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 Ca2+ 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.
Keywords: acidosis; cerebral ischemia; nanomedicine; neuroprotection; pH imaging; penumbra; smart nanosystem; spreading depolarization; tissue pH.