Remote Actuation of Magnetic Nanoparticles For Cancer Cell Selective Treatment Through Cytoskeletal Disruption

Abstract

Motion of micron and sub-micron size magnetic particles in alternating magnetic fields can activate mechanosensitive cellular functions or physically destruct cancer cells. However, such effects are usually observed with relatively large magnetic particles (>250 nm) that would be difficult if at all possible to deliver to remote sites in the body to treat disease. Here we show a completely new mechanism of selective toxicity of superparamagnetic nanoparticles (SMNP) of 7 to 8 nm in diameter to cancer cells. These particles are coated by block copolymers, which facilitates their entry into the cells and clustering in the lysosomes, where they are then magneto-mechanically actuated by remotely applied alternating current (AC) magnetic fields of very low frequency (50 Hz). Such fields and treatments are safe for surrounding tissues but produce cytoskeletal disruption and subsequent death of cancer cells while leaving healthy cells intact.

Cell-Promoted Nanoparticle Aggregation Decreases Nanoparticle-Induced Hyperthermia under an Alternating Magnetic Field Independently of Nanoparticle Coating, Core Size, and Subcellular Localization

“…Therefore, the increased cell death showed by the annexin V/PI assay and the disruption of cell membrane observed in TEM images may be due to thermal-independent factors. One of the possibilities is the generation of mechanical effects that compromise the integrity of the plasmatic membrane, leading to programmed cell death as observed in other studies 34,66 . Data were normalized using the 2 -∆∆Ct method and are shown as mean ± SD (n = 3).…”

“…The mechanisms responsible for these observations have not been elucidated yet, but some data indicate that these effects are related to an increase in lysosomal permeability, which correlates with increased production of reactive oxygen species (ROS), enhanced activity of the lysosomal protease cathepsine D in the cytoplasm, and decreased tumor cell viability [31][32][33] . This lysosomal permeabilization might be caused by mechanical rotation or vibration of SPIONs affecting the lipid membrane stability, since it has been observed that dynamic magnetic fields induce a slow rotation of lysosome-targeted SPIONs, causing the tearing of the lysosomal membrane, and resulting in apoptosis activation 34 . Other possible cause for increased lysosomal permeability might be a very localized intracellular heat release from SPIONs, which also enhances the generation of ROS by the iron oxide surface of the nanoparticles through the Fenton reaction 32,[34][35] , which is known to be temperature dependent 36 .…”

“…This lysosomal permeabilization might be caused by mechanical rotation or vibration of SPIONs affecting the lipid membrane stability, since it has been observed that dynamic magnetic fields induce a slow rotation of lysosome-targeted SPIONs, causing the tearing of the lysosomal membrane, and resulting in apoptosis activation 34 . Other possible cause for increased lysosomal permeability might be a very localized intracellular heat release from SPIONs, which also enhances the generation of ROS by the iron oxide surface of the nanoparticles through the Fenton reaction 32,[34][35] , which is known to be temperature dependent 36 . Recently, it has been observed that the application of an AMF increases the generation of ROS by SPIONs both in suspensions 37 and within cells 38 , suggesting that in response to AMF application, SPIONs convert the energy they absorb into heat, enhancing ROS generation at their surfaces 32 .…”

Magnetic Nanoparticles (MNPs) Influence on SK-BR3 Breast Cancer Cell Line - in vitro Study

“…Master AM et al, 2016 [9] suggested a mechanism by which the superparamagnetic nanoparticles (SMNP) of small size (7-8 nm in diameter) can enter the tumor cells and accumulate and form clusters into the lysosomes, thus being targeted with low frequencies magnetic fields in order to disrupt cellular architecture. We can speculate that our combustion-synthesized MNPs (10 -15 nm in diameter) can also accumulate into the tumor cells and induce per se cytoskeletal disruption.…”

Remote Actuation of Apoptosis in Liver Cancer Cells via Magneto-Mechanical Modulation of Iron Oxide Nanoparticles

“…Alternating magnetic fields have been successfully utilized for magneto-mechanical remote-control of SPIONs in a wide range of biomedical applications; e.g., magnetic tweezers, nanosensing, magnetic cell separation, specific delivery of genes and therapeutic agents, and mechanical modulation in cells [2,[9][10][11]. Interestingly, magnetic field-induced mechanical destruction of cells or cellular organelles was proposed as a promising potential tool for anti-cancer therapy [12][13][14][15].…”