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WIREs Nanomed Nanobiotechnol
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Quinoline‐n‐butylcyanoacrylate‐based nanoparticles for brain targeting for the diagnosis of Alzheimer's disease

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Abstract A survey of research activity on nanoparticles (NPs) based on polymeric devices that could cross the blood–brain barrier (BBB) is given along with the presentation of our own data on the development of NPs of n‐butyl‐2‐cyanoacrylate (BCA) for brain delivery to aid the early diagnosis of Alzeimer's disease (AD), a neurodegenerative disorder of the elderly people, the most prevalent form of dementia. Typical data are presented on in vivo detection of amyloid peptides (Aβ) (amyloid plaques) that are used as targets for developing the biological markers for the diagnosis of AD. In order to develop efficient in vivo probes, polymeric n‐butyl‐2‐cyanoacrylate (PBCA) NPs have been prepared and encapsulated with the radio‐labeled amyloid affinity drug 125I‐clioquinol (CQ, 5‐chloro‐7‐iodo‐8‐hydroxyquinoline) to improve the transport to brain and amyloid plaque retention of 125I‐CQ using the NPs of PBCA. The 125I‐CQ discriminately binds to the AD post‐mortem brain tissue homogenates versus control. 125I‐CQ‐PBCA NPs labeled the Aβ plaques from the AD human post‐mortem frontal cortical sections on paraffin‐fixed slides. Storage phosphor imaging verified preferential uptake by AD brain sections compared to cortical control sections. The 125I‐CQ‐PBCA NPs crossed the BBB in wild type mouse, giving an increased brain uptake measured in terms of % ID/g i.e., injected dose compared to 125I‐CQ. Brain retention of 125I‐CQ‐PBCA NPs was significantly increased in the AD transgenic mice (APP/PS1) and in mice injected with aggregated Aβ42 peptide versus age‐matched wild type controls. The results of this study are verified by in vivo storage phosphor imaging and validated by histopathological staining of plaques and select metal ions, viz. Fe2+ and Cu2+. The 125I‐CQ‐PBCA NPs had more efficient brain entry and rapid clearance in normal mice and enhanced the retention in AD mouse brain demonstrating the ideal in vivo imaging characteristics. The 125I‐CQ‐PBCA NPs exhibited specificity for Aβ plaques both in vitro and in vivo. This combination offered radio‐iodinated CQ‐PBCA NPs as the promising delivery vehicle for in vivo single photon emission tomography (SPECT) (123I) or PET (124I) amyloid imaging agent. The importance of the topic in relation to brain delivery and other similar type of work published in this area are covered to highlight the importance of this research to medical disciplines. WIREs Nanomed Nanobiotechnol 2010 2 35–47 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease

In vitro phosphor screen images of cortical brain (fixed) slides from postmortem AD and control subjects. The slides were deparaffinated first by immersion in xylene and ethanol, and then they were incubated with 125I‐CQ BCA Nanoparticles (2 × 106 CPM in 0.5 mL PBS buffer per slide); incubation time: 30 min; phosphor screen film exposure time: 7 min. Notice the enhanced uptake of the tracer in AD brain section compared to control brain section.

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Prussian blue staining of hippocampus of AD transgenic mouse. Prussian blue shows the presence of Fe3+ in amyloid plaques. Amyloid plaques were identified by staining with Congo red.

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This figure shows the Congo red histological staining of brain slice from 15 month old AD transgenic mouse. Amyloid aggregates are identified by the Congo red stain.

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Storage phosphor images of heads of transgenic mice injected with 125CQ BCA NPs (∼2 M CPM activity in 1 mg NPs), 60 min post administration of the tracer. Notice the enhanced activity retention in AD transgenic mouse compared to control animal.

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Storage phosphor images of heads of transgenic mice injected with 125CQ BCA NPs and 125I‐CQ (∼1M CPM activity in 0.5 mg NPs), 90 min post administration of the tracers. Notice the enhanced activity retention in animal injected with the nanoparticles compared to animal injected with the free drug.

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Storage phosphor images of heads of transgenic mice injected with 125CQ BCA NPs and 125I‐CQ (∼1M CPM activity in 0.5 mg NPs), 15 min post administration of the tracers. Notice the enhanced activity retention in animal injected with the nanoparticles compared to animal injected with the free drug.

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Storage phosphor images of heads of mice, injected with 125I‐CQ BCA NPs. 12 min post injection of (∼3 mg of NPs containing 7 × 106 CPM) 125I‐CQ‐BCA NPs: a. mouse intracranially administered with 5 µg, A‐beta (Aβ42) peptide aggregates 1 week prior to administration of the tracer. b. control mouse had saline administration.

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