M Tóth Orsolya, Menyhárt Ákos, Frank Rita, Hantosi Dóra, Farkas Eszter, Bari Ferenc
Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, H-6720 Szeged, Hungary.
Biology (Basel). 2020 Dec 11;9(12):460. doi: 10.3390/biology9120460.
Ischemic stroke is a leading cause of death and disability worldwide. Yet, the effective therapy of focal cerebral ischemia has been an unresolved challenge. We propose here that ischemic tissue acidosis, a sensitive metabolic indicator of injury progression in cerebral ischemia, can be harnessed for the targeted delivery of neuroprotective agents. Ischemic tissue acidosis, which represents the accumulation of lactic acid in malperfused brain tissue is significantly exacerbated by the recurrence of spreading depolarizations. Deepening acidosis itself activates specific ion channels to cause neurotoxic cellular Ca accumulation and cytotoxic edema. These processes are thought to contribute to the loss of the ischemic penumbra. The unique metabolic status of the ischemic penumbra has been exploited to identify the penumbra zone with imaging tools. Importantly, acidosis in the ischemic penumbra may also be used to guide therapeutic intervention. Agents with neuroprotective promise are suggested here to be delivered selectively to the ischemic penumbra with pH-responsive smart nanosystems. The administered nanoparticels release their cargo in acidic tissue environment, which reliably delineates sites at risk of injury. Therefore, tissue pH-targeted drug delivery is expected to enrich sites of ongoing injury with the therapeutical agent, without the risk of unfavorable off-target effects.
缺血性中风是全球范围内导致死亡和残疾的主要原因。然而，局灶性脑缺血的有效治疗一直是一个尚未解决的挑战。我们在此提出，缺血组织酸中毒作为脑缺血损伤进展的一个敏感代谢指标，可用于神经保护剂的靶向递送。缺血组织酸中毒表现为灌注不良脑组织中乳酸的积累，而扩散性去极化的复发会使其显著加剧。酸中毒的加深本身会激活特定离子通道，导致神经毒性细胞内钙积累和细胞毒性水肿。这些过程被认为会导致缺血半暗带的丧失。缺血半暗带独特的代谢状态已被用于通过成像工具识别半暗带区域。重要的是，缺血半暗带中的酸中毒也可用于指导治疗干预。本文建议使用具有神经保护潜力的药物，通过pH响应智能纳米系统选择性地递送至缺血半暗带。给药的纳米颗粒在酸性组织环境中释放其载药，这可靠地划定了有损伤风险的部位。因此，组织pH靶向药物递送有望使正在损伤的部位富集治疗剂，而不会有不良脱靶效应的风险。
