Fluorescent Indocarbocyanine PEGylated Lipid Nanoparticles for Understanding and Overcoming Barriers to Drug Delivery in Invasive Glioblastoma

Glioblastoma (GBM) is the most devastating and aggressive brain tumor in adults, with a median survival of only 14.6 months. Hidden behind the blood-brain and blood tumor-barrier (BBTB), the glioma cells that migrate away from the tumor invading surrounding brain tissue, represent the source of recurrence. The invasive cells are not readily accessible to most drug therapeutics, and targeting these cells is an essential goal for achieving better treatment outcomes. Nanoparticles hold promise for drug delivery, but their penetration of BBTB is limited, and the efficiency of targeting of invasive cells has not been studied. We recently discovered that fluorescent indocarbocyanine lipids formulated in PEGylated Lipid Nanoparticles (PLNs) exhibit highly efficient glioma extravasation, with a single injection resulting in accumulation in over 65%% of tumor’s cells and up to 30% of injected dose per gram brain tumor. Furthermore, data in highly invasive glioma models demonstrate that PLNs reach invasive cells at the tumor/brain margin. These findings offer a unique opportunity to comprehensively understand the mechanism of accumulation of lipid nanoparticles and improve drug delivery to invasive gliomas. We will pursue the following specific aims: 1) Study the mechanism of trafficking ICLs across BBTB and within tumor. In this aim, we will test the hypothesis that migration of lipids in tumors takes place via extracellular vesicles; 2) Understand the role of lipid structure and formulation in targeting glioma cells and tumor immune microenvironment. This aim will explore fluorescent lipid chemistries and targeting antibodies to further improve accumulation in invasive cells and immunosuppressive cells in tumors; 3) Exploit ICLs for improved delivery of therapeutics to invasive gliomas. We will explore our previously developed chemistry to conjugate small molecules to ICLs to improve their delivery, drug release, and therapeutic efficacy of cyclin-dependent kinase inhibitor dinaciclib in invasive mouse and patient-derived glioma models. These studies will expand our understanding of the drug delivery process and build a foundation for treating invasive gliomas with BBB/BTB-penetrating nanomedicine.