Development of a magnetically-targeted, MRI-monitored nano-platform for brain tumor drug delivery.

Abstract

Brain tumors inflict a heavy burden of morbidity and high risk of death. Currently employed treatment modalities fail to substantially improve these dismal outcomes. Proteins have recently emerged as a new class of agent with potent anti-glioma activity. However, their therapeutic potential has been limited by formidable challenges in their delivery to brain tumor sites. This dissertation research investigated the feasibility of utilizing magnetic nanoparticles as a carrier for delivery of proteins to brain tumor lesions. Magnetic nanoparticles composed of a superparamagnetic core and a biocompatible polymeric shell presented a promising platform for this application. The core provided high saturation magnetization of 108 emu/g Fe, suggesting that the particles would be amenable to capture within a tumor lesion by an external magnetic field, a strategy termed <italic>magnetic targeting</italic>. Moreover, high T₂ relaxivity of 43 s<super>-1</super>mM<super> -1</super> indicated a possibility for non-invasive monitoring of nanocarrier delivery to the target site by <italic>in vivo</italic> T₂ MRI. Furthermore, the polysaccharide shell of the nanoparticles allowed successful loading of a model protein, beta-Galactosidase (betaGal), with a high loading capacity of 7.5% w/w. To deliver the nanocarriers to brain tumor lesions <italic> in vivo</italic>, an improved magnetic targeting methodology has been developed. This methodology involved administration of nanoparticles via carotid artery, optimization of the magnet configuration, and MRI-guided animal alignment with respect to mapped magnetic field topography. Animal studies in rats harboring 9L-gliosarcomas revealed that utilization of the developed methodology provided a 4.7-fold increase in tumor betaGal activity (636 +/- 42 muU/g tissue) compared to non-targeted control animals (134 +/- 46 muU/g tissue). In addition, high tumor selectivity of protein localization was observed, as tumor tissues displayed 7.5-fold higher betaGal activity (636 +/- 42 muU/g tissue) than the contra-lateral brain (85 +/- 30 muU/g tissue). Moreover, the delivery of the betaGal-loaded nanocarrier to the target site was successfully validated and quantified with non-invasive T₂ MRI. In conclusion, this work established the plausibility of protein delivery to brain tumor lesions using MRI-monitored magnetically-responsive nanoplatform in conjunction with developed magnetic targeting methodology. This accomplishment may pave the way to realization of efficacious protein-based therapies for brain cancer treatment.