Ang2 and TAT peptides show differential leptomeningeal disease targeting based on intravenous vs. intrathecal administration routes

Leptomeningeal disease (LD), a severe complication of cancers like breast cancer (BC) and pediatric medulloblastoma (MB), involves metastasis to the central nervous system's leptomeningeal membranes. Current therapies often fail due to poor drug penetration across complex biological barriers to the subarachnoid space (SAS), the primary site of LD. Angiopep-2 (Ang2) and transactivating transcriptional activator (TAT) are peptides known for their brain delivery capabilities, but their efficacy in targeting LD via different administration routes, particularly intrathecal (IT) vs. intravenous (IV), remains poorly understood.

Researchers generated two xenograft models of LD by directly infusing MDA-MB231 breast cancer cells or HDMB03 medulloblastoma cells into the subarachnoid space (SAS) via intracisternal magna injection (ICM) in mice, creating BC-LD and MB-LD models. These models were characterized for overall survival, tumor growth, and hydrocephalus. Fluorescently labeled Ang2 or TAT peptides were then administered either IV or ICM into tumor-bearing mice. Peptide targeting ability was evaluated by neuraxial fluorescence imaging and ex vivo colocalization between peptide signal and tumor tissues.

The study aimed to compare the targeting capability of Ang2 versus TAT peptides when delivered via intrathecal (IT) versus intravenous (IV) routes of administration. Researchers developed and characterized two robust xenograft models of leptomeningeal disease (LD), using MDA-MB231 breast cancer cells and HDMB03 medulloblastoma cells, established through intracisternal magna injection (ICM). These models allowed for the direct assessment of peptide distribution within the subarachnoid space (SAS). The primary method for evaluating peptide targeting involved neuraxial fluorescence imaging and subsequent ex vivo colocalization analysis, which assessed the spatial overlap between the fluorescently labeled peptides and tumor tissues. This approach was designed to reveal how the choice of peptide (Ang2 vs. TAT) and the route of administration (IV vs. ICM) influenced the peptides' ability to reach and associate with LD lesions.