Objectives: According to the American Cancer Society, over 1.9 million new cases and ~0.6 million deaths are expected in the US in 2023. Therapeutic targeting is considered the gold standard in cancer treatment. However, when a tumor grows beyond a critical size, its vascular system differentiates abnormally and erratically, creating a heterogeneous endothelial barrier that further restricts drug deliveries into tumors. While several methods exist, these prompt tumor migration and the appearance of new metastatic sites. Herein, we propose an innovative method based on magneto-mechanical actuation (MMA) to induce endothelial permeability. This method employs FDA-approved PEGylated superparamagnetic iron oxide nanoparticles (PEG-SPIONs) and alternating non-heating magnetic fields. MMA lies in the translation of magnetic forces into mechanical agitation.
Design: As a proof of concept, we developed a 2D cell culture model based on human umbilical vein endothelial cells (HUVEC), which were incubated with PEG-SPIONs and then exposed to different magnetic doses. After adjusting particle concentration, incubation times, and parameters (amplitude, frequency, and exposure time) of the magnetic field generator, we induced actin filament remodeling and subsequent VE-cadherin junction disruption.
Results: This led to transient gaps in cell monolayers, through which FTIC-dextran was translocated. We observed no cell viability reduction for 3 hr of particle incubation up to a concentration of 100 μg/ml in the presence and absence of magnetic fields. For optimal permeability studies, the magnetic field parameters were adjusted to 100 mT, 65 Hz, and for 30 min in a pulse mode with 5-min OFF intervals. We found that the endothelial permeability reached the highest value (33%) when 2 hr post-magnetic field treatment was used.
Conclusions: To explain these findings, a magneto-mechanical transduced stress mechanism mediated by intracellular forces was proposed. This method can open new avenues for targeted drug delivery into anatomic regions within the body for a broad range of disease interventions.
