Molecular Imaging of Amyloid-Beta Proteins by Polymeric Anoparticles in Mouse Models of Alzheimer's Disease
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Alzheimer's disease (AD) is the most common cause of dementia among the elderly, affecting 5% of Americans over age 65, and 20% over age 80. An excess of senile plaques (beta -amyloid protein) and neurofibrillary tangles (tau protein), ventricular enlargement, and cortical atrophy characterizes it. In vivo detection of aggregated amyloid peptides (Abeta ) (amyloid plaques) presents targets for development of biological markers for Alzheimer's disease. In an effort to fabricate in vivo probes, polymeric n-butyl-2-cyanoacrylate (BCA) nanoparticles (NPs) were encapsulated with the radiolabelled amyloid affinity drug 125Iclioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline). 125ICQ was initially selected as a tracer of interest because it chelates transition metals, crosses the BBB, and is easily labeled with radioisotopes of iodine (e.g. 123I, 124I and 125I). Preliminary studies with 125ICQ showed that the agent crossed the BBB, but was retained too briefly for effective chelation. Therefore, a drug carrier is required to improve the extravascular retention of 125ICQ; BCA NPs were chosen as the drug carrier. 125I-CQ discriminately binds to AD post-mortem brain tissue homogenates, versus control. Additionally, 125I-CQ-BCA NPs labeled the Abeta plaques from AD human post-mortem frontal cortical sections, on paraffin-fixed slides. Storage phosphor imaging verified preferential uptake by the AD brain sections, compared to cortical control sections. Additionally, 125I-CQ-BCA NPs cross the BBB in the wild type mouse, with an enhanced brain uptake (%ID/g, significant with 95% confidence (p=0.05)), compared to 125I-CQ. Moreover, brain uptake of 125I-CQ-BCA NPs is enhanced in AD transgenic mice (APP/PS1 and APP/PS1/Tau), and in mice intracranially injected with the aggregated Abeta peptide, versus age-matched wild type controls. Thus, 125I-CQ-BCA NPs act as targeted drug carriers with an affinity for amyloid plaques. Brain entry of 125I-CQBCA NPs was rapid, demonstrating ideal in vivo imaging characteristics for small animal modalities; good clearance of free and non-specifically bound radioisotope affords high-quality temporal resolution, and good signal-to-noise. 125I-CQ-BCA NPs have specificity for the Abeta plaques in post-mortem tissue, and have a rapid brain entry. This combination makes radioiodinated CQ-BCA NPs a promising candidate as an in vivo SPECT (123I), or PET (124I) amyloid imaging agent.