{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:38:03Z","timestamp":1791848283199,"version":"4.3.4"},"reference-count":122,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:00:00Z","timestamp":1607644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development and Innovation Office, Hungary","award":["K120358, K134377, PD128821"],"award-info":[{"award-number":["K120358, K134377, PD128821"]}]},{"name":"Economic Development and Innovation Operational Programme in Hungary co-financed by the European Union and the European Regional Development Fund","award":["GINOP-2.3.2-15-2016-00006"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00006"]}]},{"name":"EU-funded Hungarian grant","award":["EFOP-3.6.1-16- 2016-00008"],"award-info":[{"award-number":["EFOP-3.6.1-16- 2016-00008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/biology9120460","type":"journal-article","created":{"date-parts":[[2020,12,13]],"date-time":"2020-12-13T20:56:57Z","timestamp":1607893017000},"page":"460","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Tissue Acidosis Associated with Ischemic Stroke to Guide Neuroprotective Drug Delivery"],"prefix":"10.3390","volume":"9","author":[{"given":"Orsolya","family":"M. T\u00f3th","sequence":"first","affiliation":[{"name":"Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1kos","family":"Menyh\u00e1rt","sequence":"additional","affiliation":[{"name":"Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00f3ra","family":"Hantosi","sequence":"additional","affiliation":[{"name":"Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8478-9664","authenticated-orcid":false,"given":"Eszter","family":"Farkas","sequence":"additional","affiliation":[{"name":"Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferenc","family":"Bari","sequence":"additional","affiliation":[{"name":"Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1016\/0140-6736(91)93206-O","article-title":"Classification and natural history of clinical identifiable subtypes of cerebral infarction","volume":"337","author":"Bamford","year":"1991","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1161\/01.STR.8.1.51","article-title":"Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia","volume":"8","author":"Astrup","year":"1977","journal-title":"Stroke"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1161\/01.STR.12.6.723","article-title":"Thresholds in cerebral ischemia\u2014the ischemic penumbra","volume":"12","author":"Astrup","year":"1981","journal-title":"Stroke"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nm1735","article-title":"A new penumbra: Transitioning from injury into repair after stroke","volume":"14","author":"Lo","year":"2008","journal-title":"Nat. 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