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

https://doi.org/10.1016/j.bbrc.2005.12.112Get rights and content

Abstract

The blood–brain barrier (BBB) is a persistent obstacle for the local delivery of macromolecular therapeutic agents to the central nervous system (CNS). Many drugs that show potential for treating CNS diseases cannot cross the BBB and there is a need for a non-invasive targeted drug delivery method that allows local therapy of the CNS using larger molecules. We developed a non-invasive technique that allows the image-guided delivery of antibody across the BBB into the murine CNS. Here, we demonstrate that subsequent to MRI-targeted focused ultrasound induced disruption of BBB, intravenously administered dopamine D4 receptor-targeting antibody crossed the BBB and recognized its antigens. Using MRI, we were able to monitor the extent of BBB disruption. This novel technology should be useful in delivering macromolecular therapeutic or diagnostic agents to the CNS for the treatment of various CNS disorders.

Section snippets

Methods

Antibody. The antibody used in this experiment is a rabbit anti-human dopamine D4 receptor antibody, which recognizes the 3rd extracellular domain (Ac-176-185) of the human dopamine D4 receptor (Cat# 324405, Merck KGaA, Darmstadt, Germany) [20]. Cross-reactivity of this antibody for mouse brain was confirmed by standard immunohistochemistry with a dilution of 1:10,000.

Ultrasound equipment. The ultrasound fields were generated by an in-house manufactured, focused, piezoelectric transducer with a

Results

Using a mouse model and MRI-guided focused ultrasound-induced BBB disruption, we made an attempt to deliver a polyclonal antibody against the extracellular domain of the dopamine D4 receptor to the CNS. The antibody is originated from rabbit IgG. Therefore, the rabbit polyclonal antibody should be able to be detected with an anti-rabbit IgG antibody on the sections with successful BBB disruption. The experiment setup is illustrated in Fig. 1A, which is a setup similar to those of our previous

Discussion

Today many molecular targeting drugs have been developed for various diseases, such as anti-HER2 monoclonal antibody; herceptin for breast cancer [23], and anti-CD20 monoclonal antibody; Rituximab for malignant lymphoma [24]. There are also evidences suggesting that antibodies against the Aβ can reverse cognitive deficits in early Alzheimer’s disease [25], [26]. However, for in vivo clinical treatment, these promising large molecular agents are not applicable because of the presence of BBB.

Acknowledgments

This investigation was supported by the Shinya International Exchange Fund, the Osaka Medical Research Foundation for Incurable Diseases, the Osaka Neurological Institute, NIH Grant (EB003268) and U41-RR 019703 NIH P01CA67165-03.

References (27)

  • W.M. Pardridge

    Drug and gene targeting to the brain with molecular Trojan horses

    Nat. Rev. Drug Discov.

    (2002)
  • W.M. Pardridge

    Blood–brain barrier genomics and the use of endogenous transporters to cause drug penetration into the brain

    Curr. Opin. Drug Discov. Dev.

    (2003)
  • S.R. Schwarze et al.

    In vivo protein transduction: delivery of a biologically active protein into the mouse

    Science

    (1999)
  • Cited by (287)

    • High-intensity focused ultrasound for medical therapy

      2023, Power Ultrasonics: Applications of High-Intensity Ultrasound, Second Edition
    View all citing articles on Scopus
    View full text