Gadolinium-doped biodegradable polymer microspheres for magnetic resonance imaging guided drug delivery

Angiogenesis is the process of developing new capillaries from an existing vascular network. Therapeutic angiogenesis has the potential to be an effective treatment strategy for patients who suffer from ischemic vascular disease. Evidence suggests that the mechanism of delivery is important for angiogenic therapy, and it has been proposed that local, sustained release of low amounts of angiogenic protein may be most effective in creating functional vasculature.; In this work, biodegradable polymer microspheres were proposed as a controlled drug delivery device for angiogenic therapy. In order to be able to monitor the microspheres in vivo, the magnetic resonance imaging (MRI) contrast agent Gd-DTPA was encapsulated within the microspheres. Microspheres made from poly(DL-lactic-co-glycolic acid) encapsulating the angiogenic protein vascular endothelial growth factor (VEGF) and Gd-DTPA were manufactured and characterized in vitro. A relationship was found between the release of growth factor and contrast agent, enabling the release kinetics to be monitored with MRI.; In order to test the microspheres in vivo, MRI-based metrics were developed to measure physiological parameters relevant to angiogenic therapy. Methods were developed to measure permeability surface area product, fractional interstitial volume, and fractional plasma volume using pharmacokinetic modeling and contrast MRI. Simulations were run to evaluate the signal to noise behavior of the model. In vivo studies were conducted in rabbits to investigate regional physiological heterogeneity in lower limb muscles.; A blinded study was conducted to test the potential of the VEGF microspheres to treat ischemia in a rabbit hind limb model. In animals which received VEGF microspheres, improvements in calf blood pressure ratio were observed. Elevated levels of permeability surface area product and fractional interstitial volume were also observed in animals treated with VEGF microspheres. The microspheres were easily detected with MRI and remained localized to the injection site for up to two weeks after intramuscular administration.; Biodegradable polymer microspheres can provide localized, controlled drug delivery for angiogenic therapy. The coencapsulation of a MRI contrast agent can provide in vivo feedback on localization and drug release kinetics.