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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.

SUBMITTER: Raymond SB

PROVIDER: S-EPMC2364662 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models.

Raymond Scott B SB Treat Lisa H LH Dewey Jonathan D JD McDannold Nathan J NJ Hynynen Kullervo K Bacskai Brian J BJ

PloS one 20080514 5

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, allowin ...[more]

PMID: 18478109

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Project description:A wide variety of hydrophilic imaging and therapeutic agents are unable to gain access to the central nervous system (CNS) due to the blood-brain barrier (BBB). In particular, unless a particular transporter exists that may transport the agent across the BBB, most agents that are larger than 500 Da or that are hydrophilic will be excluded by the BBB. Glutamate carboxypeptidase II (GCPII), also known as the prostate-specific membrane antigen (PSMA) in the periphery, has been implicated in various neuropsychiatric conditions. As all agents that target GCPII are hydrophilic and thereby excluded from the CNS, we used GCPII as a platform for demonstrating our MR-guided focused ultrasound (MRgFUS) technique for delivery of GCPII/PSMA-specific imaging agents to the brain.Female rats underwent MRgFUS-mediated opening of the BBB. After opening of the BBB, either a radio- or fluorescently labeled ureido-based ligand for GCPII/PSMA was administered intravenously. Brain uptake was assessed for 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([18F]DCFPyL) and YC-27, two compounds known to bind GCPII/PSMA with high affinity, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging, respectively. Specificity of ligand binding to GCPII/PSMA in the brain was determined with co-administration of a molar excess of ZJ-43, a compound of the same chemical class but different structure from either [18F]DCFPyL or YC-27, which competes for GCPII/PSMA binding.Dynamic PET imaging using [18F]DCFPyL demonstrated that target uptake reached a plateau by ?1 h after radiotracer administration, with target/background ratios continuing to increase throughout the course of imaging, from a ratio of ?4:1 at 45 min to ?7:1 by 80 min. NIRF imaging likewise demonstrated delivery of YC-27 to the brain, with clear visualization of tracer in the brain at 24 h. Tissue uptake of both ligands was greatly diminished by ZJ-43 co-administration, establishing specificity of binding of each to GCPII/PSMA. On gross and histological examination, animals showed no evidence for hemorrhage or other deleterious consequences of MRgFUS.MRgFUS provided safe opening of the BBB to enable specific delivery of two hydrophilic agents to target tissues within the brain. This platform might facilitate imaging and therapy using a variety of agents that have heretofore been excluded from the CNS.

Project description:Rationale: Despite recent advances in the use of adeno-associated viruses (AAVs) as potential vehicles for genetic intervention of central and peripheral nervous system-associated disorders, gene therapy for the treatment of neuropathology in adults has not been approved to date. The currently FDA-approved AAV-vector based gene therapies rely on naturally occurring serotypes, such as AAV2 or AAV9, which display limited or no transport across the blood-brain barrier (BBB) if systemically administered. Recently developed engineered AAV variants have shown broad brain transduction and reduced off-target liver toxicity in non-human primates (NHPs). However, these vectors lack spatial selectivity for targeted gene delivery, a potentially critical limitation for delivering therapeutic doses in defined areas of the brain. The use of microbubbles, in conjunction with focused ultrasound (FUS), can enhance regional brain AAV transduction, but methods to assess transduction in vivo are needed. Methods: In a murine model, we combined positron emission tomography (PET) and optical imaging of reporter gene payloads to non-invasively assess the spatial distribution and transduction efficiency of systemically administered AAV9 after FUS and microbubble treatment. Capsid and reporter probe accumulation are reported as percent injected dose per cubic centimeter (%ID/cc) for in vivo PET quantification, whereas results for ex vivo assays are reported as percent injected dose per gram (%ID/g). Results: In a study spanning accumulation and transduction, mean AAV9 accumulation within the brain was 0.29 %ID/cc without FUS, whereas in the insonified region of interest of FUS-treated mice, the spatial mean and maximum reached ~2.3 %ID/cc and 4.3 %ID/cc, respectively. Transgene expression assessed in vivo by PET reporter gene imaging employing the pyruvate kinase M2 (PKM2)/[18F]DASA-10 reporter system increased up to 10-fold in the FUS-treated regions, as compared to mice receiving AAVs without FUS. Systemic injection of AAV9 packaging the EF1A-PKM2 transgene followed by FUS in one hemisphere resulted in 1) an average 102-fold increase in PKM2 mRNA concentration compared to mice treated with AAVs only and 2) a 12.5-fold increase in the insonified compared to the contralateral hemisphere of FUS-treated mice. Conclusion: Combining microbubbles with US-guided treatment facilitated a multi-hour BBB disruption and stable AAV transduction in targeted areas of the murine brain. This unique platform has the potential to provide insight and aid in the translation of AAV-based therapies for the treatment of neuropathologies.

Dataset Information

Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models.

Publications

Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models.

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