Sterically Controlled Cyclobutane-Dioxetane Ultrabright Afterglow Nanosystem for Cyclic Therapy of Choroidal Neovascularization in Mice
Jia‐Wei Zhang, Haoliang Shi, Xuan Qin, Pengcheng Wang, Yufan Ling, Xiangbowen Jin, Mingyue Cui, Bin Song, Houyu Wang, Yao He
Abstract
Afterglow occurring after light excitation ceases offers a safer light source to the laser-activated verteporfin therapy approved by the FDA for choroidal neovascularization (CNV). However, conventional afterglow molecules, especially adamantane-dioxetanes with high steric hindrance, exhibit limited chemiexcitation, restricting electron transfer and diminishing therapeutic effects. Here, we constructed ultrabright afterglow nanosystems by integrating low-hindrance cyclobutane moieties into the dioxetane framework. Among these cyclobutane substituents, the benzyl oxocyclobutane-dioxetane is the brightest afterglow molecule due to its lowest hindrance, showing 35.7 times faster relative chemiexcitation rate and 59 times higher afterglow intensity than adamantane-dioxetane, alongside a three-order-of-magnitude increase in total afterglow emission. Consequently, at the equivalent concentration, the benzyl oxocyclobutane-dioxetane-based nanosystem produces nearly five times more singlet oxygen than free verteporfin. In a CNV mouse model, cyclic treatment with our nanosystem reduced lesion areas by 64.9%, outperforming the 39.3% reduction achieved by free verteporfin counterpart. By eliminating the need for laser activation, this strategy minimizes ocular damage, providing a safe and effective treatment for CNV and other retinal disorders.