The treatment of glioblastoma multiforme (GBM) has shown limited efficacy and remains the most lethal form of brain cancer despite therapeutic advancements in recent decades. As a standard-of-care, the combination of surgery and radio-chemotherapy regimens show only moderate benefits with a median survival of just 12-15 months and 5-year survival of less than 5%. Surrounded by functional brain tissue and protected by the blood-brain barrier (BBB), the limited success in treating GBM can be attributed to the pathological hallmarks of the disease, including rapid tumor growth, extensive infiltration, prevalent vascularization and developed resistance to chemotherapeutic agents. Here, we develop a novel type of tumor-targeting, tissue-penetrating nanoparticle capable of effectively interacting with, and traversing the BBB to deliver therapeutic siRNA.<br/>Human serum albumin (HSA) nanoparticles loaded with siRNA and the tumor-targeting, tissue penetrating peptide, iRGD, were synthesized using electrohydrodynamic (EHD) jetting. Physical characterization of the resulting nanoparticles included measuring size and morphology via dynamic light scattering (DLS) and scanning electron microscopy (SEM). Release of encapsulated siRNA, cellular uptake, and intracellular fate was characterized. The targeted delivery of siRNA from albumin nanoparticles and subsequent protein-specific knockdown was validated in GL26 glioma cells. Finally, biodistribution of the targeted nanoparticles, immunogenicity, and in vivo efficacy of the developed system was validated in an established intracranial murine GBM model following systemic administration. Combined with focused radiation, we observe both long-term survivors and complete tumor regression.

Blood-brain barrier penetrating nanoparticle delivery of siRNA for glioblastoma multiforme

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.