Imaging plaques in animal models of AD using nanoparticles encapsulated with radioiodinated clioquinol

Abstract

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Objectives: Imaging Alzheimer’s plaques in humans was not successful with radioiodinated clioquinol (CQ). This has been attributed to inefficient transport of the agent across the blood brain barrier (BBB). The purpose of the study was to evaluate butyl cynoacrylate nanoparticles to enhance the delivery of radiolabeled CQ and their efficacy in imaging plaques in animal models of AD. Methods: Butyl cynoacrylate nanoparticles (NPs) were prepared by polymerizing the monomer in acidic medium with dextran-70, tween-80 and I-125-CQ and purified by ultracentrifugation. They were characterized by dynamic light scattering and SEM. Biodistribution of I-125-CQ and I-125-CQ-NPs was performed in BALB/c mice. Autoradiography of post mortem human brain sections exposed to I-125-CQ-NPs was performed with a Phosphor Screen. Aβ (1-42) peptide aggregates (1-5 μg/μl) were injected into the hippocampus of normal BALB/c mice by direct stereotaxis. Double transgenic mice for AD (APP & PS1) were derived from (B6xC3H) F2 background. The animals were tested for cognitive impairment with Y maze. Mice brains were taken out 1-2 h post i.v. injection of I-125-CQ (1-5 μCi) or I-125-CQ-NPs and autoradiographed as before. Results: The nanoparticles were spherical in nature with 40-45 nm average diameters. Postmortem AD brain sections had enhanced uptake of the I-125-CQ-NPs compared to the control subjects in Phosphor Screen images. Rapid uptake and washout of the I-125-CQ-NPs from blood and brains of normal mice were similar to I-125-CQ. However, the brain uptake was enhanced by 25-50 %. Experimental animals had impaired brain function compared to the controls. Autoradiography images showed localized uptake in brains of experimental animals, and was more pronounced in animals injected with I-125-CQ-NPs compared to I-125-CQ. Congo red staining confirmed the presence of plaques. Conclusions: I-125-CQ-NPs showed enhanced binding to plaques compared to I-125-CQ in brains of transgenic mice and mice injected with Aβ (1-42) peptide aggregates. Nanoparticles may serve as efficient carriers of imaging agents for Alzheimer’s disease.