Ang2 and TAT targeting of leptomeningeal disease by the intravenous and intrathecal routes: a comparative analysis

Abstract

Leptomeningeal disease (LD) refers to the metastasis of cells to the leptomeningeal membranes in the central nervous system (CNS), and it is a deadly complication of several different types of cancer, including breast cancer (BC) and pediatric medulloblastoma (MB). Angiopep-2 (Ang2) and transactivating transcriptional activator (TAT) peptides have been reported to transport therapeutic cargos into the CNS. Here, compared the LD-targeting capability of Ang2 vs TAT by intrathecal (intracisternal magna, ICM) vs intravenous (IV) routes of administration. We first generated two xenograft models of LD by directly infusing breast cancer cells (MDA-MB231) or medulloblastoma cells (HDMB03) via the ICM route, characterizing models for survival, tumor growth patterns, and presence of hydrocephalus. Second, we administered fluorescently labeled Ang2 or TAT peptides either IV or ICM into tumor bearing mice to examine ligand localization. We discovered that the median survival of both models was negatively related to the number of the cells infused. While HDMB03 cells tended to metastasize preferentially to the brain region, MDA-MB231 cells tended to metastasize preferentially to the spinal cord. Compared to the healthy control, MB-LD yielded a 7.3-fold increase and BC-LD a 26.5-fold increase in ventricular volume. Furthermore, targeting achieved by TAT was significantly higher than targeting achieved by Ang2 in thoracic spine for the MB-LD model. For BC-LD, TAT targeting was superiot to Ang2 in the olfactory bulbs, brain stem, thoracic spine, and lumbar spine regions. Significantly, these data provide evidence that ICM will be a preferable route of administration over IV for maximally targeting LD.