Ultrasound-sensitizing nanoparticle complex for overcoming the blood-brain barrier: an effective drug delivery system

Shin-Woo Ha,1,2,* Kihwan Hwang,3,* Jun Jin,3 Ae-Sin Cho,1 Tae Yoon Kim,1,2 Sung Il Hwang,1 Hak Jong Lee,1–2,4–5 Chae-Yong Kim3,61Department of Radiology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam 13605, South Korea; 2Research Institute, IMGT Co., Ltd, Seongnam, 13605, South Korea; 3Department of Neurosurgery, Seoul National University Bundang Hospital, Seongnam-si, South Korea; 4Department of Nanoconvergence, Seoul National University Graduate School of Convergence Science and Technology, Seoul, South Korea; 5Research Strategy and Management Division and Medical Device R&D Center, Seoul National University Bundang Hospital, Seongnam 13605, South Korea; 6Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University, Seoul, South Korea*These authors contributed equally to this workBackground: Crossing the blood–brain barrier (BBB) is crucial for drug delivery to the brain and for treatment of brain tumors, such as glioblastoma, the most common of all primary malignant brain tumors. Microbubble (MB) is oscillated and destroyed by controlling ultrasound (US) parameters. This oscillation and destruction of MB can open the BBB transiently, and a drug can be delivered to the brain.Materials and methods: For testing the efficiency of delivery to the brain, we synthesized a US-sensitizing nanoparticle (NP) complex via chemically binding MBs and NPs for the BBB opening, including near-infrared dye-incorporated albumin nanoparticles (NIR-Alb NPs) for fluorescence detection.Results: The human-derived, biocompatible NIR-Alb NPs did not show significant cytotoxicity to 500 μg/mL for 3 days in four human glioma cell lines. In an in vivo animal study, some US parameters were investigated to determine optimal conditions. The optimized US conditions were applied in a U87MG orthotopic mouse model. We found that the fluorescence intensity in the brain was 1.5 times higher than in the control group.Conclusion: Our US-sensitizing NP complex and US technique could become one of the critical technologies for drug delivery to the brain.Keywords: blood–brain barrier, ultrasound, nanoparticle, microbubble, complex, drug delivery