Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption

Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11719-23. doi: 10.1073/pnas.0604318103. Epub 2006 Jul 25.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / administration & dosage*
  • Blood-Brain Barrier / anatomy & histology
  • Blood-Brain Barrier / diagnostic imaging*
  • Brain* / anatomy & histology
  • Brain* / metabolism
  • Breast Neoplasms / drug therapy
  • Drug Delivery Systems / methods*
  • Female
  • Humans
  • In Situ Nick-End Labeling
  • Magnetic Resonance Imaging
  • Mice
  • Trastuzumab
  • Ultrasonography / instrumentation
  • Ultrasonography / methods

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Trastuzumab