Dual pH‐ and thermal‐responsive nanocomposite hydrogels for controllable delivery of hydrophobic drug baicalein

Hydrogels have been widely used as mild biomaterials due to their bio‐affinity, high drug loading capability and controllable release profiles. However, hydrogel‐based carriers are greatly limited for the delivery of hydrophobic payloads due to the lack of hydrophobic binding sites. Herein, nano‐liposome micelles were embedded in semi‐interpenetrating poly[(N‐isopropylacrylamide)‐co‐chitosan] (PNIPAAm‐co‐CS) and poly[(N‐isopropylacrylamide)‐co‐(sodium alginate)] (PNIPAAm‐co‐SA) hydrogels which were responsive to both temperature and pH, thereby establishing tunable nanocomposite hydrogel delivery systems. Nano‐micelles formed via the self‐assembly of phospholipid could serve as the link between hydrophobic drug and hydrophilic hydrogel due to their special amphiphilic structure. The results of transmission and scanning electron microscopies and infrared spectroscopy showed that the porous hydrogels were successfully fabricated and the liposomes encapsulated with baicalein could be well contained in the network. In addition, the experimental results of response release in vitro revealed that the smart hydrogels showed different degree of sensitiveness under different pH and temperature stimuli. The results of the study demonstrate that combining PNIPAAm‐co‐SA and PNIPAAm‐co‐CS hydrogels with liposomes encapsulated with hydrophobic drugs is a feasible method for hydrophobic drug delivery and have potential application prospects in the medical field. © 2018 Society of Chemical Industry     

Dual‐stimuli‐responsive polymer‐coated mesoporous silica nanoparticles used for controlled drug delivery

In this article, a temperature‐ and pH‐responsive delivery system based on block‐copolymer‐capped mesoporous silica nanoparticles (MSNs) is presented. A poly[2‐(diethylamino)ethyl methacrylate)] (PDEAEMA)‐b‐poly(N‐isopropyl acrylamide) (PNIPAM) shell on MSNs was obtained through the surface‐initiated atom transfer radical polymerization. The block copolymer PDEAEMA‐b‐PNIPAM showed both temperature‐ and pH‐responsive properties. The release of the loaded model molecules from PDEAEMA‐b‐PNIPAM‐coated MSNs could be controlled by changes in the temperature or pH value of the medium. The as‐desired drug‐delivery carrier may be applied to biological systems in the future. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42395.     

pH‐responsive hydrogels with dispersed hydrophobic nanoparticles for the delivery of hydrophobic therapeutic agents

To investigate the delivery of hydrophobic therapeutic agents, a new class of polymer carriers was synthesized. These carriers are composed of two components: (i) a pH‐responsive hydrogel composed of methacrylic acid grafted with poly(ethylene glycol) tethers, P(MAA‐g‐EG), and (ii) hydrophobic poly(methyl methacrylate) (PMMA) nanoparticles. Before the P(MAA‐g‐EG) hydrogel was crosslinked, PMMA nanoparticles were added to the solution and upon exposure to UV light they were photoencapsulated throughout the P(MAA‐g‐EG) hydrogel structure. The pH‐responsive behavior of P(MAA‐g‐EG) is capable of triggered release of a loaded therapeutic agent, such as a low molecular weight drug or protein, when it passes from the stomach (low pH) to upper small intestine (neutral pH). The introduction of PMMA nanoparticles into the hydrogel structure affected the swelling behavior, therapeutic agent loading efficiency, and solute release profiles. In equilibrium swelling conditions the swelling ratio of nanoparticle‐containing hydrogels decreased with increasing nanoparticle content. Loading efficiencies of the model therapeutic agent fluorescein ranged from 38% to 51% and increased with increasing hydrophobic content. Release studies from neat P(MAA‐g‐EG) and the ensuing P(MAA‐g‐EG) hydrogels containing nanoparticles indicated that the transition from low pH (2.0) to neutral pH (7.0) triggered fluorescein release. Maximum fluorescein release depended on the structure and hydrophobicity of the carriers used in these studies. Copyright © 2012 Society of Chemical Industry     

Biological properties of iron oxide nanoparticles for cellular and molecular magnetic resonance imaging

Superparamagnetic iron-oxide particles (SPIO) are used in different ways as contrast agents for magnetic resonance imaging (MRI): Particles with high nonspecific uptake are required for unspecific labeling of phagocytic cells whereas those that target specific molecules need to have very low unspecific cellular uptake. We compared iron-oxide particles with different core materials (magnetite, maghemite), different coatings (none, dextran, carboxydextran, polystyrene) and different hydrodynamic diameters (20-850 nm) for internalization kinetics, release of internalized particles, toxicity, localization of particles and ability to generate contrast in MRI. Particle uptake was investigated with U118 glioma cells und human umbilical vein endothelial cells (HUVEC), which exhibit different phagocytic properties. In both cell types, the contrast agents Resovist, B102, non-coated Fe(3)O(4) particles and microspheres were better internalized than dextran-coated Nanomag particles. SPIO uptake into the cells increased with particle/iron concentrations. Maximum intracellular accumulation of iron particles was observed between 24 h to 36 h of exposure. Most particles were retained in the cells for at least two weeks, were deeply internalized, and only few remained adsorbed at the cell surface. Internalized particles clustered in the cytosol of the cells. Furthermore, all particles showed a low toxicity. By MRI, monolayers consisting of 5000 Resovist-labeled cells could easily be visualized. Thus, for unspecific cell labeling, Resovist and microspheres show the highest potential, whereas Nanomag particles are promising contrast agents for target-specific labeling.     

Thermo‐ and pH‐responsive microgels for controlled release of insulin

Microgel particles were prepared, made of hydroxypropylcellulose‐graft‐(acrylic acid) (HPC‐g‐AA) and acrylic acid(AA). The particles undergo reversible volume phase transitions in response to both pH and temperature changes while keeping the inherent properties of PAA and HPC‐g‐AA. Dynamic light scattering measurements reveal that the average hydrodynamic radius and hydrodynamic radius distributions of the microgel particles depend on temperature and pH. The microgels exhibit excellent pH sensitivity and a higher swelling ratio at higher pH in aqueous solution. In vitro release study shows that the amount of insulin released from the microgels is less at pH = 1.2 than at pH = 6.8. The results indicate that the resultant microgels seem to be of great potential for intelligent oral drug delivery. Copyright © 2012 Society of Chemical Industry     

PEGylated hollow pH‐responsive polymeric nanocapsules for controlled drug delivery

Novel pH‐responsive PEGylated hollow nanocapsules (HNCaps) were fabricated through a combination of distillation–precipitation copolymerization and surface thiol–ene ‘click’ grafting reaction. For this purpose, SiO₂ nanoparticles were synthesized using the Stöber approach, and then modified using 3‐(trimethoxysilyl)propyl methacrylate (MPS). Afterward, a mixture of triethyleneglycol dimethacrylate (as crosslinker), acrylic acid (AA; as pH‐responsive monomer) and MPS‐modified SiO₂ nanoparticles (as sacrificial template) was copolymerized using the distillation–precipitation approach to afford SiO₂@PAA core–shell nanoparticles. The SiO₂ core was etched from SiO₂@PAA using HF solution, and the obtained PAA HNCaps were grafted with a thiol‐end‐capped poly(ethylene glycol) (PEG) through a thiol–ene ‘click’ reaction to produce PAA‐g‐PEG HNCaps. The fabricated HNCaps were loaded with doxorubicin hydrochloride (DOX) as a model anticancer drug, and their drug loading and encapsulation efficiencies as well as pH‐dependent drug release behavior were investigated. The anticancer activity of the drug‐loaded HNCaps was extensively evaluated using MTT assay against human breast cancer cells (MCF7). The cytotoxicity assay results as well as superior physicochemical and biological features of the fabricated HNCaps mean that the developed DOX‐loaded HNCaps have excellent potential for cancer chemotherapy. © 2020 Society of Chemical Industry     

Magnetic resonance imaging of glioma with novel APTS-coated superparamagnetic iron oxide nanoparticles

We report in vitro and in vivo magnetic resonance (MR) imaging of C6 glioma cells with a novel acetylated 3-aminopropyltrimethoxysilane (APTS)-coated iron oxide nanoparticles (Fe₃O₄ NPs). In the present study, APTS-coated Fe₃O₄ NPs were formed via a one-step hydrothermal approach and then chemically modified with acetic anhydride to generate surface charge-neutralized NPs. Prussian blue staining and transmission electron microscopy (TEM) data showed that acetylated APTS-coated Fe₃O₄ NPs can be taken up by cells. Combined morphological observation, cell viability, and flow cytometric analysis of the cell cycle indicated that the acetylated APTS-coated Fe₃O₄ NPs did not significantly affect cell morphology, viability, or cell cycle, indicating their good biocompatibility. Finally, the acetylated APTS-coated Fe₃O₄ nanoparticles were used in magnetic resonance imaging of C6 glioma. Our results showed that the developed acetylated APTS-coated Fe₃O₄ NPs can be used as an effective labeling agent to detect C6 glioma cells in vitro and in vivo for MR imaging. The results from the present study indicate that the developed acetylated APTS-coated Fe₃O₄ NPs have a potential application in MR imaging.     

Investigation on characterization and transfection of a novel multi‐polyplex gene delivery system

pDNA was condensed by polycationic peptide polylysine (PLL) to form a core, and then encapsulated in biodegradable monomethoxy (poly ethylene glycol)-poly(lactide-co-glycolide)-monomethoxy (poly ethylene glycol) (PELGE) to form core-shell nanoparticles (NPs) as a novel multi-polyplex gene delivery system—PPD(PELGE-PLL-DNA). NPs were prepared by a double emulsification-solvent evaporation technique, using F68 (Pluronic F68, namely Poloxamer 188) as surfactant (not traditional stabilizer PVA), and characterized by morphology, particle size, zeta potential, nuclease, and sonication protection ability, as well as transfection efficiency. Results showed that PPD had a regular spherical shape, with an average diameter of 155 ± 2.97 nm and a zeta potential of −25.6 ± 1.35 mV. PPD could protect plasmid DNA from nuclease degradation and sonication during preparation, while the transfection efficiencies in HepG2 cells and Hela cells were much higher than that of NPs without PLL. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007     

Redox‐ and pH‐Responsive Nanogels Based on Thiolated Poly(aspartic acid)

Nanogels loaded with fluorescent dextran as a model drug are synthesized by the oxidation induced cross‐linking of water soluble redox responsive thiolated poly(amino acid) in miniemulsion without the introduction of any cross‐linker molecule. Two types of high energy methods, namely, ultrasonication and high pressure homogenization (HPH), are compared. Dynamic light scattering and transmission electron microscopy measurements confirm that spherical nanogels in 100–150 nm diameter range are prepared successfully by HPH method. Size and surface charge of the nanogels can easily be controlled by environmental pH. The release of encapsulated drug is triggered by the degradation of nanogels in reducing environment due to the cleavage of disulphide bonds.

     

Physico‐mechanical properties of natural rubber sheets coated by polyethyleneimine‐functionalized poly(methyl methacrylate) nanoparticles

The surface modification of sulfur‐prevulcanized natural rubber (SPNR) sheets by the polyethyleneimine‐functionalized‐poly(methyl methacrylate) (PMMA/PEI) nanoparticles was successfully performed via a simple dipping method. The percentage of surface coverage (C_s) of the nanoparticles on SPNR sheets was found to be affected by a variation of nanoparticle latex concentrations and immersion times. The adsorption isotherm of PMMA/PEI nanoparticles on SPNR sheets was analyzed and found to fit well to the Freundlich model. After coating, it can be observed that the presence of PMMA/PEI nanoparticles on SPNR surface had no effects over the SPNR mechanical properties e.g., tensile strength, elongation at break, and hardness. On the other hand, the coated SPNR sheets showed a reduction of surface friction coefficients and interfacial adhesion up to 45 and 59%, respectively. Furthermore, PMMA/PEI nanoparticles adsorbed on the SPNR surface was subjected to stretching and wearing conditions, and found to be stable for at least seven stretching and wearing cycles. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

pH‐responsive hydrogel microparticles as intelligent delivery carriers for α‐MSH antagonists

For a first step in the development of an intelligent delivery system for a nonapeptide as an α‐MSH antagonist, pH‐responsive P(MAA‐co‐EGMA) hydrogel microparticles were prepared and their feasibility as intelligent delivery carriers was evaluated. There was a drastic change in the swelling ratio of P(MAA‐co‐EGMA) microparticles at a pH of around 5 and as the MAA amount in the hydrogel increased, the swelling ratio increased at a pH above 5. The loading efficiency of the nonapeptide at pH 7 increased with the amount of Methacrylic acid (MAA) in the hydrogel and at pH 2, where the electrostatic attraction was greatest, a high loading efficiency was not obtained because of the low swelling ratio of the hydrogel. The P(MAA‐co‐EGMA) microparticles demonstrated a pH‐sensitive release behavior for the nonapeptide. In addition, the P(MAA‐co‐EGMA) microparticles showed a protective ability for the nonapeptide and preserved the stability of the nonapeptide. © 2010 American Institute of Chemical Engineers AIChE J, 2010     

Multi‐responsive hydrogels based on N‐isopropylacrylamide and sodium alginate

Hydrogels consisting of sodium alginate and N‐isopropylacrylamide covalently crosslinked with N,N′‐methylenebisacrylamide were prepared. The mixed‐interpenetrated networks obtained were characterized using elemental analysis, Fourier transform infrared and Raman spectroscopy, swelling measurements and environmental scanning electron microscopy. The thermo‐ and pH‐responsive properties of these hydrogels were evidenced by their swelling behaviour, which depended also on the amount of crosslinking agent and hydrogel composition. Copyright © 2010 Society of Chemical Industry     

Fabrication of pH‐responsive molecularly imprinted polyethersulfone particles for bisphenol‐A uptake

pH‐responsive molecularly imprinted particles were successfully fabricated by pore‐filling poly (acrylic acid) (PAA) gels into bisphenol‐A (BPA)‐imprinted polyethersulfone particles. The adsorbed BPA amount (or rate) decreased after filling the PAA gels both for the imprinted and nonimprinted particles. However, it was confirmed that changing the acidity of the solution reversibly controls the rebinding ability toward BPA and that the BPA uptake of the pore‐filled particles exhibited chemical valve behavior at a pH between 3 and 6. This finding can be attributed to the swelling of the PAA gels in the particles. The present methodology provides a simple way to prepare pH‐responsive molecularly imprinted materials and is expandable to the imprinting of other hydrophobic molecules, such as dibenzofuran. Also, the results of this work demonstrate the potential of stimuli‐responsive molecularly imprinted polymer materials as smart chemicals and as drug‐delivery systems. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

6‐O‐dodecyl‐chitosan carbamate–based pH‐responsive polymeric micelles for gene delivery

pH‐responsiveness is highly desirable in the stimuli‐responsive controlled release because of the distinct advantages of the fast response of pH‐triggered release and the available pH‐difference between intra‐ and extra‐cells. The present work reported a kind of novel pH‐responsive polymeric micelles, which was derived from biopolymer of 6‐O‐dodecyl‐chitosan carbamate (DCC) and evaluated as gene‐controlled release vector. The amphiphilic and amino‐rich DDC was synthesized through a protection‐graft‐deprotection method. ¹³C CP/MAS NMR, FTIR, and elemental analysis identified that dodecyls were chemoselectively grafting at 6‐hydroxyls of chitosan via the pH‐responsive bonds of carbamate, and the substitute degree (SD) was 14%. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) showed that DCC self‐assembled into polymeric micelles in aqueous solutions. The DCC polymeric micelles formed complexes with pDNA, which was elucidated by Gel retardation, TEM, and DLS. Transfection and cytotoxicity assays in A549 cells showed that DCC polymeric micelles were suitable for gene delivery. The improved transfection was attributed to the pH‐responsiveness and the moderate pDNA‐binding affinity, which led to easier release of pDNA intra‐cells. The synthesized DCC polymeric micelles might be a promising and safe candidate as nonviral vectors for gene delivery. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42469.     

Temperature‐responsive polymers with LCST in the physiological range and their applications in textiles

Current academic and industrial research sustains large efforts to synthesize and develop environmentally responsive smart materials. The temperature‐responsive materials with a trigger temperature in the physiological range attract much attention due to their potential biomedical applications. We describe their chemistry and the way to synthesize them, focusing on applications for smart clothing fabrication. Copyright © 2007 Society of Chemical Industry     

Multifunctional liposomal drug delivery with dual probes of magnetic resonance and fluorescence imaging

Many liposomal drug carriers have shown great promise in the clinic. To ensure the efficient preclinical development of drug-loaded liposomes, the drug retention and circulation properties of these systems should be characterized. Iron oxide (Fe₃O₄) magnetic nanoparticles (MNPs) are used as T2 contrast agents in magnetic resonance imaging (MRI). Gold nanoclusters (GNCs) contain tens of atoms with subnanometer dimensions; they have very low cytotoxicity and possess superb red emitting fluorescent properties, which prevents in vivo background autofluorescence. The aim of this study was to develop dual imaging, nanocomposite, multifunctional liposome drug carriers (Fe₃O₄-GNCs) comprising MNPs of iron oxide and GNCs. First, MNPs of iron oxide were synthesized by co-precipitation. The MNP surfaces were modified with amine groups using 3-aminopropyltriethoxysilane (APTES). Second, GNCs were synthesized by reducing HAuCl₄·3H₂O with NaBH4 in the presence of lipoic acid (as a stabilizer and nanosynthetic template). The GNCs were grown by adsorption onto particles to control the size and stability of the resultant colloids. Subsequently, dual Fe₃O₄-GNCs imaging probes were fabricated by conjugating the iron oxide MNPs with the GNCs via amide bonds. Finally, liposome nanocarriers were used to enclose the Fe₃O₄-GNCs in an inner phase (liposome@Fe₃O₄-GNCs) by reverse phase evaporation. These nanocarriers were characterized by dynamic light scattering (DLS), fluorescence spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectrophotometry, superconducting quantum interference device (SQUID), nuclear magnetic resonance (NMR) imaging and in vivo imaging systems (IVIS). These multifunctional liposomal drug delivery systems with dual probes are expected to prove useful in preclinical trials for cancer diagnosis and therapy.