Liusheng Zha

Stimulus responsive nanogels for drug delivery

Stimulus responsive nanogels are polymeric nanoparticles which are capable of responding to external stimuli by changing their physico-chemical properties, such as volume, water content, refractive index, permeability, and hydrophilicity–hydrophobicity. Compared with other polymer nanoparticles used for drug delivery, stimulus responsive nanogels are noted for their ability to encapsulate bioactive drugs, their high stability for prolonged circulation in the blood stream, and their controlled release and site-specific targeting of loaded drugs modulated by environment stimuli. Particularly, the application of stimulus responsive nanogels provides an interesting opportunity for drug delivery in which the delivery system becomes an active participant, rather than a passive carrier, in the optimization of disease therapy. In this article, the authors review the recent developments in the preparation and application in drug delivery of stimulus responsive nanogels which can respond to small temperature and pH changes, light, magnetic field, biomolecule recognition (specifically glucose responsive nanogels for insulin delivery), and multi-responsive nanogels. The limitations and future improvements of stimulus responsive nanogels are also discussed.

Dual stimuli responsive hollow nanogels with IPN structure for temperature controlling drug loading and pH triggering drug release

Monodisperse temperature/pH dual stimuli responsive hollow nanogels with an interpenetrating polymer network (IPN) structure based on a poly(acrylic acid) (PAA) network and a poly(N-isopropylacrylamide) (PNIPAM) network (PNIPAM/PAA IPN hollow nanogels) were fabricated by a two-step sequential colloidal template polymerization and subsequent removal of the cavity templates. Their chemical composition, IPN structure and hollow structure were verified by Fourier transformation infrared spectroscopy (FTIR) and transmission electron microscopy (TEM), respectively. pH and temperature dependent particle sizes measured by dynamic light scattering indicated that the hollow nanogels have both pH and temperature dual stimuli responsive properties. Isoniazid (INH), an antitubercular drug, was loaded into PNIPAM/PAA IPN hollow nanogels by controlling the equilibrium temperature ensuring it is lower than their volume phase transition temperature, so that the drug loading capacity can reach 668 mg INH per gram of the hollow nanogel. It can be seen from the TEM results that the encapsulated INH is mainly located in the cavities of the hollow nanogels. In vitrodrug release studies showed that the INH loaded PNIPAM/PAA IPN hollow nanogels possess distinct acid triggered drug release behavior, which may make them suitable for a stomach-specific drug delivery system.

A novel route to prepare pH-and temperature-sensitive nanogels via a semibatch process

A novel method via a semibatch process in the absence of surfactant has been adopted to prepare pH- and temperature-sensitive nanogels. The shape, charge distribution, temperature, and pH-induced volume phase transition behavior of the latexes were investigated by scanning electronic microscopy, zeta potentials, dynamic laser light scattering, and UV/vis spectroscopy. It was found that, in the absence of surfactant, with increasing the amount of AAc from 5 to 20 mol% of N-isopropylacrylamide (NIPAM), the hydrodynamic diameters (D(H)) decrease from 230 to 60 nm. With increasing pH value from 3 to 11, the D(H) values increase slightly, which is different than the dramatic increase seen when using a conventional batch method with a range from 680 to 1700 nm. However, at pH 3, the turbidity curves of these kinds of particles increase dramatically at temperatures between 33 and 37 degrees C, while remaining constant at first and then increasing directly at pH 11. Furthermore, the distribution of carboxylic groups located not only on the interior but also on the exterior of colloidal particles as a result of adoption of the semibatch method, other than simple surface distribution of poly(NIPAM-co-AAc) latexes via the batch method.

Temperature- and pH-tunable plasmonic properties and SERS efficiency of the silver nanoparticles within the dual stimuli-responsive microgels

The silver nanoparticle (AgNP)-loading microgels with an interpenetrating polymer network structure composed of separately cross-linked poly(acrylic acid) and poly(N-isopropylacrylamide) were prepared through an in situ reduction reaction of silver ions coordinated into their networks. The temperature- or pH-dependent hydrodynamic diameters measured using dynamic laser light scattering show that the hybrid microgels produced has dual pH and temperature stimuli-responsive properties with little mutual interference between the temperature- and pH-responsive components. The localized surface plasmon resonance wavelength of the AgNPs inside the microgels can be reversibly tuned with temperature changing from 20 °C to 45 °C or pH values changing from 3.0 to 7.0. When the hybrid microgels were used as the surface-enhanced Raman scattering (SERS) substrates for probing minute amounts of 4-mercapto benzoic acid in an aqueous solution, its SERS intensity is remarkably increased with pH value lowering from 7.0 to 3.0 or temperature rising from 20 °C to 45 °C. If the two stimuli are simultaneously exerted, the SERS intensity is greatly elevated. The temperature and pH value measuring results show that the hybrid microgels are able to be utilized as SERS microsensors for measuring both pH value and the temperature of their surroundings.

Silver nanoparticles loading pH responsive hybrid microgels: pH tunable plasmonic coupling demonstrated by surface enhanced Raman scattering

The pH responsive hybrid microgels containing homogeneously distributed silver nanoparticles (Ag NPs) were created by in situ reduction of Ag+ ions coordinated into the microgels with semi-interpenetrating polymer network structure composed of linear poly(acrylic acid) and crosslinked poly(N-isopropylacrylamide). When the pH value of the aqueous medium lowers from 6.0 to 4.0, the localized surface plasmon resonance (LSPR) band of the entrapped Ag NPs is pronouncedly red-shifted because of the decreased spatial distances between them as a result of shrinkage of the microgels, leading to their plasmonic coupling. The pH tunable plasmonic coupling is demonstrated by pH dependence of the surface enhanced Raman scattering (SERS) signal of 4-mercapto benzoic acid anchored on the Ag NPs surfaces. Differing from static plasmonic coupling modes from nanostructured assembly or array system of noble metals, the here reported plasmonic coupling can be dynamically controlled by environmental pH value. Therefore, the pH responsive hybrid microgels have potential applications in mobile LSPR or SERS microsensors for probing pH values of living tissues or cells.

The Relationship of Reaction Temperature, Tg and Rich‐Syndiotacticity of Poly(alkyl methacrylate)s in Modified Microemulsion Polymerization

Nanoscale poly(alkyl methacrylate)s including poly(methyl methacrylate), poly(ethyl methacrylate), poly(cyclohexyl methacrylate), poly(iso‐butyl methacrylate) and poly(benzyl methacrylate) were prepared by a modified microemulsion polymerization procedure. NMR analysis suggested that these poly(methacrylate)s samples were higher in syndiotactic content, lower in isotactic content and the glass transition temperatures (Tgs) of them were also higher than those reported in the literature. The tacticities of the poly(methacrylate)s, beside the restricted volume effect of nanoparticles during the modified microemulsion polymerization, were mainly influenced by the reaction temperature, the lower the reaction temperature, the higher the syndiotacticity of the products. The syndiotacticity of the product decreased obviously when the polymerization was carried out at a temperature far above the Tg of the resulting polymer. It was also shown that the tacticity of the polymer was affected by the monomer structure, a monomer with the bulkier alkyl side group would liable to result in a polymer with richer syndiotacticity. Possible mechanism of rich‐syndiotacticity was also discussed.

Preparation of Poly(N‐isopropylacrylamide) Microgels using Different Initiators Under Various pH Values

Ammonium persulfate (APS), 2,2′‐azobis(amidinopropane) dihydrochloride (V50) and 4,4′‐azobis(4‐cyanovaleric acid) (ACVA) were utilized to prepare temperature‐sensitive poly(N‐isopropylacrylamide) (PNIPAM) microgels by precipitation polymerization under various reaction pH conditions. Their particle sizes and swelling ratios depended on the reaction pH due to the pH dependence on the ionization degree of the decomposed fragments originating from the initiators and their hydrophilicity‐hydrophobicity. The more hydrophobic initiator, under the reaction pH conditions used, could be partitioned to a greater extent into the microgel particles due to the hydrophobicity of PNIPAM chains at the reaction temperature, which led to a more cross‐linked structure inside the microgels resulting in their smaller swelling ratio. pH dependence of surface charge density of the microgels with amidino groups or carboxylic acid groups on their surfaces was evidenced by the variation of their zeta potentials as a function of pH.

Self-assembly of hollow PNIPAM microgels to form discontinuously hollow fibers

A new kind of hollow hydrogel microfiber with discontinuous hollow structure was prepared by an ice-segregation-induced self-assembly process. Monodisperse thermo-responsive hollow poly(N-isopropylacrylamide) (PNIPAM) microgels were first synthesized by seed precipitation polymerization using colloidal SiO2 nanoparticles as seeds, followed by removing the silica cores of the formed SiO2/PNIPAM core/shell composite microgels with hydrofluoric acid. Then, the discontinuously hollow hydrogel microfibers were produced by unidirectional freezing of 1 wt% hollow PNIPAM microgel aqueous dispersion in liquid nitrogen bath, followed by freeze-drying to remove the formed ice crystals. Many orderly arrayed dents were observed on the surfaces of the hydrogel microfibers by field-emission scanning electron microscopy, indicating that they are constructed by closely packed monodisperse hollow PNIPAM microgels. The effect of freezing method and the hollow microgel concentration in the aqueous dispersion on the morphological structure of the hollow hydrogel microfibers was investigated.

Preparation of Silica/Poly(tert‐butylmethacrylate) Core/Shell Nanocomposite Latex Particles

Nanocomposite latex particles, with a silica nanoparticle as core and crosslinked poly(tert‐butylmethacrylate) as shell, were prepared in this work. Silica nanoparticles were first synthesized by a sol‐gel process, and then modified by 3‐(trimethoxysilyl)propyl methacrylate (MPS) to graft C˭C groups on their surfaces. The MPS‐modified silica nanoparticles were characterized by elemental analysis, FTIR, and 29Si NMR and 13C‐NMR spectroscopy; the results showed that the C˭C groups were successfully grafted on the surface of the silica nanoparticles and the grafted substance was mostly the oligomer formed by the hydrolysis and condensation reaction of MPS. Silica/poly(tert‐butylmethacrylate) core/shell nanocomposite latex particles were prepared via seed emulsion polymerization using the MPS‐modified silica nanoparticle as seed, tert‐butylmethacrylate as monomer and ethyleneglycol dimethacrylate as crosslinker. Their core/shell nanocomposite structure and chemical composition were characterized by means of TEM and FTIR, respectively, and the results indicated that silica/poly(tert‐butylmethacrylate) core/shell nanocomposite latex particles were obtained.

Fabrication of monodispersed Au@Ag bimetallic nanorod-loaded nanofibrous membrane with fast thermo-responsiveness and its use as a smart free-standing SERS substrate

A novel type of metal nanoparticle-loaded smart nanofibrous membrane with fast thermo-responsiveness was fabricated by electrospinning an aqueous solution containing poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide) and monodispersed Au@Ag bimetallic nanorods with a core–shell structure, followed by heat treatment. The results obtained by electron microscopy show that the anisotropic nanoparticles are oriented along the axes of its constituent nanofibers. The membrane produced has high stability in aqueous media and remarkable thermo-responsiveness. It takes less than 10 seconds to reach its deswelling or swelling equilibrium state with the temperature alternating between 25 °C and 50 °C. The smart nanofibrous membrane with macroscopic mechanical strength can be used as a free-standing surface-enhanced Raman scattering (SERS) substrate with high Raman signal reproducibility for quantitative analysis, and its SERS efficiency can be readily elevated by raising the detection temperature across its phase transition temperature due to its fast thermo-response rate. Particularly, since the composite nanofibrous membrane possesses catalytic properties toward the reduction of 4-nitrothiophenol to 4-aminothiophenol by NaBH4, it has the ability to act as an in situ SERS monitor for the reaction, and it was deduced from the detected intermediate that the reaction proceeds via a condensation reaction route.