Seminars in Pharmaceutical Sciences
Ph.D. Thesis Defense
Drug Delivery Core, Pharmaceutical Sciences, UW-Madison
(under the supervision of Prof. Robert Thorne)
Thursday, May 10, 2018
Room 2002 Rennebohm Hall
Intrathecal antibody delivery in health and disease: distribution, osmotic enhancement, and receptor-mediated transport in normal rodents and brain cancer models
Communication between the cells and fluids of the central nervous system (CNS) is incredibly complex and poorly understood, which has contributed to a paucity of CNS drugs. Despite the relatively limited understanding of drug transport between the cerebrospinal fluid (CSF) and the brain, there are currently three FDA-approved non-small molecule drugs delivered into the CSF for treatment of CNS disorders and more than 130 in clinical trials. Thus, there is a critical need to improve our knowledge of CSF-to-brain transport mechanisms for macromolecule drugs (e.g., antibodies) to aid in interpretation of results from clinical trials.
In the present study, we demonstrated two main mechanisms of CSF-to-brain transport following infusion into the CSF of rats: slow, size-dependent diffusion at brain-CSF interfaces in the brain’s extracellular spaces and rapid, relatively size-independent transport along the cerebral perivascular spaces. We demonstrated using intrathecal infusion of single-domain antibody fragments (4.5 nm), full-length goat IgG (10 nm), and dual-labeled nanoparticles (13.5 nm) that access into the perivascular spaces was size-dependent and could be enhanced for goat IgG by administration of intrathecal hyperosmolar mannitol. Surprisingly, species-matched rat IgG (10 nm) demonstrated extensive access to the perivascular spaces, which was attributed to Fc receptor mediated entry. These results suggested that rat IgG had a physiological role in the perivascular spaces, i.e., for surveillance of antigens. Thus we probed for endogenous rat IgG (and albumin, the most abundant CSF protein) in untreated animals and revealed endogenous IgG was predominantly localized to CSF interfaces and perivascular spaces, suggesting that rat IgG under physiological conditions in vivo utilizes the perivascular pathways extensively for transport into the brain. However, in a primary rat model of glioma intrathecal infusion of rat IgG failed to access the tumor and there was a significant and global reduction in rat IgG accessing the perivascular spaces. Altogether, these results illuminate the mechanisms and pathways of macromolecule transport between the CSF and brain and suggest that rapid perivascular transport is likely to provide substantial delivery to the larger human brain. However, size-dependent sieving of molecules from CSF-to-brain may significantly hamper distribution of large therapeutic substances, e.g., gene therapy vectors or species-mismatched antibodies and may require strategies to enhance access.