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

www.nature.com/scientificreports OPEN Locomotion and disaggregation control of paramagnetic nanoclusters using wireless electromagnetic fields for enhanced targeted drug delivery Kim Tien Nguyen1,5, Gwangjun Go1,5, Jin Zhen4,5, Manh Cuong Hoang1,2,5, Byungjeon Kang1,3, Eunpyo Choi1,2, Jong‑Oh Park1* & Chang‑Sei Kim1,2* 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. Over the past decade, numerous untethered externally powered microrobots and nanorobots have been developed for biomedical a pplications1–8. Wirelessly powered microrobots/nanorobots have been shown to have potential, particularly in targeted cancer therapy, as they offer advantages in performing tasks in minimally invasive surgery, including targeting inaccessible parts of the human b ody9–12. Targeted drug delivery can remarkably improve the access rate of drugs to the target, increase drug absorption, and minimize the required dose. It can also reduce damage to healthy cells compared to conventional therapy methods, such as chemotherapy, where more than 99% of the drug eventually ends up in normal c ells13. To successfully control untethered microrobots/nanorobots in the human body, a number of critical problems should be solved. The first problem is to find a way to transmit the power required for robot motion through human tissues. Among the external power sources, the electromagnetic field has been considered as a distinct solution, because it can penetrate the human body and has been shown to be compatible with medical u se14. With its help, microrobots/nanorobots can be controlled to reach their targets through the interaction of magnetic force and torque. Second, the physics governing microrobot/nanorobot motion is greatly different from the motion in macro-scale environment, where surface friction, Van der Waals, and electrostatic forces dominate 1 Korea Institute of Medical Microrobotics (KIMIRo), 43‑26 Cheomdangwagi‑ro, Buk‑gu, Gwangju, Korea. 2School of Mechanical Engineering, Chonnam National University, 77 Yongbong‑ro, Buk‑gu, Gwangju, Korea. 3College of AI Convergence, Chonnam National University, 77 Yongbong‑ro, Buk‑gu, Gwangju, Korea. 4College of Medical Engineering, Xinxiang Medical University, Xinxiang, Henan, China. 5These authors contributed equally: Kim Tien Nguyen, Gwangjun Go, Jin Zhen, and Manh Cuong Hoang. *email: ; Scientific Reports | (2021) 11:15122 | https://doi.org/10.1038/s41598-021-94446-4 1 Vol.:(0123456789) www.nature.com/scientificreports/ inertial forces15. Furthermore, microrobots/ nanorobots are expected to move in the bloodstream, where blood is considered as an inhomogeneous, non-Newtonian fluid; blood flow and wall effects strongly interfere with robot motion. Consequently, the control of untethered microrobots/nanorobots in targeted drug delivery using an electromagnetic field is limited by several factors, such as the structure, material, and locomotion method of microrobot/nanorobot, as well as the achievable strengths of the magnetic and gradient fields of the actuation system. Motivated by naturally inspired mechanisms, effective control of robot locomotion is researched to improve robot performance. Eukaryotic flagellum or sperm-inspired microrobots driven by wave propulsion using an oscillating field probably have the most efficient motion in fluids with a low Reynolds number16,17. Helical propulsion of bacterial flagellum-inspired microrobots also shows the very accurate performance when using a rotating magnetic field18,19. However, in a targeting task, a robot must carry the drug cargo through blood vessels that are only a few micrometers in diameter. The reduction of the structure size to a few micrometers and the amount of payload dose carried by microrobots were limited3. Therefore, the development of controllable nano-agents is required to carry the drug or magnetic nanoparticle itself as a therapeutic agent. In particular, the dispersion of nanorobots in bio-fluids immediately after injection is typically large; therefore, individual control of these robots by induction of extremely low magnetic forces must be addressed. One possible solution to the above problems is to aggregate the nanorobots into chains or clusters so that they can move in unison, allowing the total magnetic torque and force acting on the aggregated structures to be sufficient for locomotion. In addition to clustering, these structures must be able to disaggregate after reaching the target or entering a narrow vessel. Snezhko et al. presented an extremely interesting cluster of self-assembled colloidal asters based on magnetic nanoparticles by applying a rotating field to the nanoparticle suspension confined between two immiscible liquids. The aster-like swarm can be controlled to change shape by changing frequency; it is also capable of moving and can perform the grasping function using the directed in-plane fi eld20. However, the application of this approach to a real in vivo environment in blood vessels is limited because the assembly principle only occurs at the interface of two immiscible fluids. Yu et al. and Mohorič et al. reported that rotating nanoparticle chains could be induced to swarm out into a vortex-like structure as well as perform translational motion and pick-and-place function using the in-plane rotating magnetic field by changing the pitch angle21–24. By changing the rotation frequency, this approach was able to generate a single vortex or multiple vortices. Recently, the ribbon-like swarm has shown promising locomotion, capable of size elongation, dividing, merging, and even retaining (...truncated)