Reactive Oxygen Species-Responsive Transformable and Triple-Targeting Butylphthalide Nanotherapy for Precision Treatment of Ischemic Stroke by Normalizing the Pathological Microenvironment

Abstract

High potency and safe therapies are still required for ischemic stroke, which is a leading cause of global death and disability. Herein, a reactive oxygen species (ROS)-responsive, transformable, and triple-targeting DL-3-n-butylphthalide (NBP) nanotherapy was developed for ischemic stroke. To this end, a ROS-responsive nanovehicle (OCN) was first constructed using a cyclodextrin-derived material, which showed considerably enhanced cellular uptake in brain endothelial cells due to notably reduced particle size, morphological transformation, and surface chemistry switching upon triggering via pathological signals. Compared to a nonresponsive nanovehicle, this ROS-responsive and transformable nanoplatform OCN exhibited a significantly higher brain accumulation in a mouse model of ischemic stroke, thereby affording notably potentiated therapeutic effects for the nanotherapy derived from NBP-containing OCN. For OCN decorated with a stroke-homing peptide (SHp), we found significantly increased transferrin receptor-mediated endocytosis, in addition to the previously recognized targeting capability to activated neurons. Consistently, the engineered transformable and triple-targeting nanoplatform, i.e., SHp-decorated OCN (SON), displayed a more efficient distribution in the injured brain in mice with ischemic stroke, showing considerable localization in endothelial cells and neurons. Furthermore, the finally formulated ROS-responsive transformable and triple-targeting nanotherapy (NBP-loaded SON) demonstrated highly potent neuroprotective activity in mice, which outperformed the SHpdeficient nanotherapy at a 5-fold higher dose. Mechanistically, our bioresponsive, transformable, and triple-targeting nanotherapy attenuated the ischemia/reperfusion-induced endothelial permeability and improved dendritic remodeling and synaptic plasticity of neurons in the injured brain tissue, thereby promoting much better functional recovery, which were achieved by efficiently enhancing NBP delivery to the ischemic brain tissue, targeting injured endothelial cells and activated neurons/microglial cells, and normalizing the pathological microenvironment. Moreover, preliminary studies indicated that the ROS-responsive NBP nanotherapy displayed a good safety profile. Consequently, the developed triple-targeting NBP nanotherapy with desirable targeting efficiency, spatiotemporally controlled drug release performance, and high translational potential holds great promise for precision therapy of ischemic stroke and other brain diseases.

Anti‐Inflammatory Nanotherapies Based on Bioactive Cyclodextrin Materials

“…Various NPs, including polymeric NPs, liposomes, dendrimers, solid Reproduced with permission. [148] Copyright 2023, American Chemical Society.…”

“…Most recently, we developed ROS‐sensitive, deformable, and triple‐targeting DL‐3‐ n ‐butylphthalide (NBP) nanoplatform for precise treatment of ischemic stroke ( Figure 8 a,b). [ 148 ] In this case, a ROS‐sensitive nanocarrier (OCN) was prepared utilizing a CD derivative, which displayed high cellular internalization in brain endothelial cells, resulting from the considerably reduced particle size, morphological change, and surface chemistry alteration under pathological conditions. By decorating OCN with a stroke‐homing peptide (SHp), the obtained nanoplatform displayed a noticeably enhanced accumulation in the injured brain in MCAO mice, with high localization in endothelial cells and neurons.…”

“…d) Digital photos of TTC-stained brain sections after treatment with different formulations. e) Brain water contents of MCAO mice.Reproduced with permission [148]. Copyright 2023, American Chemical Society.…”

Luminescence Nanoprobes for Drug Screening, Pharmaceutical Analysis, and Therapeutic Evaluations

“…Cardiovascular diseases (CVDs), including myocardial infarction (MI), heart failure, atherosclerosis (AS), aneurysm, thrombosis, and stroke, are still the first cause of global death. [164][165][166][167] Early diagnosis and appropriate therapeutic treatments are critical to [160] Copyright 2020. American Chemical Society.…”

Near-Infrared Afterglow ONOO–-Triggered Nanoparticles for Real-Time Monitoring and Treatment of Early Ischemic Stroke

“…The appropriate timing and dosage of drugs, accompanied by early detection, are the main challenges in effective clinical treatment for IS. − Curcumin (Cur) is a naturally occurring substance that exhibits positive neuroprotective effects for IS because of its antioxidation, antiapoptosis, and anti-inflammatory properties. , However, curcumin possesses poor water solubility, non-negligible cellular toxicity, and fast metabolism, causing suboptimal treatment efficacy for IS . Importantly, the release of conventional potential therapeutic agents cannot be controlled according to the degree of disease progression, resulting in inaccurate dosage of drugs and unsafe stroke treatment. − Therefore, exploring endogenous ONOO – as a trigger to obtain an NIR afterglow image-guided system that integrates real-time evaluation of ONOO – levels in the I/R brain injury area with dynamic monitoring of the release status of curcumin is of great significance for safe stroke treatment.…”