Locomotion and disaggregation control of paramagnetic nanoclusters using wireless electromagnetic fields for enhanced targeted drug delivery

Abstract

Magnetic nanorobots (MNRs) based on paramagnetic nanoparticles/nanoclusters for the targeted therapeutics of anticancer drugs have been highlighted for their efficiency potential. Controlling the locomotion of the MNRs is a key challenge for effective delivery to the target legions. Here, we present a method for controlling paramagnetic nanoclusters through enhanced tumbling and disaggregation motions with a combination of rotating field and gradient field generated by external electromagnets. The mechanism is carried out via an electromagnetic actuation system capable of generating MNR motions with five degrees of freedom in a spherical workspace without singularity. The nanocluster swarm structures can successfully pass through channels to the target region where they can disaggregate. The results show significantly faster response and higher targeting rate by using rotating magnetic and gradient fields. The mean velocities of the enhanced tumbling motion are twice those of the conventional tumbling motion and approximately 130% higher than the gradient pulling motion. The effects of each fundamental factor on the locomotion are investigated for further MNR applications. The locomotion speed of the MNR could be predicted by the proposed mathematical model and agrees well with experimental results. The high access rate and disaggregation performance insights the potentials for targeted drug delivery application.

Figure 1

Conceptual schematic of targeted drug delivery. Nanorobots are driven to targeted area by EnEMAs with proposed swarm motion and visualized by X-ray monitoring; enhanced tumbling motion steers magnetic clusters to reach target area, and disaggregation motion breaks cluster into smaller sizes to enter micro-vessels at site. Drug release is triggered by external stimulus after approaching target area.

Figure 2

Characteristic and biocompatibility of nanoparticles used for locomotion method. (a) TEM image of nanoparticles, (b) magnetization curve of fabricated nanoparticles obtained using vibrating sample magnetometer, (c) cell viability on NIH3T3, and (d) cell viability on 4T1 cells.

Figure 3

Design and implementation of EMA system. (a) Design of enhanced EMA system integrated with biplane X-ray system. θ and α are the alignment angle of the object’s desired orientation projected onto the X axis and XY plane, respectively. (b) Digital photograph of EMA system used in this work for investigating nanorobot motion. (c) COMSOL simulation results of magnetic field map generated by EnEMA system with magnetic and gradient fields of 70 mT and 1.7 T/m at orientations of θ = 0°, 45°, 90° and α = 0°, respectively. (d) Measured and simulated B–I curves of electromagnetic coil showing linearity of generated field with respect to applied current; green area represents linear region in which generated field is highly linear with respect to applied current; red area indicates non-linear region due to core saturation. (e) Propulsion test of system using 300 µm cylindrical magnet at 5 mT and 0.1 T/m. (f) Achievable magnetic and gradient fields in workspace at three orientations: θ_B = 0°, α_B = 0°, θ_F = 90°, α_F = 0°; θ_B = 0°, α_B = 0°, θ_F = 0°, α_F = 90°; θ_B = 0°, α_B = 90°, θ_F = 0°, α_F = 90°. In which θ_B and θ_F are the magnetic field and magnetic force angle along with the θ direction, respectively, and α_B and α_F are the magnetic field and magnetic force angle along with the α direction, respectively.

Figure 4

Enhanced tumbling motion of nanoparticles. (a) Three-dimensional schematic of magnetic field and gradient field applied to generate enhanced tumbling motion. (b) Two-dimensional force and torque exerted on particle chains in proposed locomotion method. (c,d) Captured images of particles chains using proposed method in two different control orientations. (e) Disaggregation mechanism of particle chain. (f) Combination of perpendicular alternative field and gradient field breaks chain structure by chain–chain and dipole–dipole repulsion as illustrated by captured image (f). Scale bars: 500 µm.

Figure 5

Locomotion test of nanoparticles. (a) Experimental results of different particle control methods including conventional tumbling motion, gradient pulling motion, vortex-like swarming motion, and proposed enhanced tumbling motion. (b) Measured moving speed of enhanced tumbling motion at constant 10 mT field with various rotating frequencies (5, 10, 15, 20, 25, and 30 Hz) and gradient field strengths (0, 0.2, 0.4, 0.6, 0.8, and 1 T/m). c Estimated length of chains under conditions similar to (b). Orange bounded regions in (b,c) are data for conventional tumbling motion with zero gradient field. (d) Plot of moving velocity with respect to chain length; orange region represents data for conventional tumbling motion, green is gradient-active region, and blue is inactive region for both rotating frequency and gradient. (e) Measured and simulated data of moving speed of chain-like cluster with different particle concentrations. (f) Simulation results of moving speed dependent on rotating frequency and gradient under conditions similar to (b,c,d).

Figure 6

Time-lapse image of targeting tests in channel using vortex-like swarm toward top (a) and bottom (d) target sites. The red numbers at each point indicate the time when vortex is located; (b,e) enhanced tumbling motion toward top and bottom target sites, respectively. (c,f) Disaggregation of pattern after targeting top and bottom of channel. Scale bar: 10 mm.

Figure 7

Targeting performance of MNR in a channel with flow condition. A frame capture of targeting test using the proposed method to (a) left channel, (b) right channel under a flow rate of 20 mL/min. A frame capture of targeting test using vortex-like swarm to (c) right and (d) left channel under a flow rate of 10 mL/min. (e) A time-lapse vortex formation test under a flow rate of 10 mL/min, where the green arrow represents the flow direction. (d) Recorded targeting rate of the MNR using the proposed method under a different flow rate of 10 mL/min and 20 mL/min and vortex-like swarm with a flow rate of 10 mL/min. Where LT, C, and RT are left targeting, control, and right targeting, respectively. (Please refer to the supplementary videos for more details of these results).