Ultrasound Enhanced Delivery of Molecular Imaging and Therapeutic Agents in Alzheimer's Disease Mouse Models
Abstract
Alzheimer's disease is a neurodegenerative disorder typified by the accumulation of
a small protein, beta-amyloid, which aggregates and is the primary component of amyloid
plaques. Many new therapeutic and diagnostic agents for reducing amyloid plaques have
limited efficacy in vivo because of poor transport across the blood-brain barrier.
Here we demonstrate that low-intensity focused ultrasound with a microbubble contrast
agent may be used to transiently disrupt the blood-brain barrier, allowing non-invasive,
localized delivery of imaging fluorophores and immunotherapeutics directly to amyloid
plaques. We administered intravenous Trypan blue, an amyloid staining red fluorophore,
and anti-amyloid antibodies, concurrently with focused ultrasound therapy in plaque-bearing,
transgenic mouse models of Alzheimer's disease with amyloid pathology. MRI guidance
permitted selective treatment and monitoring of plaque-heavy anatomical regions, such
as the hippocampus. Treated brain regions exhibited 16.5 +/- 5.4-fold increase in
Trypan blue fluorescence and 2.7 +/- 1.2-fold increase in anti-amyloid antibodies
that localized to amyloid plaques. Ultrasound-enhanced delivery was consistently reproduced
in two different transgenic strains (APPswe:PSEN1dE9, PDAPP), across a large age range
(9-26 months), with and without MR guidance, and with little or no tissue damage.
Ultrasound-mediated, transient blood-brain barrier disruption allows the delivery
of both therapeutic and molecular imaging agents in Alzheimer's mouse models, which
should aid pre-clinical drug screening and imaging probe development. Furthermore,
this technique may be used to deliver a wide variety of small and large molecules
to the brain for imaging and therapy in other neurodegenerative diseases.
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https://hdl.handle.net/10161/4493Published Version (Please cite this version)
10.1371/journal.pone.0002175Citation
Raymond,Scott B.;Treat,Lisa H.;Dewey,Jonathan D.;McDannold,Nathan J.;Hynynen,Kullervo;Bacskai,Brian
J.. 2008. Ultrasound Enhanced Delivery of Molecular Imaging and Therapeutic Agents
in Alzheimer's Disease Mouse Models. Plos One 3(5): e2175-e2175.
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