Noninvasive Localized Delivery of Herceptin to the Mouse Brain by MRI-Guided Focused Ultrasound-Induced Blood-Brain Barrier Disruption

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 31; pp. 11719 - 11723
• Main Authors: Kinoshita, Manabu, McDannold, Nathan, Jolesz, Ferenc A., Hynynen, Kullervo
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01.08.2006; National Acad Sciences
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic Agents - administration & dosage; Biological Sciences; Blood brain barrier; Blood-Brain Barrier - anatomy & histology; Blood-Brain Barrier - diagnostic imaging; Brain; Brain - anatomy & histology; Brain - metabolism; Brain damage; Brain diseases; Breast cancer; Breast Neoplasms - drug therapy; Central nervous system; Chemotherapy; Drug Delivery Systems - methods; Female; Flood damage; Humans; In Situ Nick-End Labeling; Lesions; Magnetic Resonance Imaging; Medical treatment; Mice; Monoclonal antibodies; Nervous system; NMR; Nuclear magnetic resonance; Skull; Trastuzumab; Tumors; Ultrasonography; Ultrasonography - instrumentation; Ultrasonography - methods
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0604318103

Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/ c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood-brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound blood-brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system.