Superparamagnetic iron oxide-gold nanoparticles conjugated with porous coordination cages: Towards controlled drug release for non-invasive neuroregeneration.

This paper reports a smart intracellular nanocarrier for sustainable and controlled drug release in non-invasive neuroregeneration. The nanocarrier is composed by superparamagnetic iron oxide-gold (SPIO-Au) core-shell nanoparticles (NPs) conjugated with porous coordination cages (PCCs) through the thiol-containing molecules as bridges. The negatively charged PCC-2 and positively charged PCC-3 are compared for intracellular targeting. Both types result in intracellular targeting via direct penetration across cellular membranes. However, the pyrene (Py)-PEG-SH bridge enabled functionalization of SPIO-Au NPs with PCC-3 exhibits higher interaction with PC-12 neuron-like cells, compared with the rhodamine B (RhB)-PEG-SH bridge enabled case and the stand-alone SPIO-Au NPs. With neglectable toxicities to PC-12 cells, the proposed SPIO-Au-RhB(Py)-PCC-2(3) nanocarriers exhibit effective drug loading capacity of retinoic acid (RA) at 13.505 µg/mg of RA/NPs within 24 h. A controlled release of RA is achieved by using a low-intensity 525 nm LED light (100% compared to 40% for control group within 96 h).

Engineered nanomedicine for neuroregeneration: light emitting diode-mediated superparamagnetic iron oxide-gold core-shell nanoparticles functionalized by nerve growth factor.

This paper reports nerve growth factor functionalized superparamagnetic iron oxide-gold core-shell nanoparticles (NGF-SPIO-Au NPs), an engineered nanomedicine for non-invasive neuron regeneration when irradiated by a low-intensity light-emitting diode (LED). NGF-SPIO-Au NPs of 20 µg/ml, were tested on PC-12 neuron-like cells, irradiated by LEDs (525 nm, 1.09, 1.44, and 1.90 mW/cm2). A remarkable Ca2+ influx was detected in differentiated PC-12 cells treated with NPs, irradiated by LED of 1.90 and 1.44 mW/cm2 with great cell viability (>84%) and proliferations. The strong heat generated through their plasmonic surface upon LED irradiation on NGF-SPIO-Au NPs was observed. For cells treated with LED (1.90 mW/cm2) and NGF-SPIO-Au NPs, a dramatic enhancement of neuronal differentiation (83%) and neurite outgrowth (51%) was found, and the upregulation of both the neural differentiation specific marker (ß3-tubulin) and the cell adhesive molecule (integrin ß1) was observed by the reverse transcription-polymerase chain reaction and western blot analysis.

Promoting neuroregeneration by applying dynamic magnetic fields to a novel nanomedicine: Superparamagnetic iron oxide (SPIO)-gold nanoparticles bounded with nerve growth factor (NGF).

Neuroregeneration imposes a significant challenge in neuroscience for treating neurodegenerative diseases. The objective of this study is to evaluate the hypothesis that the nerve growth factor (NGF) functionalized superparamagnetic iron oxide (SPIO)-gold (Au) nanomedicine can stimulate the neuron growth and differentiation under external magnetic fields (MFs), and dynamic MFs outperform their static counterparts. The SPIO-Au core-shell nanoparticles (NPs) (Diameter: 20.8 nm) possessed advantages such as uniform quasi-spherical shapes, narrow size distribution, excellent stabilities, and low toxicity (viability >96% for 5 days). NGF functionalization has enhanced the cellular uptake. The promotion of neuronal growth and orientation using NGF functionalized SPIO-Au NPs, driven by both the static and dynamic MFs, was revealed experimentally on PC-12 cells and theoretically on a cytoskeletal force model. More importantly, dynamic MFs via rotation performed better than the static ones, i.e., the cellular differentiation ratio increased 58%; the neurite length elongation increased 63%.

Bioactive superparamagnetic iron oxide-gold nanoparticles regulated by a dynamic magnetic field induce neuronal Ca2+ influx and differentiation.

Treating neurodegenerative diseases, e.g., Alzheimer's Disease, remains a significant challenge due to the limited neuroregeneration rate in the brain. The objective of this study is to evaluate the hypothesis that external magnetic field (MF) stimulation of nerve growth factor functionalized superparamagnetic iron oxide-gold (NGF-SPIO-Au) nanoparticles (NPs) can induce Ca2+ influx, membrane depolarization, and enhance neuron differentiation with dynamic MF (DMF) outperforming static MF (SMF) regulation. We showed the that total intracellular Ca2+ influx of PC-12 cells was improved by 300% and 535% by the stimulation of DMF (1 Hz, 0.5 T, 30min) with NGF-SPIO-Au NPs compared to DMF alone and SMF with NGF-SPIO-Au NPs, respectively, which was attributed to successive membrane depolarization. Cellular uptake performed with the application of sodium azide proved that DMF enhanced cellular uptake of NGF-SPIO-Au NPs via endocytosis. In addition, DMF upregulated both the neural differentiation marker (ß3-tubulin) and the cell adhesive molecule (integrin-ß1) with the existence of NGF-SPIO-Au NPs, while SMF did not show these effects. The results imply that noninvasive DMF-stimulated NPs can regulate intracellular Ca2+ influx and enhance neuron differentiation and neuroregeneration rate.

Blood-brain barrier crossing using magnetic stimulated nanoparticles.

Due to the low permeability and high selectivity of the blood-brain barrier (BBB), existing brain therapeutic technologies are limited by the inefficient BBB crossing of conventional drugs. Magnetic nanoparticles (MNPs) have shown great potential as nano-carriers for efficient BBB crossing under the external static magnetic field (SMF). To quantify the impact of SMF on MNPs' in vivo dynamics towards BBB crossing, we developed a physiologically based pharmacokinetic (PBPK) model for intraperitoneal (IP) injected superparamagnetic iron oxide nanoparticles coated by gold and conjugated with poly (ethylene glycol) (PEG) (SPIO-Au-PEG NPs) in mice. Unlike most reported PBPK models that ignore brain permeability, we first obtained the brain permeabilities with and without SMF by determining the concentration of SPIO-Au-PEG NPs in the cerebral blood and brain tissue. This concentration in the brain was simulated by the advection-diffusion equations and was numerically solved in COMSOL Multiphysics. The results from the PBPK model after incorporating the brain permeability showed a good agreement (regression coefficient R2 = 0.848) with the in vivo results, verifying the capability of using the proposed PBPK model to predict the in vivo biodistribution of SPIO-Au-PEG NPs under the exposure to SMF. Furthermore, the in vivo results revealed that the distribution coefficient from blood to brain under the exposure to SMF (4.01%) is slightly better than the control group (3.68%). In addition, the modification of SPIO-Au-PEG NPs with insulin (SPIO-Au-PEG-insulin) showed an improvement of the brain bioavailability by 24.47% in comparison to the non-insulin group. With the SMF stimulation, the brain bioavailability of SPIO-Au-PEG-insulin was further improved by 3.91% compared to the group without SMF. The PBPK model and in vivo validation in this paper lay a solid foundation for future study on non-invasive targeted drug delivery to the brain.

Progress, Opportunities, and Challenges of Magneto-Plasmonic Nanoparticles under Remote Magnetic and Light Stimulation for Brain-Tissue and Cellular Regeneration.

Finding curable therapies for neurodegenerative disease (ND) is still a worldwide medical and clinical challenge. Recently, investigations have been made into the development of novel therapeutic techniques, and examples include the remote stimulation of nanocarriers to deliver neuroprotective drugs, genes, growth factors, and antibodies using a magnetic field and/or low-power lights. Among these potential nanocarriers, magneto-plasmonic nanoparticles possess obvious advantages, such as the functional restoration of ND models, due to their unique nanostructure and physiochemical properties. In this review, we provide an overview of the latest advances in magneto-plasmonic nanoparticles, and the associated therapeutic approaches to repair and restore brain tissues. We have reviewed their potential as smart nanocarriers, including their unique responsivity under remote magnetic and light stimulation for the controlled and sustained drug delivery for reversing neurodegenerations, as well as the utilization of brain organoids in studying the interaction between NPs and neuronal tissue. This review aims to provide a comprehensive summary of the current progress, opportunities, and challenges of using these smart nanocarriers for programmable therapeutics to treat ND, and predict the mechanism and future directions.

Thermocouple-tip-exposing temperature assessment technique for evaluating photothermal conversion efficiency of plasmonic nanoparticles at low laser power density.

A new thermocouple (TC) tip-exposing temperature assessment technique that combines experimental temperature measurements with a numerical model of the photothermal conversion efficiency η is presented. The proposed technique is designed to evaluate η for a gold-coated superparamagnetic iron oxide nanoparticle (SPIO-Au NP) solution (26 nm, 12-70 ppm) at low continuous wave laser power (103 mW, 532 nm) irradiation in a convenient manner under ambient conditions. The TC tip temperature is measured during the first 30 s of the laser exposure, and the results are combined with a finite element model to simulate the temperature rise of the NP solution for a given concentration. The value of η is adjusted in the model until the model agrees with the measured transient TC temperature rise. Values of η = 1.00 were observed for all concentrations. Theoretical predictions of η derived by Mie theory confirmed the near unity conversion efficiency of the as-synthesized SPIO-Au NPs. Advantages of the current technique include co-locating the TC tip in the geometric center of the laser-heated region, rather than outside of this region. In addition, the technique can be done under ambient room conditions using unmodified commercially available hardware.

SPIO-Au core-shell nanoparticles for promoting osteogenic differentiation of MC3T3-E1 cells: Concentration-dependence study.

This work aims to explore the concentration-dependence of SPIO-Au core-shell nanoscale particles (NPs) (17.3 ± 1.2 nm in diameter) on biocompatibility and osteogenic differentiation of preosteoblast MC3T3-E1 cells. The stability of NPs was first investigated by UV-vis absorption spectra and zeta potential measurement. Then concentration effects of NPs (1-80 µg/mL) were evaluated on viability, morphology, proliferation, cellular uptake, and alkaline phosphate (ALP) activity levels. Results have shown strong stability and no acute toxicity (viability > 93%) or morphological difference at all concentration levels of NPs. The proliferation results indicated that the concentration of NPs below 40 µg/mL does not affect the cell proliferation for 7 days of incubation. Transmission electron microscopy images revealed the successful internalization of NPs into MC3T3-E1 cells and the dose-dependent accumulation of NPs inside the cytoplasm. The ALP level of MC3T3-E1 cells was improved by 49% (of control) after treated with NPs at 10 µg/mL for 10 days, indicating their positive effect on early osteogenic differentiation. This study confirmed the excellent biocompatibility of SPIO-Au NPs and their great potential for promoting osteogenic differentiation and promised the future application for these NPs in bone engineering including drug delivery, cell labeling, and activity tracking within scaffolds. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3350-3359, 2017.