Chemiexcitation-Triggered Photosensitizer Activation for Photooxidation of Aβ_1–42 Aggregates

Abstract

Oxidative degradation of the pathogenic amyloid-β-peptide (Aβ) aggregation is an effective and promising method to treat Alzheimer's disease under light irradiation. However, the limited penetration of external light sources into deep tissues has hindered the development of this treatment. Therefore, we have designed an unprecedented chemiluminescence-initiated photodynamic therapy system to replace external laser irradiation, primarily composed of D-glucose-based polyoxalate (G-poly-(oxalate)), the novel photosensitizer (BD-Se-QM), and bis [2,4,5-trichloro-6-(pentoxy-carbonyl) phenyl] ester. BD-Se-QM possesses excellent singlet oxygen ( 1 O 2 ) generation efficiency and the ability to photooxidize Aβ 1−42 aggregates under white light. G-poly(oxalate) not only helps the nanosystem to cross the blood−brain barrier but also has sufficient oxalate ester groups to significantly enhance the efficiency of chemiluminescence resonance energy transfer. The oxalate ester groups in BD-Se-QM/NPs can chemically react with H 2 O 2 to produce high-energy intermediates that activate BD-Se-QM, which can generate 1 O 2 to inhibit Aβ 1−42 aggregates and also promote microglial uptake of Aβ 1−42 , reducing the Aβ 1−42 -induced neurotoxicity. The chemically stimulated nanoplatform not only solves the drug delivery problem but also eliminates the need for external light sources. We anticipate that this chemically excited nanosystem could also be used for targeted delivery of other small molecule drugs.