Study of pH/temperature dual stimuli‐responsive nanogels with interpenetrating polymer network structure

Nanogels with interpenetrating polymer network (IPN) structure based on poly(N‐isopropylacrylamide) (PNIPAM) and poly(acrylic acid) (PAA) were synthesized by in situ polymerization of acrylic acid and N, N′‐methylenebisacrylamide within the PNIPAM nanogels. Their IPN structure was confirmed using transmission electron microscopy after staining by uranyl acetate. The temperature‐ or pH‐dependent hydrodynamic diameters measured using dynamic laser light scattering show that the IPN nanogels have pH and temperature dual stimuli‐responsive properties. As compared to previously reported pH/temperature dual stimuli‐responsive nanogels, these IPN nanogels have the advantage of less mutual interference between the temperature‐responsive and pH‐responsive components, which is beneficial for their applications in controlled drug release and sensors. The temperature‐ and pH‐triggered volume phase transition mechanisms of the IPN nanogels were tested by probing the microenvironment change of their PNIPAM and PAA chains upon phase transition using infrared (IR) absorption spectra measured at different pH values and IR difference spectra obtained by subtracting the IR spectrum obtained before temperature‐induced phase transition from that obtained after phase transition. Copyright © 2012 Society of Chemical Industry     

Synthesis and properties of carboxymethyl cellulose‐graft‐poly(acrylic acid‐co‐acrylamide) as a novel cellulose‐based superabsorbent

A new cellulose‐based superabsorbent polymer, carboxymethyl cellulose‐graft‐poly(acrylic acid‐co‐acrylamide), was prepared by the free‐radical grafting solution polymerization of acrylic acid (AA) and acrylamide (AM) monomers onto carboxymethyl cellulose (CMC) in the presence of N,N′‐methylenebisacrylamide as a crosslinker with a redox couple of potassium persulfate and sodium metabisulfite as an initiator. The influences of reaction variables such as the initiator content, crosslinker content, bath temperature, molar ratio of AA to AM, and weight ratio of the monomers to CMC on the water absorbency of the carboxymethylcellulose‐graft‐poly(acrylic acid‐co‐acrylamide) copolymer were investigated. The copolymer's structures were characterized with Fourier transform infrared spectroscopy. The optimum reaction conditions were obtained as follows: the bath temperature was 50°C; the molar ratio of AA to AM was 3 : 1; the mass ratio of the monomers to CMC was 4 : 1; and the weight percentages of the crosslinker and initiator with respect to the monomers were 0.75 and 1%, respectively. The maximum water absorbency of the optimized product was 920 g/g for distilled water and 85 g/g for a 0.9 wt % aqueous NaCl solution. In addition, the superabsorbent possessed good water retention and salt resistance. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 1382–1388, 2007     

Preparation of stimuli‐responsive nanogels of poly [2‐(dimethylamino) ethyl methacrylate] by heterophase and microemulsion polymerization using gamma radiation

Poly [2‐(dimethylamino) ethyl methacrylate], PDMAEMA, was synthesized by heterophase polymerization at 70°C using sodium dodecylsulfate (SDS) as stabilizer and potassium persulfate (KPS) as the initiator. Conversions were 60%, polymer content 18%, and intensity average particle diameter, D_p, 32 nm. γ‐rays irradiation of PDMAEMA nanolatexes and DMAEMA/H₂O/SDS microemulsions using ethyleneglycol dimethacrylate produced nanogels responding to temperature and pH. Nanogels shrinked as temperature increased, swelled excessively in acidic solutions (maximum D_p: 498 nm) and deswelled (minimum D_p: 257 nm) in basic solutions for the case of the nanogels obtained from PDMAEMA nanolatexes. pH response to swelling is due to protonation of amine groups in the backbone of PDMAEMA in acidic conditions leading to electrostatic interactions in the nanogel. POLYM. ENG. SCI., 54:1625–1631, 2014. © 2013 Society of Plastics Engineers     

pH/redox/thermo-stimulative nanogels with enhanced thermosensitivity via incorporation of cationic and anionic components for anticancer drug delivery

To explore the potential biomedical applications of nanogels, it is a key factor to improve their thermosensitivity. In this paper, triple-responsive nanogels poly(N-isopropylacrylamide–N,N′-dimethylaminoethyl methacrylate–acrylic acid) (PNDA) were synthesized via in situ incorporating both cationic components and anionic components into a normal thermosensitive polymer matrix. The triple-monomer constructed PNDA nanogels displayed an enhanced thermosensitivity as compared with dual-monomer constructed PND nanogels. The PNDA nanogels presented higher encapsulation efficiency (～89%) and exhibited better pH/redox/thermo-responsivenesses in an anticancer drug delivery. In vitro biological study indicated that the PNDA nanogels have excellent biocompatibility and improved anticancer cytotoxicity to A549 cells after loading drug DOX.     

Fabrication and biomedical potential of nanogels: An overview

Nanogels are one of the innovative hydrogel systems that comprise cross-linked polymers of natural or synthetic origin having good water holding capacity. The hydrophilic nature of nanogels possess good water uptake and exhibit controlled, targeted and sustained release. Nanogels show promising features like high biodegradability, biocompatibility, drug loading capacity and good penetration power. This overview mainly focuses on the biomedical applications of nanogels as the drug delivery system, imaging agent, therapeutic carrier, theranostic agent, also its fabrication techniques. In current scenario, nanogels play promising roles to deliver drugs such as anticancer, autoimmune, ophthalmics, anti-microbials, anti-inflammatory, proteins and peptides.     

Effect of attapulgite contents on release behaviors of a pH sensitive carboxymethyl cellulose‐g‐poly(acrylic acid)/attapulgite/sodium alginate composite hydrogel bead containing diclofenac

A series of pH‐sensitive composite hydrogel beads, carboxymethyl cellulose‐g‐poly(acrylic acid)/attapulgite/sodium alginate (CMC‐g‐PAA/APT/SA), were prepared by combining CMC‐g‐PAA/APT composite and SA, using Ca²⁺ as the ionic crosslinking agent and diclofenac sodium (DS) as the model drug. The effects of APT content and external pH on the swelling properties and release behaviors of DS from the composite hydrogel beads were investigated. The results showed that the composite hydrogel beads exhibited good pH‐sensitivity. Introducing 20% APT into CMC‐g‐PAA hydrogel could change the surface structure of the composite hydrogel beads, decrease the swelling ability, and relieve the burst release effect of DS. The drug cumulative release ratio of DS from the hydrogel beads in simulated gastric fluid was only 3.71% within 3 hour, but in simulated intestinal fluid about 50% for 3 hour, 85% for 12 hour, up to 90% after 24 hour. The obtained results indicated that the CMC‐g‐PAA/APT/SA hydrogel beads could be applied to the drug delivery system as drug carriers in the intestinal tract. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Development,In Vitro and In Vivo Evaluation of Hydrogel Based System of Carboxymethyl Arabinoxylan for Controlled Delivery of Rabeprazole Sodium

Present study deals with development of polymeric systems for rabeprazole sodium to accomplish a lingering therapeutic outcome. Carboxymethyl arabinoxylan exhibited variety of ideal characteristics for polymeric drug carrier. Free radical polymerization was successfully employed to prepare pH responsive polymeric network of carboxymethyl arabinoxylan with acrylic acid. FTIR, SEM, thermogravimetric analysis and X-ray diffraction verified the graft copolymerization. Graft copolymers revealed highly pH responsive swelling, consequently drug release at intestinal pH. In vivo evaluation indicated improvement in relative bioavailability by exhibiting increase in C_max of polymeric system and same oral dose of rabeprazole sodium were 103.71?±?16.081 and 61.263?±?5.37?ng/mL, respectively.     

A thermo/pH/magnetic-responsive nanogel based on sodium alginate by modifying magnetic graphene oxide: Preparation,characterization, and drug delivery

A novel thermo/pH/magnetic-triple-responsive nanogel was synthesized by grafting N-isopropylacrylamide and acrylic acid onto sodium alginate to modify magnetic graphene oxide as a drug delivery system. The synthesized nanogel was characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), vibrating sample magnetometer (VSM), atomic force micrographs (AFM), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). The obtained nanogel displayed excellent reversible transmittance changes in response to pH, temperature, and magnetic field. The performance of the nanogels to load doxorubicin (DOX) drug and to sustain doxorubicin release was tested upon exposure to pH, temperature, and magnetic field variations. The mechanism of drug release was proposed in this paper by different kinetic models. In addition, the effects of nanogels and DOX-loaded nanogels on MCF-7 cells were examined and results were compared with free DOX drug. The in vitro results demonstrated that this triple-responsive nanogel can be an appropriate candidate for applications in cancer therapy.     

Synthesis and characterization of novel core‐shell magnetic nanogels based on 2‐acrylamido‐2‐methylpropane sulfonic acid in aqueous media

Ultrafine well‐dispersed Fe₃O₄ magnetic nanoparticles were directly prepared in aqueous solution using controlled coprecipitation method. The synthesis of Fe₃O₄/poly (2‐acrylamido‐2‐methylpropane sulfonic acid) (PAMPS), Fe₃O₄/poly (acrylamide‐co‐2‐acrylamido‐2‐methylpropane sulfonic acid) poly(AM‐co‐AMPS) and Fe₃O₄/poly (acrylic acid‐co‐2‐acrylamido‐2‐methylpropane sulfonic acid) poly(AA‐co‐AMPS) ‐core/shell nanogels are reported. The nanogels were prepared via crosslinking copolymerization of 2‐acrylamido‐2‐methylpropane sulfonic acid, acrylamide and acrylic acid monomers in the presence of Fe₃O₄ nanoparticles, N,N′‐methylenebisacrylamide (MBA) as a crosslinker, N,N,N′,N′‐tetramethylethylenediamine (TEMED) and potassium peroxydisulfate (KPS) as redox initiator system. The results of FTIR and ¹H‐NMR spectra indicated that the compositions of the prepared nanogels are consistent with the designed structure. X‐ray powder diffraction (XRD) and transmission electron microscope (TEM) measurements were used to determine the size of both magnetite and stabilized polymer coated magnetite nanoparticles. The data showed that the mean particle size of synthesized magnetite (Fe₃O₄) nanoparticles was about 10 nm. The diameter of the stabilized polymer coated Fe₃O₄ nanogels ranged from 50 to 250 nm based on polymer type. TEM micrographs proved that nanogels possess the spherical morphology before and after swelling. These nanogels exhibited pH‐induced phase transition due to protonation of AMPS copolymer chains. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Targeting of a Thermosensitive Nanogel Copolymerized With Macromonomer for Cell Uptake and Drug Controlled Release

In this study, N-isopropylacrylamide (NIPAAm), propyl acrylic acid (PAAC), and poly(N-isopropylacrylamide-co-undecylenic acid) acrylamide were introduced to synthesize PNIPAAm-based nanogels (NG). The morphology of NG particles was characterized via transmission electron microscopy (TEM). The nanogels exhibited a lower critical solution temperature (LCST) of 34°C and a temperature-induced drug release in vitro. After conjugation of arginine-glycine-aspartic acid (RGD)–containing peptide (GRGDS), the cellular uptake of doxorubicin (Dox)-loaded nanogel by HeLa cells had been greatly enhanced. The Dox molecules in endocytosed nanogels could be released efficiently at 37°C and subsequently kill tumor cells, suggesting that the nanogel has great potential for targeting delivery.     

Preparation and characterization of tetracycline‐loaded interpenetrating polymer networks of carboxymethyl cellulose and poly(acrylic acid): water sorption and drug release study

Tetracycline (TC)‐loaded ionic interpenetrating polymer networks (IPNs) of carboxymethyl cellulose (CMC) and crosslinked poly(acrylic acid) (PAA) were prepared and characterized by infrared spectral analysis, differential scanning calorimetry and scanning electron microscopy techniques. The prepared IPNs were evaluated for in vitro blood compatibility by clot formation and hemolysis methods and their water imbibitions capacity was determined. Fractional release dynamics of tetracycline was also investigated from loaded IPNs of CMC and PAA. The entrapped drug was examined for antibacterial activity and structural integrity and effects of various parameters such as percentage loading of the drug, chemical composition of the carrier IPN, pH and temperature of the release medium were investigated on the release profiles of TC. The drug was also released in different simulated biological fluids. Copyright © 2005 Society of Chemical Industry     

Cerium–initiated Polymerisation of some Vinyl Compounds in Cellulose Fibres

The effects of monomer and initiator concentration on the graft polymerisation of acrylic acid and of 2–vinylpyridine in viscose rayon and cotton, initiated by ceric ammonium sulphate in dilute sulphuric acid, have been examined. Polymerisation of acrylic acid occurs less readily in cotton treated with caustic soda, and in acid–modified cotton, than in the parent fibre. Neither preliminary treatment with initiator nor partial oxidation with sodium periodate affects the extent of subsequent grafting of poly(acrylic acid) to viscose rayon under selected conditions. The rate of polymerisation of 2–vinylpyridine in cellulose is lower than that of acrylic acid, but polymerisation is greatly accelerated by substituting dilute perchloric acid for sulphuric acid as the solvent. This is apparently a manifestation of the ‘gel effect’ and has been observed with other basic monomers that form insoluble polymer perchlorates. Proof is offered that both acrylic acid and 2–vinylpyridine afford true graft copolymers with cellulose. These polymers do not improve the mechanical properties of viscose rayon filaments. Support for the view that oxidative C₍₂₎–C₍₃₎ bond–fission participates in the initiation of polymerisation in cellulose by eerie salts is provided indirectly by the isolation of adipaldehyde as a major product from the oxidation of cyclohexane–trans–l, 2–diol with ceric ammonium nitrate.     

pH-responsive PEGylated nanogel containing platinum nanoparticles: Application to on–off regulation of catalytic activity for reactive oxygen species

Synthesis of pH-responsive PEGylated nanogels platinum nanoparticles (PtNPs: <2 nm) was successfully carried out through the reduction of K₂PtCl₆ within the PEGylated nanogels constructed from cross-linked poly[2-(N,N-diethylamino)ethyl methacrylate] (PDEAMA) core and tethered PEG chains. The resulting PEGylated nanogels containing PtNPs showed significant catalytic activity for reactive oxygen species (ROS) in response to skin-environmental pH (acid), whereas the almost no catalytic activity for ROS was observed at physiological pH due to the volume phase transition of the PDEAMA gel core. Thus, pH-responsive and PEGylated nanogel containing PtNPs can be utilized to the skin-specific ROS-scavengers for the skin aging.     

Synthesis,characterization, and biomedical applications of core–shell-type stimuli-responsive nanogels – Nanogel composed of poly[2-(N,N-diethylamino)ethyl methacrylate] core and PEG tethered chains

We present a review of stimuli-responsive smart PEGylated nanogels and their biomedical applications. We describe the synthesis and characterization of stimuli-responsive PEGylated nanogels composed of a cross-linked poly[2-(N,N-diethylamino)ethyl methacrylate] (PDEAMA) core and PEG tethered chains that bear a carboxylic acid group as a platform moiety for the installation of bio-tags. In addition, PEGylated nanogels show unique properties and functions in synchronizing with the reversible volume phase transition of the PDEAMA core in response to various stimuli, such as pH, ionic strength and temperature. We list some of the biomedical applications of the nanogels, including endosomolytic agents for nonviral gene delivery, drug delivery carriers, nanoreactors, and skin-specific nanocatalysts for reactive oxygen species (ROS).     

Absolute online monitoring of acrylic acid polymerization and the effect of salt and pH on reaction kinetics

Using recently introduced Automatic Continuous Online Monitoring of Polymerization reactions (ACOMP), the kinetics of acrylic acid polymerization was studied. ACOMP yields the absolute weight‐averaged mass (M_w), monomer conversion, and other quantities. As the initiator concentration increased, it was shown that the rate increased and the M_w decreased as in regular free‐radical polymerization. The effect of salt on acrylic acid polymerization in an aqueous solution was investigated. The polymerization rate and M_w both decreased with an increasing salt concentration. ACOMP molecular weights were also compared with size‐exclusion chromatography on aliquots periodically withdrawn during the reaction, and good agreement was found. The effect of the pH on the rate and the molecular weight was also investigated, and when the medium pH was changed from 2 to 5 with sodium hydroxide, the rate and M_w both decreased as the pH increased. Light‐scattering results of reaction end products in the reference solvent showed that molecules synthesized at higher pH were in a more expanded form. When equimolar sodium hydroxide was added to the acrylic acid (pH ? 5) and sodium acrylate formed, adding salt did not effect the reaction kinetics of the poly(sodium acrylate); its effect on the products was a relatively minor decrease of M_w. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 1352–1359, 2004     

Synthesis,characterization and swelling behaviors of hydroxyethyl cellulose‐g‐poly(acrylic acid)/attapulgite superabsorbent composite

In this work, a series of novel hydroxyethyl cellulose‐ g‐poly(acrylic acid)/attapulgite (HEC‐g‐PAA/APT) superabsorbent composites were prepared through the graft polymerization of hydroxyethyl cellulose (HEC), partially neutralized acrylic acid (AA), and attapulgite (APT) in aqueous solution, and the composites were characterized by means of Fourier‐transform spectroscopy, scanning electron microscopy, and transmission electronmicroscopy. The effects of polymerization variables including concentrations of the initiator and crosslinker and APT content on water absorbency were studied, and the swelling properties in various pH solutions as well as the swelling kinetics in various saline solutions were also systematically evaluated. Results showed that the introduction of 5 wt% APT into HEC‐g‐PAA polymeric network could improve both water absorbency and water absorption rate of the superabsorbent composites. In addition, the superabsorbent composites retained high water absorbency over a wide pH range of 4–10, and the swelling kinetics of the superabsorbent composites in CaCl₂ and FeCl₃ solutions exhibited a remarkable overshooting phenomenon. POLYM. ENG. SCI., 2010. © 2010 Society of Plastics Engineers     

A versatile strategy to construct surface functionalized pH/redox dual stimuli-responsive nanogels for targeted drug delivery

Developing facile, green, and efficient synthetic methodology for preparing surface-functionalized nanogels has attracted tremendous attention in the field of polymer chemistry and biomaterials engineering. Herein, a series of “clickable” P(MAA-PMA) nanogels with reactive alkyne groups were conveniently prepared by “one-pot” reflux-precipitation polymerization (RPP), their particle sizes and zeta potentials are solid content-dependent. Using P(MAA-PMA)-1 nanogels as the model, the physicochemical properties including particle size, surface potential, morphology, solution stability, and pH/redox responsiveness were characterized in detail. Moreover, the pH/redox dual-responsive drug release feature/kinetics and parameters were analyzed using Korsmeyer–Peppas model and Gallagher–Corrigan model. Then the surface of nanogels was facilely modified with various thiol-containing functional ligands via thiol-yne photo click reaction. As targeted drug carriers, doxorubicin (DOX)-loaded folic acid (FA)-functionalized nanogels (FA@Nanogels/DOX) demonstrated higher tumor cell proliferation inhibition effect in B16F10 cancer cells than that in CHO-K1 normal cells, while the non-FA-functionalized counterparts (Nanogels/DOX) do not show similar effect. This work provides a versatile “one-pot RPP-photo Click functionalization” strategy to construct surface-functionalized pH/redox dual responsive nanogels for efficient and targeted drug delivery.     

A novel polymeric biomaterial based on carboxymethylstarch and its application in controlled drug release

This study reports investigation of the sustained release behavior of a model drug (acetylsalicylic acid) from carboxymethylstarch (CMS) based matrix. CMS was prepared by incorporation of carboxymethyl groups in the starch moiety; by reacting starch with sodium salt of monochloro acetic acid in presence of sodium hydroxide. The in vitro drug release study was performed by United States Pharmacopeia rotating paddle method, at various pH. The rate of drug release from the above matrix was found to increase with increase in pH. Further, the release behavior of the drug from the CMS based matrix was found to be non‐Fickian, n value being between 0.80 and 0.85, suggesting that the release was controlled by a combination of tablet erosion and diffusion of the drug from the swollen matrix. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Multi stimuli-responsive HPC-PAA/Eu(AA)3Phen complex nanogels and their decoration with 3-APBA for detecting glucose

In this paper, novel multi stimuli-responsive complex nanogels of hydroxypropylcellulose (HPC)-PAA/Eu(acrylic acid [AA])₃Phen were synthesized by radical polymerization method with HPC, rare earth complex (Eu(AA)₃Phen) and AA as raw materials, and the 3-aminophenylboronic acid (3-APBA) decorated nanogels (HPC-PAAPBA/Eu(AA)₃Phen) were fabricated via condensation of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride with 3-APBA. The microstructure, morphology and diameter of the nanogel were characterized by Fourier transform infrared spectrometer, UV–Visible spectrophotometer, transmission electron microscope, dynamic light scattering. Moreover, the fluorescence responsive performance of complex nanogels to temperature, pH value and glucose concentration was investigated by photoluminescence spectroscopy. The results showed that both of the as-prepared nanogels were uniform in size and had good monodispersity. The temperature and pH value had significant effects on the particle size and the fluorescence emission intensity of the HPC-PAA/Eu(AA)₃Phen complex nanogels; after decoration with 3-APBA, the obtained HPC-PAAPBA/Eu(AA)₃Phen nanogels showed excellent stimulus-response to glucose concentration.