Targeted Treatment of Ischemic Stroke by Bioactive Nanoparticle-Derived Reactive Oxygen Species Responsive and Inflammation-Resolving Nanotherapies

Abstract

Stroke is a primary cause of death and disability worldwide, while effective and safe drugs remain to be developed for its clinical treatment. Herein, we report bioactive nanoparticlederived multifunctional nanotherapies for ischemic stroke, which are engineered from a pharmacologically active oligosaccharide material (termed as TPCD) prepared by covalently conjugating a radical-scavenging compound (Tempol) and a hydrogen-peroxideeliminating moiety of phenylboronic acid pinacol ester (PBAP) on β-cyclodextrin. Of note, combined functional moieties of Tempol and PBAP on β-cyclodextrin contribute to antioxidative and antiinflammatory activities of TPCD. Cellularly, TPCD nanoparticles (i.e., TPCD NPs) reduced oxygen−glucose deprivation-induced overproduction of oxidative mediators, increased antioxidant enzyme expression, and suppressed microglial-mediated inflammation, thereby inhibiting neuronal apoptosis. After intravenous (i.v.) delivery, TPCD NPs could efficiently accumulate at the cerebral ischemic injury site of mice with middle cerebral artery occlusion (MCAO), showing considerable distribution in cells relevant to the pathogenesis of stroke. Therapeutically, TPCD NPs significantly decreased infarct volume and accelerated recovery of neurological function in MCAO mice. Mechanistically, efficacy of TPCD NPs is achieved by its antioxidative, antiinflammatory, and antiapoptotic effects. Furthermore, TPCD NPs can function as a reactive oxygen species labile nanovehicle to efficiently load and triggerably release an inflammation-resolving peptide Ac2-26, giving rise to an inflammation-resolving nanotherapy (i.e., ATPCD NP). Compared to TPCD NP, ATPCD NP demonstrated notably enhanced in vivo efficacies, largely resulting from its additional inflammation-resolving activity. Consequently, TPCD NP-derived nanomedicines can be further developed as promising targeted therapies for stroke and other inflammation-associated cerebrovascular diseases.

Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions

“…Primary astrocytes were cultured according to previously described methods ( 17 ). The cerebral hemisphere of mice born within 3 days was excised and the pia mater was stripped off.…”

An Optimally Designed Engineering Exosome–Reductive COF Integrated Nanoagent for Synergistically Enhanced Diabetic Fester Wound Healing

“…These indicators screen revealed that PCOF significantly inhibited H 2 O 2 ‐induced overproduction of malondialdehyde (MDA) (Figure 2i), indicating a potential utility for PDA‐coated reductive COFs in the prevention of cellular oxidative damage. [ 34 ] By contrast, the decline of two representative antioxidant proteins by H 2 O 2 ‐mediated, glutathione peroxidase (GSH‐Px), and superoxide dismutase (SOD) were prominently reversed by the therapeutic of PCOF (Figure 2j,k), implying the effective suppression of the intracellular ROS level.…”

Progresses and Prospects of Neuroprotective Agents-Loaded Nanoparticles and Biomimetic Material in Ischemic Stroke

“…During cerebral ischemia-reperfusion injury, pharmacologically active oligosaccharide material prepared by covalently conjugating a radical-scavenging compound (Tempol) and a hydrogen-peroxide-eliminating moiety of phenylboronic acid pinacol ester (PBAP) on β-cyclodextrin (TPCD) preserved the inter-endothelial tight junctions and significantly suppressed neuronal apoptosis, O 2– production, thence reduced BBB damage and infarction volume. In general, it can provide neurovascular unit protection ( Hosoo et al, 2017 ; Yuan et al, 2021 ).…”