Rational Design, Synthesis, and Evaluation of Rofecoxib-Based Photosensitizers for the NIR Imaging and Photo-Oxidization of Aβ Aggregates

Abstract

The photo-oxidation of amyloid-β (Aβ) protein catalyzed by Aβtargeting photosensitizers shows high potential in treating Alzheimer's disease (AD). Herein, we report the first example of photosensitizers based on the rofecoxib scaffold, in which rational introduction of the electron-absorbing pyridinium/ quinolinium moiety to the skeleton of rofecoxib could not only extend the absorption and emission wavelengths but also increase the efficiency of singlet oxygen ( 1 O 2 ) production. The emission wavelengths of R-S-MP, R-S-MC, and R-S-MQ are red-shifted to 860 nm, which might benefit the NIR imaging of Aβ aggregates with low photoscattering and autofluorescence. In addition, R-S-MP can identify Aβ plaques in brain sections of AD mice and detect abnormal viscosity environments, facilitating the pathological study of Alzheimer's disease. Most importantly, upon complexation with Aβ plaques, R-S-MP and R-S-MC could produce high singlet oxygen ( 1 O 2 ) under light irradiation, which can achieve the specific photo-oxidation of Aβ protein. Our optimized photosensitizers could change the conformation of β-rich Aβ protein and enhance its clearance through the lysosomal pathway, leading to the reduction of the Aβ-mediated neurotoxicity. All these excellent characteristics of our dual-functional photosensitizers for simultaneous imaging and photo-oxidation of Aβ aggregates suggest their promising prospects in pathological research in AD.