Magnetically targeted drug delivery

Currently, there are multiple approaches to targeted therapies being researched that involve the use of magnetic micro/nanoparticles. Their high biocompatibility as a result of magnetite's composition and the ability to position the magnetite in biocompatible polymer coatings such as PLA and PLGA makes them a potential resource for cancer treatment and gene delivery. Magnetic targeting utilizes an external magnetic field in combination with MNPs to allow delivery of particles to the desired target area and fixation to a local site while the medication is released and acts locally. This technique allows for decreased dosage of chemical therapies that may otherwise cause deleterious systemic effects. While much work has been completed on functionalizing MNPs and targeting them in vitro, there is minimal work that examines how these MNPs can move through soft tissues to treat disease. Our work uses an alternating magnetic field, applied perpendicularly to a static magnetic gradient to increase magnetic nanoparticle motion through a simulated soft tissue. In order to increase magnetic susceptibility highly superparamagnetic nanoparticles were synthesized with magnetite concentrations of up to 70% (w/w). We found that magnetic nanoparticle uptake is a force dependent process and that an increase in MNP magnetite concentration not only leads to an increase in magnetic force applied to the cell but also increases MNP uptake. Using this process we were able to load bovine aortic endothelial cells with up to 15% of their cell volume without any deleterious effects to the cytoskeletal or mitochondrial function. As a result of the minimal toxic effects, we tested the ability to manipulate the movement of loaded cells and showed that under the influence of a magnetic gradient from a permanent magnet there was significant increase in MNP loaded cell migration through a collagen coated transwell membrane in comparison to control cells. The loaded cells offer less toxic magnetically targeted vectors with a much higher magnetic susceptibility in comparison to MNPs alone. Further research is needed to determine if the "shaking" effect exhibited in the MNP viscous fluid study would work with MNP loaded endothelial cells. This thesis analyzes magnetic nanoparticle synthesis with varying magnetite incorporation and how these differences affect magnetic nanoparticle motion with and without an alternating magnetic field. Through this research it has been found that we can load magnetite crystals into polymer nanoparticles up to 70% w/w without affecting the structural integrity of the particle. As a result, the particles synthesized were on average 250 nm in diameter and were significantly more responsive to external magnetic fields in comparison to standard commercially available nanoparticles that are approximately 30-40% w/w. The increase in magnetic responsiveness yields an increase in magnetic nanoparticle velocity through a viscous fluid, under the influence of a magnetic field provided by a neodymium magnet. The velocity in which particles moved increased linearly with respect to the amount of magnetite incorporated into the particle. The addition of the alternating current field that was applied perpendicular to the line of movement allowed the leading edge of the MNP group to move a 10 mm distance more quickly than the static only group. Additionally, the MNPs exposed to the alternating current field, also had an increase in the percentage of particles that made it the entire 10 mm length.