Magnetic Control of the Endothelium Permeability via Magneto-Mechanical Actuation Using Iron Oxide Nanoparticles

Cancer treatment is one of the major health problems that burdens our society. According to the latest publication of the American Cancer Society, the cancer mortality rate has reached 32% in 2021. Tumor hypoxia is one of the main cancer complications, wherein solid tumors grow as they develop larger resistance to current therapies due to the extracellular matrix remodeling of cancer cells. Extracellular remodeling involves the development of abnormal vasculature that can be twisted leading to a dead end and subsequent back blood pressure flow. This imposes certain limitations on drug therapy due to the heterogeneous tumor hypoxic microenvironment. One way to overcome this problem is to disrupt the vascular endothelial-cadherin (VE-cadherin) junctions, using superparamagnetic iron oxide nanoparticles (SPIONs). Direct treatment of SPIONs can cause uncontrolled leakiness and subsequent tumor migration, thus prompting the appearance of new metastatic sites. In this project, we use an indirect approach to internalize ND-PEG SPIONs into human umbilical vein endothelial cells (HUVECs). Then these particles are magnetically activated to induce leakiness on HUVEC monolayers. We control the magnetic activity of ND-PEG SPIONs using non-heating AC magnetic fields. Intracellular ND-PEG SPIONs can assemble near the cytoskeleton and induce hypostress, which can affect cellular integration and VE-Cadherin proteins and in turn the adherens junctions. Our findings indicate that the controlled mechanical motion induced over ND-PEG SPIONs by magnetic torques can disrupt these junctions and enable the passage of therapeutic drugs. This approach can also have the potential to avert cancer migration. This innovative magnetic control provides an effective remotely-controlled drug delivery method harnessing the physics and biology of endothelial adherens junctions. This approach can open a new avenue for targeted drug delivery to specific anatomic regions within the body for a broad range of disease interventions.