Project Summary/Abstract Despite recent progress in cancer therapy, the brain tumor glioblastoma (GBM) remains an extremely challenging disease and new therapies are badly needed. One of the biggest obstacles to effective treatment of GBM is the presence of the blood-brain barrier (BBB), which prevents the passage of many drugs into the brain. The highly invasive nature of GBM means there are always cells that remain after surgery in otherwise normal brain tissue, and these cells are protected behind the BBB, preventing many drugs from reaching them. To address this we have formed a collaboration between Sean Lawler’s pre-clinical GBM therapeutics group at BWH, and Brad Pentelute’s peptide chemistry group at MIT to develop approaches to 1) specifically target glioblastoma cells, and 2) to identify agents which will cross the BBB. Our collaboration has identified a novel peptide (M13) modified with fluorinated linkers that penetrate the BBB in vivo. To build on this our aims are as follows: Specific Aim 1. Investigate effects of altered chemical properties on BBB penetration by peptides modified with fluorinated linkers. Specific Aim 2. Examine therapeutic effects of a BBB penetrant p53/MDM2 inhibitor. Specific Aim 3. Delivery of BBB-penetrant macrocyclic peptide-drug conjugates in glioblastoma mouse models. Our goal is to use our findings to provide the basis for further development of improved therapeutics and provide a platform for clinical trials for glioblastoma and potentially other tumors of the central nervous system.