Multimodal theranostic amyloid-β targeted upconversion gadolinium-based nanoprobe for Alzheimer’s disease Chengke Wang, Xueli Wang, and Man Shing Wong Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China Amyloid-β (Aβ) plaque is one of the pathological hallmarks of incurable Alzheimer’s disease (AD), which are believed to be closely related to its pathogenesis.1 Thus, amyloid-β species, particularly more pathogenic and toxic Aβ oligomers, are a key biomarker to monitor for disease diagnosis and progression, and evaluate for efficacy in the drug development. Current plaque imaging in humans based on positron emission tomography (PET) is expensive with limited availability at hospitals and requires a radioactive tracer affording relatively low spatial resolution. Thus, PET is not ideal for prognosis and early diagnosis as well as a population-wide and routine screening of the disease. In contrast, magnetic resonance imaging (MRI), commonly available in clinical setting and being a powerful non-invasive and non-radiative diagnostic technique offers excellent spatio-temporal resolution and unlimited depth of tissue penetration. Owing to its intrinsic low sensitivity, a contrast agent is often needed to enhance the specificity and image contrast of tissues/pathology of interest in MRI.2 However, such contrast agents for AD biomarker imaging are not yet available for human use. Intriguingly, multimodality imaging can overcome the limitations of the single modal imaging, which provides complementary and expanded scope of information for more accurate disease diagnosis and pathological features investigation. Toward this end, we report herein the development and investigation of the first oligomeric Aβ-specific Gd³⁺- based nanoparticles (NPs) as a multimodal MR/near-infrared (NIR) imaging contrast agent for in vivo detection and imaging of Aβ contents in AD mouse model. To achieve a higher capability to tune the unique functional and magnetic properties of the nanoparticle, the core–shell NaGdF4:Yb3+,Tm3+@NaGdF4 nanoparticles were synthesized using the classical solvothermal method by doping NaGdF4 NPs with Yb3+/Tm3+. To stabilize the hydrophobic NaGdF4:Yb3+,Tm3+@NaGdF4 core–shell NPs, the synthesized NPs were protected and coated by a mesoporous silica (SiO2) layer. The Aβ targeting capability of the Gd3+-based NPs was achieved by incorporation of theranostic Aβ oligomer-selective NIR emissive dye, F-SLOH, into the mesoporous silica layer. F-SLOH was recently shown to be able to mitigate multiple neuropathological abnormalities in AD mouse models. Such oligomeric Aβ-specific Gd³⁺-based NP was demonstrated as an effective and sensitive multimodal contrast agent for in vivo and ex vivo NIR imaging with high sensitivity and selectivity for Aβ oligomers and for MR imaging with good spatial resolution in different age groups in an AD mouse model. This nanoprobe also exhibited an inhibitory effect on Aβ fibrillation and neuroprotection against Aβ-induced reactive oxygen species generation indicating its desirable therapeutic potential for AD. Our design strategy has provided an alternative avenue to develop effective and potentially clinically useful theranostic MRI probes for AD diagnosis and treatment in humans References 1. (1) A. Rauk, Chem. Soc. Rev. 2009, 38, 2698. 2. (2) M. Salerno, D. S. D. Porqueras, Coord. Chem. Rev. 2016, 327, 27.
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