Targeted delivery of GDNF through the blood-brain barrier by MRI-guided focused ultrasound

• Published in: PloS one 2012-12, Vol.7 (12), p.e52925-e52925
• Main Authors: Wang, Feng, Shi, Yu, Lu, Lin, Liu, Li, Cai, Youli, Zheng, Hairong, Liu, Xin, Yan, Fei, Zou, Chao, Sun, Chengyu, Shi, Jie, Lu, Shukun, Chen, Yun
• Format: Article
• Language: English
• Subjects: Addictions; Alzheimer's disease; Alzheimers disease; Animals; Apoptosis; Avidin; Biology; Biomedical research; Biotin; Blood; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain; Brain - drug effects; Brain - metabolism; Brain cancer; Brain research; Brain-derived neurotrophic factor; Central nervous system; Chemical compounds; Diseases; Drug Delivery Systems - methods; Engineering; Enzyme-linked immunosorbent assay; Extravasation; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - administration & dosage; Growth factors; Health aspects; High-Energy Shock Waves; Hospitals; Laboratories; Lauterbur, Paul C; Macromolecules; Magnetic resonance; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Male; Medicine; Microbubbles; Nervous system diseases; Neurodegenerative diseases; Neuroimaging; Neurological diseases; Neuronal-glial interactions; Neurosciences; Neurotrophic factors; NMR; Nuclear magnetic resonance; Parkinson's disease; Parkinsons disease; PC12 Cells; Permeability; Pharmacology; Proteins; Rats; Rats, Sprague-Dawley; Rodents; Substance abuse treatment; Ultrasonic imaging; Ultrasound
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0052925

Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), are promising therapeutic agents for neurodegenerative diseases. However, the application of GDNF to treat these diseases effectively is limited because the blood-brain barrier (BBB) prevents the local delivery of macromolecular therapeutic agents from entering the central nervous system (CNS). Focused ultrasound combined with microbubbles (MBs) using appropriate parameters has been previously demonstrated to be able to open the BBB locally and noninvasively. This study investigated the targeted delivery of GDNF MBs through the BBB by magnetic resonance imaging (MRI)-guided focused ultrasound. Evans Blue extravasation and histological examination were used to determine the optimum focused ultrasound parameters. Enzyme-linked immunosorbent assay was performed to verify the effects of GDNF bound on MBs using a biotin-avidin bridging chemistry method to promote GDNF delivery into the brain. The results showed that GDNF can be delivered locally and noninvasively into the CNS through the BBB using MRI-guided focused ultrasound combined with MBs under optimum parameters. MBs that bind GDNF combined with MRI-guided focused ultrasound may be an effective way of delivering neurotrophic factors directly into the CNS. The method described herein provides a potential means of treating patients with CNS diseases.