Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, pathologically characterized by the accumulation of aggregated amyloid beta (Aβ) in the brain. Here, we describe for the first time the development of a new, pioneering nanotechnology-based drug delivery approach for potential therapies for neurodegenerative diseases, particularly AD. We demonstrated the delivery of fluorescent carboxyl magnetic Nile Red particles (FMNPs) to the brains of normal mice using a functionalized magnetic field (FMF) composed of positive- and negative-pulsed magnetic fields generated by electromagnetic coils. The FMNPs successfully reached the brain in a few minutes and showed evidence of blood-brain barrier (BBB) crossing. Moreover, the best FMF conditions were found for inducing the FMNPs to reach the cortex and hippocampus regions. Under the same FMF conditions, dextran-coated FeO magnetic nanoparticles (MNPs) loaded with osmotin (OMNP) were transported to the brains of Aβ-treated mice. Compared with native osmotin, the OMNP potently attenuates Aβ-induced synaptic deficits, Aβ accumulation, BACE-1 expression and tau hyperphosphorylation. This magnetic drug delivery approach can be extended to preclinical and clinical use and may advance the chances of success in the treatment of neurological disorders like AD in the future.

The "impermeability" of the blood-brain barrier (BBB) has hindered effective treatment of central nervous system (CNS) disorders such as Alzheimer's disease (AD), which is one of the most common neurodegenerative disorders. A drug can be delivered to a targeted disease site effectively by applying a strong electromagnetic force to the conjugate of a drug and magnetic nanocontainers. This study developed a novel nanotechnology-based strategy to deliver therapeutic agents to the brain via the BBB as a possible therapeutic approach for AD. First, a novel approach for an electromagnetic actuator for guiding nanocontainers is introduced. Then, we analyzed the in vivo uptake in mice experimentally to evaluate the capacity of the nanocontainers. In the mouse model, we demonstrated that magnetic particles can cross the normal BBB when subjected to external electromagnetic fields of 28 mT (0.43 T/m) and 79.8 mT (1.39 T/m). Our study also assessed the differential effects of pulsed (0.25, 0.5, and 1 Hz) and constant magnetic fields on the transport of particles across the BBB in mice injected with magnetic nanoparticles (MNPs) via a tail vein. The applied magnetic field was either kept constant or pulsed on and off. Relative to a constant magnetic field, the rate of MNP uptake and transport across the BBB was enhanced significantly by a pulsed magnetic field. Localization inside the brain was established using fluorescent MNPs. These results using 770-nm fluorescent carboxyl magnetic nanocontainers demonstrated the feasibility of the proposed electromagnetic targeted drug delivery actuator. These results establish an effective strategy for regulating the biodistribution of MNPs in the brain through the application of an external electromagnetic field. This might be a valuable targeting system for AD diagnosis and therapy.

Abstract-Magnetic drug targeting is an approach to guide and concentrate magnetic nanoparticles (MNPs) into the diseased target organ after being injected into blood vessels. Although many works for drug targeting have been conducted, there are few studies on delivering the nanoparticles to the target region. Drug delivery performance has not been addressed sufficiently or fully. In this paper, we investigate the effect of dominant factors to MNPs delivery performance. Then, an optimized field function scheme with a pulsed magnetic actuation is proposed to significantly improve the MNPs guidance performance. With a specific condition of blood vessel size, particle size, and applied magnetic field, the optimized parameters of the field function are selected through extensive simulation studies. We find out that the optimal negative and positive time for the magnetic pulsed field mainly depends on the exit time for particles to reach the bifurcation and the critical time as the maximum time for them to reach the vessels wall, respectively. With the chosen parameters, we show that ratios of correctly guided particles in a Y-channel are reached to 100%. In addition, to minimize the power consumption, a modified field function (MFF) scheme is introduced. The MFF includes a no-power time, called zero-time, between the positive and negative time. It is shown that with the proposed MFF, the energy consumption and the heating problem of the actuator system can be significantly reduced. Therefore, the proposed guidance scheme for MNPs can overcome the sticking issue and maximize the guidance performance as well as reducing the power consumption. It should be noted that the MFF can be easily implement by programmable DC power supplies connected to electromagnetic coils.

Magnetic nanoparticles (MNPs) are recently used in a drug delivery system to pass the blood brain barrier. However, because the magnetic force acting on particles is proportional to their volumes, as the size of particles is small, the large magnetic field is required to produce enough magnetic force for overcoming the hydrodynamic drag force as well as other forces in blood vessels. Other difficulties for controlling MNPs are the complicated behavior of hydrodynamic drag force and uncertain factors in their dynamics. Therefore, open-loop control methods cannot guarantee guiding every MNP to the correct location. Considering these challenges, this paper introduces a feedback control approach for magnetic nanoparticles (MNPs) in blood vessels. To the best of our knowledge, this is the first time feedback controller that is designed for MNPs without aggregation. Simulation studies in MATLAB and real-time verifications on a physical model in COMSOL-MATLAB interface are performed to prove the feasibility of the proposed approach. It is shown that the proposed control scheme can accurately and effectively navigate the MNP to the correct path with feasible hardware supports.