. The pronounced effect of carboxylic acid content on degradation of hydrogels was observed after 4 h of incubation with dextranase and the influence significantly decreased after exposure to the enzyme for 8 h. The mechanism of bulk degradation of hydrogels under high swelling extent was substantiated using Coomassie blue protein assay. The release rate of bovine serum albumin from hydrogels was primarily determined by the swelling extent. The release rate was further enhanced by addition of dextranase in buffer solutions.

Amphiphilic graft copolymers comprising monomeric units of stearyl methacrylate, methyl acrylate, acrylic acid and poly(ethylene glycol) acrylate were synthesized and their properties in aqueous systems characterized. The structures of these copolymers were analysed by Fourier transform infra-red and nuclear magnetic resonance spectroscopies while their molecular weights were estimated by static light scattering. The study of critical micelle concentrations and micellar sizes indicated that the formation of micelles is primarily determined by the hydrophobic/hydrophilic properties of these copolymers. Encapsulation of pyrene (as a drug model) into the micelles was found to be dependent on their stearyl methacrylate content. These copolymers also exhibited a sustained release pattern for pyrene in aqueous solutions and might indicate their future applications as potential drug delivery systems.

Dual stimuli-responsive hollow nanogel spheres serving as an efficient intracellular drug delivery platform were obtained from the spontaneous coassociation of two graft copolymers into the vesicle architecture in aqueous phase. Both copolymers comprise acrylic acid (AAc) and 2-methacryloylethyl acrylate (MEA) units as the backbone and either poly(N-isopropylacrylamide) (PNIPAAm) alone or both PNIPAAm and monomethoxypoly(ethylene glycol) (mPEG) chain segments as the grafts. The assemblies were then subjected to covalent stabilization within vesicle walls with ester-containing cross-links by radical polymerization of MEA moieties, thereby leading to hollow nanogel particles. Taking the advantage of retaining a low quantity of payload within polymer layer-enclosed aqueous chambers through the entire loading process, doxorubicin (DOX) in the external bulk phase can be effectively transported into the gel membrane and bound therein via electrostatic interactions with ionized AAc residues and hydrogen-bond pairings with PNIPAAm grafts at pH 7.4. With the environmental pH being reduced (e.g., from 7.4 to 5.0) at 37 °C, the extensive disruption of AAc/DOX complexes due to the reduced ionization of AAc residues within the gel layer and the pronounced shrinkage of nanogels enable the rapid release of DOX species from drug-loaded hollow nanogels. By contrast, the drug liberation at 4 °C was severally restricted, particularly at pH 7.4 at which the DOX molecules remain strongly bound with ionized AAc residues and PNIPAAm grafts. The in vitro characterizations suggest that the DOX-loaded hollow nanogel particles after being internalized by HeLa cells via endocytosis can rapidly release the payload within acidic endosomes or lysosomes. This will then lead to significant drug accumulation in nuclei (within 1 h) and a cytotoxic effect comparable to free drug. This work demonstrates that the novel DOX-loaded hollow nanogel particles show great promise of therapeutic efficacy for potential anticancer treatment.

Graft copolymer comprising acrylic acid (AAc) units as the backbone and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts undergoes phase transition and supramolecular assembly into colloidal particles in water upon the thermally induced hydrophobic association. The structural characteristics of the polymeric assemblies made from the graft copolymer in water are strongly dependent on the copolymer concentration and the way that the copolymer solution is subjected to heating from 25 degrees C to the phase transition region (occurring in the range 30 approximately 35 degrees C). The resultant assemblies are characterized by forming hydrophobic PNIPAAm regions with the multicore architecture and intercore connections. Interesting enough, these colloidal systems obtained from the copolymer solutions at different concentrations (10.0 and 1.0 mg/mL) and heating methods (fast and slow heating) exhibit very different structural responses when subjected to further temperature increase (from 30 approximately 35 to 60 degrees C). The mutual interactions among the components (PAAc backbone and PNIPAAm and mPEG grafts) of the copolymer were shown to play a crucial role in the evolution of the ultimate assembly structure. A molecular packing model was proposed to illustrate the mechanisms of the thermally induced structural transformation processes for the amphiphilic graft copolymer in water.

In this study, pH-responsive inulin hydrogels were prepared by radical copolymerization of methacrylated inulin (MA-inulin) with acrylic acid (AAc) in aqueous solution using ammonium peroxydisulfate (APS) and N,N,N',N'-tetramethylethylenediamine (TMEDA) as an initiation system. The AAc content in hydrogels was evaluated by FTIR spectroscopy. The covalent bridging of AAc among MA moieties of MA-inulins was observed by a significant increase in the effective network density of hydrogels and further confirmed by TGA studies. While, at a low content of AAc, the hydration of hydrogels at pH 7.4 decreased owing to the increased crosslinking density, the swelling subsequently increased with further increasing AAc as a consequence of the increased ionic osmotic pressure within hydrogels. The change in swelling of hydrogels in response to pH change between 7.4 and 2.2 was therefore enlarged when the AAc content increased.

Native chymotrypsin and its polyethylene glycol (PEG) conjugates, obtained using the succinimidyl carbonate of methoxy-PEG (SC-PEG) as the amino group modifying reagent, were tested for their activity toward several low and high molecular weight substrates. Tripeptide and tetrapeptide p-nitroanilides either as N alpha-benzyloxycarbonyl derivatives or attached via their N-terminals to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers or to PEG, as well as the proteins albumin and azoalbumin, were used as substrates. Extensively modified chymotrypsin bearing on average of 14 PEG chains per chymotrypsin molecule (PEG14CHT) and a moderately modified one containing 10 PEG chains (PEG10CHT) both degraded the low molecular weight p-nitroanilides at rates comparable to, and in the case of PEG10CHT, greater than, the rates exhibited by the native enzyme. Synthetic high molecular weight substrates and azoalbumin were also degraded by the PEG-modified enzymes. However, rates of such enzymatic reactions were lower for the PEG-enzymes than for the native one. Native albumin, as compared to azoalbumin, resisted degradation by both PEGCHTs yet was readily digested by the native chymotrypsin. The results obtained indicate that substrate-size-dependent specificity of PEG-modified enzymes cannot be explained solely by steric hindrance considerations. The decreased activity of PEG-enzymes toward protein substrates is consistent with the well-documented ability of PEG to exclude proteins from its surroundings and with the influence of protein unfolding on the susceptibility to degradation.