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Novel dual-functional nanospheres composed of magnetic iron oxide nanoparticles embedded in a thermo-sensitive Pluronic F127 (F127) matrix were successfully synthesized by an in situ coprecipitation process. The nanospheres were characterized by X-ray diffraction, transmission electron microscopy, X-ray photoelectron spectroscopy, and Raman spectroscopy. Experimental observations indicated that the F127 was subjected to a rapid structural change when the magnetic phase caused rapid heating after a short exposure to a high-frequency magnetic field. During the field duration, considerable volume shrinkage of the nanospheres (2.3-fold diameter reduction) was detected. This has been translated to an instantaneous release of a drug, Doxorubicin (DOX), when the DOX was encapsulated within the nanospheres. Such a rapidly responsive release of the DOX from the nanospheres was due to an intimate contact between the nanomagnet and F127, where an effective thermal and mechanical transfer between core and shell phases efficiently took place in the presence of the magnetic field.

In this study, a magnetic-sensitive microcapsule was prepared using Fe 3O 4/poly(allylamine) (Fe 3O 4/PAH) polyelectrolyte to construct the shell. Structural integrity, microstructural evolution, and corresponding release behaviors of fluorescence dyes and doxorubicin were systematically investigated. Experimental observations showed that the presence of the magnetic nanoparticles in the shell structure allowed the shell structure to evolve from nanocavity development to final rupture of the shell under a given magnetic stimulus of different time durations. Such a microstructural evolution of the magnetic sensitive shell structure explained a corresponding variation of the drug release profile, from relatively slow release to burst-like behavior at different stages of stimulus. It has proposed that the presence of magnetic nanoparticles produced heat, due to magnetic energy dissipation (as Brown and Neel relaxations), and mechanical vibration and motion that induced stress development in the thin shell. Both mechanisms significantly accelerated the relaxation of the shell structure, causing such a microstructural evolution. With such a controllable microstructural evolution of the magnetic-sensitive shell structure, active substances can be well-regulated in a manageable manner with a designable profile according to the time duration under magnetic field. A cell culture study also indicated that the magnetic-sensitive microcapsules allowed a rapid uptake by the A549 cell line, a cancerous cell line, suggesting that the magnetic-sensitive microcapsule with controllable rupturing behavior of the shell offers a potential and effective drug carrier for anticancer applications.

Nanocomposites hydrogel (nanohydrogel) composed of chitosan (CS) and montmorillonite (MMT) were prepared and systematically studied for drug release behavior following electrostimulation. The deterioration of the responsiveness and reversibility of CS upon repeated on-off electrostimulation switching operations are major limitations for clinical applications, as it suffers from too much structural instability for the precise control of the release of drug upon cyclic electrostimulation. To overcome these limitations, an inorganic phase, MMT, was incorporated in the CS matrix to enhance the anti-fatigue property and corresponding long-term stable release kinetics. X-ray diffraction analysis and time-dependent optical absorbance showed that the MMT incorporated into the nanohydrogel exhibited an exfoliated nanostructure. The exfoliated silica nanosheets are able to act as cross-linkers to form a network structure between the CS and MMT, and this difference in the cross-linking density strongly affects the release of vitamin B(12) under electrostimulation. With a lower MMT concentration (1 wt.%), the release kinetics of vitamin B(12) from the nanohydrogel shows a pseudo-zero-order release, and the release mechanism was changed from a diffusion-controlled mode to a swelling-controlled mode under electrostimulation. Further increasing the MMT content reduced both the diffusion exponent n and the responsiveness of the nanohydrogel to electrostimulation. In addition, a consecutively repeated "on" and "off" operation shows that the electroresponsiveness of the nanohydrogel with higher MMT concentrations was reduced, but its anti-fatigue behavior was considerably improved. In this work, the nanohydrogel with 2 wt.% MMT achieved a mechanically reliable and practically desirable pulsatile release profile and excellent anti-fatigue behavior, compared with that of the pure CS.

A PVA-based magnetic-sensitive hydrogel (ferrogel) was fabricated by physical cross-linking through a freezing-thawing method. The influence of the constituting components, i.e., Fe3O4 and PVA, on the magnetic-sensitive behavior of the ferrogels was systematically investigated in terms of permeability coefficient (P), partition coefficient (H), space restriction and magnetization. The results show that, the P value in these ferrogels decreases and displays a magnetic sensitivity when it is subjected to magnetic field (MF), which is correlated with the change of H value. In addition, it was found that although the factor of space restriction or magnetization exerts opposite effect on resulting magnetic-sensitive behavior, the superior magnetic-sensitive behavior was observed for the ferrogels with an optimal composition of 17-34% Fe3O4 and 10-12.5% PVA, and can be well correlated with theoretical calculation from the critical parameters of available free volume per nanoparticle (V(free)) and magnetization. A map of magnetic-sensitive behavior was constructed, where a region with relatively stable and highly stimuli-responsive behavior in terms of the concentration of Fe3O4 was observed, however, below or above the "saturation" region (17-34% Fe3O4), a reduction in the magnetic-sensitive behavior was detected. The resulting ferrogels can be engineered with a precise control of the opening and closure of pore configuration, which allows a burst release or no-release action of therapeutically active agent to be controlled externally and magnetically. This suggests that this type of ferrogel can be considered as a class of novel magnetically-tunable drug delivery system.

Magnetic sponge-like hydrogels (ferrosponges) were fabricated by using an in-situ synthesis of magnetic nanoparticles (MNPs) in the presence of various concentrations of gelatin. The resulting ferrosponges show an interconnected nanopore structure which serves as a reservoir to accommodate therapeutic drugs and the nanoporous networks demonstrate magnetic sensitive behavior under the application of magnetic field. The ferrosponges showed high swelling ratios, together with excellent elasticity and hydrophilicity, allow them to response rapidly to an external magnetic stimulation for fast and repeatable swelling-deswelling (or expansion-contractile) operations. The ferrosponges with lower gelatin concentration exhibited good performance on magnetification. Furthermore, drug release from the ferrosponges is relatively magnetic-sensitive and is dominated by its magnetism and associated interaction between the magnetic nanoparticle and the gelatin matrix under an external magnetic field. Higher MNPs concentration in the ferrosponges exhibited higher degree of magnetic sensitive which is due to stronger interparticle forces. By taking these peculiar magnetic sensitive behaviors of the ferrosponges, a novel drug delivery system can be designed for medical uses.

An intelligent magnetic hydrogel (ferrogel) was fabricated by mixing poly(vinyl alcohol) (PVA) hydrogels and Fe3O4 magnetic particles through freezing-thawing cycles. Although the external direct current magnetic field was applied to the ferrogel, the drug was accumulated around the ferrogel, but the accumulated drug was spurt to the environment instantly when the magnetic fields instantly switched "off". Furthermore, rapid to slow drug release can be tunable while the magnetic field was switched from "off" to "on" mode. The drug release behavior from the ferrogel is strongly dominated by the particle size of Fe3O4 under a given magnetic field. The best "magnetic-sensitive effects" are observed for the ferrogels with larger Fe3O4 particles due to its stronger saturation magnetization and smaller coercive force. Furthermore, the amount of drug release can be controlled by fine-tuning of the switching duration time (SDT) through an externally controllable on-off operation in a given magnetic field. It was demonstrated that the highest burst drug amounts and best "close" configuration of the ferrogel were observed for the SDT of 10 and 5 min, respectively. By taking these peculiar magnetic-sensitive characteristics of the novel ferrogels currently synthesized, it is highly expected to have a controllable or programmable drug release profile that can be designed for practical clinical needs.

Calcium-deficient hydroxyapatite (CDHA) nano-crystals incorporated with bovine serum albumin (BSA) to form BSA-loaded nano-carriers were synthesized via both in-situ and ex-situ processes. Amount of BSA uptake by the CDHA nano-crystals and subsequent release behaviors of the BSA-loaded nano-carriers were investigated. The amount of BSA uptake by CDHA decreases with increasing pH but a larger amount was observed in the ex-situ compared to in-situ process above pH=8.0. The release profile showed a bursting behavior for the nano-carrier prepared via the ex-situ process, which is probably due to the desorption of BSA molecules. In contrast, for the sample synthesized via the in-situ process at a higher pH level, a slower release profile without bursting behavior due to the dissolution of the BSA-incorporated CDHA crystal is seen from high solution TEM that indicates different extent of interaction between BSA and CDHA. On the other hand, for the nano-carriers prepared via the same process at lower pH level, a two-stage release profile was detected. An initial bursting release is due to the desorption of BSA from the CDHA surface, followed by a slow release as a result of the dissolution of the BSA-incorporated nano-crystals along its c-axis direction.

Summary: Several biocompatible polymers are capable of large responses to small temperature changes around 37°C. In water, their responses include shrinkage and swelling as well as transitions in wettability. These properties have been harnessed for biomedical applications such as tissue engineering scaffolds and drug delivery carriers. A soft material/hard material hybrid in which a magnetic metal or oxide is embedded in a temperature-responsive polymer matrix can combine the thermal sensitivity with magnetic signatures. Importantly, nanosizing such construct brings about new desirable features of extremely fast thermal response time, small magnetic hysteresis and enhanced magnetic susceptibility. Remote magnetic maneuvering and heating of the hybrid nanocolloids makes possible such applications as high-throughput enzyme separation and cell screening. Robust drug release on demand may also be obtained using these colloids and nanoparticle-derived thin film devices of combined thermal magnetic sensitivity. [Copyright &y& Elsevier]

Abstract: Chitosan is among the most abundant biopolymers on earth and has been either used or exhibited potential in a wide variety of industrial and biomedical applications. With the advancement of materials technologies, chitosan has been chemically modified to self-assemble into nanoarchitectures that are usable in advanced biomedical applications, such as drug nanocarriers, macroscopic injectables, tissue-engineering scaffolds, and nanoimaging agents. Colloidal amphiphilically modified chitosan (AMC) is a relatively recent material receiving increased attention with numerous publications addressing the medical advantages of specific systems. To date, many reviews have focused on the synthesis and biomedical properties of chitosan-based biomaterials, but a comprehensive study focusing on the colloidal properties of AMC in relation to biomedical performance appears to be lacking. This review provides a survey of the field, critically reviewing the colloidal properties and biomedical performance of AMC systems, such as nanoparticle drug delivery systems and macroscopic medical devices. Finally, the future development, market potential, and clinical implications of these promising colloidal-structured biomaterials are summarised. [Copyright &y& Elsevier]

Abstract: Thermo-gelling injectable nanogels, with no burst release of loaded drug, were prepared by a simple route by combining self assembled nanocapsules of amphiphilically modified chitosan with glycerophosphate di-sodium salt and glycerol. The potential as a depot drug delivery system was demonstrated in vivo through the therapeutic effect of ethosuximide (ESM) loaded nanogels, suppressing spike wave discharges (SWDs) in Long Evan rat model. Simultaneously clearance of gels from the site of administration was monitored non-invasively using MRI. The gel structure was characterized using TEM and SEM, confirming the gels to be an assembly of nanocapsules and using two-photon microscopy to visualize the network structure. In vitro drug release studies using ESM revealed that the nanogels exhibited extended, mostly Fickian release. Finally, all investigated formulations displayed excellent cytotoxicity data determined by MTT assay using human retinal pigmented epithelium cells. All presented properties are highly desirable for injectable depot gels for drug delivery. [Copyright &y& Elsevier]

Abstract: Silane-modified amphiphilic chitosan was synthesized by anchoring a silane coupling agent, (3-aminopropyl)triethoxysilane, to a novel amphiphilic carboxymethyl-hexanoyl chitosan (CHC). The chemical structure of this new organic–inorganic hybrid molecule was characterized by FTIR and 13C-, 29Si-nuclear magnetic resonance, while the structural evolution was examined using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and dynamic light scattering (DLS). Experimental results indicated a self-assembly behaviour of molecules into nanoparticles with a stable polygonal geometry, consisting of ordered silane layers of 6nm in thickness. The self-assembly property was found to be influenced by chemical composition and concentration of silane incorporated, while the size can be varied by the amount of anchored silane. It was also demonstrated that such vesicle exhibited excellent cytocompatibility and cellular internalization capability in ARPE-19 cell line, and presented well-controlled encapsulation and release profiles for (S)-(+)-camptothecin. These unique properties render it as a potential drug delivery nanosystem. [Copyright &y& Elsevier]

Abstract: A flexible drug delivery device was designed and fabricated using electrophoretic deposition of drug-carrying magnetic core-shell Fe3O4 at SiO2 nanoparticles onto an electrically conductive flexible PET substrate. The PET substrate was first patterned to a desired layout and subjected to deposition. In doing so, a uniform and nanoporous membrane could be produced. After lamination of the patterned membranes, a final chip-like device of thickness less than 0.5mm is formed that is used for controlled delivery of an anti-epileptic drug, i.e., ethosuximide (ESM). The release of useful drugs can be controlled by directly modulating the magnetic field, and the chip is capable of demonstrating a variety of release profiles (i.e., slow release, sustained release, step-wise release and burst release profiles). These profiles can follow a wide spectrum of patterns ranging from zero to pulsatile release kinetics depending on the mode of magnetic operation. When the magnetic field was removed, the release behavior was instantly ceased, and vice versa. A preliminary in-vivo study using Long–Evans rat model has demonstrated a significant reduction in spike-wave discharge after the ESM was burst released from the chip under the same magnetic induction as in-vitro, indicating the potential application of the drug delivery chip. The flexible and membrane-like drug delivery chip utilizes drug-carrying magnetic nanoparticles as the building blocks that ensure a rapid and precise response to magnetic stimulus. Moreover, the flexible chip may offer advantages over conventional drug delivery devices by improvement of dosing precision, ease of operation, wider versatility of elution pattern, and better compliance. [Copyright &y& Elsevier]

Abstract: A PVA-based magnetic-sensitive hydrogel (ferrogel) was fabricated by physical cross-linking through a freezing–thawing method. The influence of the constituting components, i.e., Fe3O4 and PVA, on the magnetic-sensitive behavior of the ferrogels was systematically investigated in terms of permeability coefficient (P), partition coefficient (H), space restriction and magnetization. The results show that, the P value in these ferrogels decreases and displays a magnetic sensitivity when it is subjected to magnetic field (MF), which is correlated with the change of H value. In addition, it was found that although the factor of space restriction or magnetization exerts opposite effect on resulting magnetic-sensitive behavior, the superior magnetic-sensitive behavior was observed for the ferrogels with an optimal composition of 17–34% Fe3O4 and 10–12.5% PVA, and can be well correlated with theoretical calculation from the critical parameters of available free volume per nanoparticle (V free) and magnetization. A map of magnetic-sensitive behavior was constructed, where a region with relatively stable and highly stimuli-responsive behavior in terms of the concentration of Fe3O4 was observed, however, below or above the “saturation” region (17–34% Fe3O4), a reduction in the magnetic-sensitive behavior was detected. The resulting ferrogels can be engineered with a precise control of the opening and closure of pore configuration, which allows a burst release or no-release action of therapeutically active agent to be controlled externally and magnetically. This suggests that this type of ferrogel can be considered as a class of novel magnetically-tunable drug delivery system. [Copyright &y& Elsevier]

Abstract: The magnetic hydrogels were successfully fabricated by chemically cross-linking of gelatin hydrogels and Fe3O4 nanoparticles (ca. 40–60nm) through genipin (GP) as cross-linking agent. The cross-sectional SEM observation demonstrates that the Fe3O4 nanoparticles were fairly uniformly distributed in the gelatin matrix. Moreover, in vitro release data reveal that drug release profile of the resulting hydrogels is controllable by switching on or off mode of a given magnetic field. While applying magnetic fields to the magnetic hydrogels, the release rate of vitamin B12 of the hydrogels was considerably decreased as compared with those when the field was turned off, suggesting a close configuration of the hydrogels as a result of the aggregation of Fe3O4 nanoparticles. Based on this on-&-off mechanism, the smart magnetic hydrogels based on the gelatin-ferrite hybrid composites can be potentially developed for application in novel drug delivery systems. [Copyright &y& Elsevier]