Systemic nanotherapies targeting neuroinflammation: Unexpected therapeutic actions of hydroxylated dendrimers in the CNS

Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of cerebral palsy (CP), autism, retinal degeneration, and other debilitating neurodegenerative disorders. 'Engineering' the functional response of the microglia, to achieve targeted attenuation of neuroinflammation, can be a potent therapeutic strategy. However, drug delivery to the central nervous system is strongly restricted for most drugs by the blood-brain-barrier, making treatment of diffuse neuroinflammation a challenge. We take advantage of the unique, intrinsic, pathology-dependent, biodistribution patterns of dendrimers (with no targeting moieties) in diseases models of neurodegeneration. For example, dendrimers are transported to the periventricular region of the brain of newborn rabbit kits with cerebral palsy (CP), whereas relatively little brain uptake is seen in healthy animals. Interestingly, they further localize selectively in activated microglia and astrocytes in animals with CP. Such selective localization in activated microglia is also seen in multiple brain and retinal injury small and large animal models. Building on these findings, we have designed and synthesized dendrimer-drug nanodevices, taking advantage of their rich surface functionality using appropriate linking chemistry. They can deliver and release the drug in the targeted tissue in a tailored and sustained manner. Two examples of this approach of targeting neuroinflammation the retina and the brain (from systemic administration) will be presented. We show that a single intravenous dose of dendrimer-drug conjugate, administered after birth to rabbit kits with CP, results in significant improvement in motor function along with decrease in neuroinflammation and oxidative/neuronal injury, followed by improved myelination, by 5 days of age.1 This improvement is sustained till adulthood, paving way for new approaches to pediatric/neonatal brain injuries. These studies suggest that attenuation of ongoing neuroinflammation, achieving by appropriate manipulation of the glial response, can have significant positive consequences in these and other debilitating neurodegenerative diseases. We are studying the mechanism of how the dendrimers target CNS inflammation, and how to take advantage of it for developing therapies for neuroinflammation-associated disorders.

Biography
Dr. Rangaramanujam M. Kannan is a professor of ophthalmology and co-director of center for nanomedicine at the Wilmer Eye Institute at Johns Hopkins School of Medicine. He holds joint appointments in Kennedy Krieger Institute, and Chemical & Biomolecular Engineering and Materials Science. He obtained his PhD from the California Institute of Technology, and a post-doc from the University of Minnesota. His research spans a wide range of nanomaterial applications, including nanomedicine and nanocomposites. He has initiated an interdisciplinary translational research program based on dendrimers, with a specific focus on targeted drug delivery for ocular and neurodegenerative diseases such as cerebral palsy, and age-related macular degeneration. Dr. Kannan is an author of many patents, more than 80 peer-reviewed publications. He has won several recognitions, including the NSF CAREER and Unilever awards, and serves on the editorial board of Nanomedicine (NBM). He is a co-founder and CTO of two recent companies Ashvattha Therapeutics LLC, and Orpheris Inc., which seek to translate/commercialize the dendrimer therapy approaches.

Molecular Engineering and Sciences Seminar Series

This weekly seminar brings together students, faculty and invited guests from various disciplines across campus to explore current trends in molecular engineering and nanotechnology. It is a  forum for active interdisciplinary discussions.  These talks are open to the public and attract a diverse audience of students and faculty.