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

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Project Abstract Glioblastoma (GBM) is the most devastating and aggressive brain tumor in adults, with patients surviving a median of only 14.6 months. Hidden behind the blood-brain and blood tumor-barrier (BBTB), the glioma cells migrating away from the tumor and invading surrounding brain tissue, are 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 the BBTB is limited, and the efficiency of targeting invasive cells remains unknown. We recently discovered that fluorescent indocarbocyanine lipids (ICLs) formulated in PEGylated Lipid Nanoparticles (PLNs) exhibit highly efficient glioma extravasation, with a single injection resulting in accumulation in ~60% of tumor cells and up to 30% of injected dose per gram of brain tumor. Furthermore, data in highly invasive models demonstrate 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 trafficking mechanism of ICLs across the BBTB and in tumors. In this aim, we will test the hypothesis that lipids migrate in tumors via extracellular vesicles; 2) Understand the role of lipid structure and formulation in targeting glioma cells and the tumor immune microenvironment. This aim will test if accumulation in invasive cells and immunosuppressive cells can be further improved through lipid chemistry, formulation and targeting to glioma marker IL13R2; 3) Exploit ICLs to understand and improve small molecule delivery 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 guide treatment of invasive gliomas with brain tumor-penetrating nanomedicine.