Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China.
ACS Nano. 2021 Oct 26;15(10):16076-16094. doi: 10.1021/acsnano.1c04753. Epub 2021 Oct 4.
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 nanoparticle-derived 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-peroxide-eliminating 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 anti-inflammatory activities of TPCD. Cellularly, TPCD nanoparticles (, 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, anti-inflammatory, 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 (, ATPCD NP). Compared to TPCD NP, ATPCD NP demonstrated notably enhanced 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.
中风是全球范围内主要的死亡和残疾原因，而有效的治疗药物仍有待开发。在此，我们报告了生物活性纳米颗粒衍生的多功能纳米疗法用于治疗缺血性中风，这些纳米疗法是由一种药理学上有效的寡糖材料（称为 TPCD）构建的，该材料是通过将自由基清除化合物（Tempol）和苯硼酸频哪醇酯（PBAP）的过氧化物消除部分共价连接到β-环糊精上制备的。值得注意的是，Tempol 和 PBAP 的组合功能部分在β-环糊精上有助于 TPCD 的抗氧化和抗炎活性。在细胞水平上，TPCD 纳米颗粒（TPCD NPs）减少了氧葡萄糖剥夺诱导的氧化介质的过度产生，增加了抗氧化酶的表达，并抑制了小胶质细胞介导的炎症，从而抑制了神经元凋亡。静脉注射（i.v.）给药后，TPCD NPs 能够有效地在大脑中动脉闭塞（MCAO）小鼠的脑缺血损伤部位积聚，在与中风发病机制相关的细胞中表现出相当大的分布。在治疗上，TPCD NPs 显著降低 MCAO 小鼠的梗死体积并加速神经功能恢复。机制上，TPCD NPs 的功效是通过其抗氧化、抗炎和抗凋亡作用实现的。此外，TPCD NPs 可以作为一种活性氧不稳定的纳米载体，有效地负载和触发释放一种抗炎肽 Ac2-26，从而引发抗炎纳米治疗（ATPCD NP）。与 TPCD NP 相比，ATPCD NP 表现出明显增强的功效，这主要归因于其额外的抗炎活性。因此，TPCD NP 衍生的纳米药物可进一步开发为用于中风和其他炎症相关脑血管疾病的有前途的靶向治疗药物。
