Combination of Polyethylene Glycol-Conjugated Urokinase Nanogels and Urokinase for Acute Ischemic Stroke Therapeutic Implications
© 2020. Springer Science+Business Media, LLC, part of Springer Nature..
Tissue reperfusion is a serious therapeutic strategy of ischemic stroke in addition to recanalization. In this work, we aimed to establish new urokinase-based therapeutics in order to dissolve large vessel thrombus together with microthrombi for stroke implications. Formulations consisted of free urokinase (UK), polyethylene glycol-crosslinked urokinase nanogel (PEG-UK), and a 1:1 mixture of UK and PEG-UK (PEG-UK+UK) were tested both in vitro and in vivo. In vitro experiments confirmed the pH-dependent release of PEG-UK in the PEG-UK+UK formulation. It was activated at pH 6.50, an environmental pH in the infarct brain tissue, owing to the dynamic crosslink property of PEG-UK. In vivo tests on a thromboembolic stroke rat model showed that the formulations containing UK, i.e., free UK and PEG-UK+UK, demonstrated better neurological scores and smaller infarction volumes within the time window, in which the PEG-UK+UK formulation relatively performed better. On the other hand, the formulations containing PEG-UK, i.e., PEG-UK and PEG-UK+UK, gained sufficient thrombolytic efficiency beyond the time window. Further investigation on the mechanism revealed that PEG-UK could reduce microthrombus in distal microcirculation, and its destructive effect was also less than that of free UK. The PEG-UK+UK formulation actually provided a "dual targeting" delivery of UK to both the large vessels and the microcirculation, which was beneficial to the treatment of cerebral ischemic stroke both within and beyond the therapeutic time window.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2021 |
---|---|
Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
---|---|
Enthalten in: |
Translational stroke research - 12(2021), 5 vom: 16. Okt., Seite 844-857 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Nan, Ding [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 13.01.2022 Date Revised 13.01.2022 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1007/s12975-020-00865-2 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM316372196 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM316372196 | ||
003 | DE-627 | ||
005 | 20231225160934.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2021 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1007/s12975-020-00865-2 |2 doi | |
028 | 5 | 2 | |a pubmed24n1054.xml |
035 | |a (DE-627)NLM316372196 | ||
035 | |a (NLM)33067776 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Nan, Ding |e verfasserin |4 aut | |
245 | 1 | 0 | |a Combination of Polyethylene Glycol-Conjugated Urokinase Nanogels and Urokinase for Acute Ischemic Stroke Therapeutic Implications |
264 | 1 | |c 2021 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 13.01.2022 | ||
500 | |a Date Revised 13.01.2022 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2020. Springer Science+Business Media, LLC, part of Springer Nature. | ||
520 | |a Tissue reperfusion is a serious therapeutic strategy of ischemic stroke in addition to recanalization. In this work, we aimed to establish new urokinase-based therapeutics in order to dissolve large vessel thrombus together with microthrombi for stroke implications. Formulations consisted of free urokinase (UK), polyethylene glycol-crosslinked urokinase nanogel (PEG-UK), and a 1:1 mixture of UK and PEG-UK (PEG-UK+UK) were tested both in vitro and in vivo. In vitro experiments confirmed the pH-dependent release of PEG-UK in the PEG-UK+UK formulation. It was activated at pH 6.50, an environmental pH in the infarct brain tissue, owing to the dynamic crosslink property of PEG-UK. In vivo tests on a thromboembolic stroke rat model showed that the formulations containing UK, i.e., free UK and PEG-UK+UK, demonstrated better neurological scores and smaller infarction volumes within the time window, in which the PEG-UK+UK formulation relatively performed better. On the other hand, the formulations containing PEG-UK, i.e., PEG-UK and PEG-UK+UK, gained sufficient thrombolytic efficiency beyond the time window. Further investigation on the mechanism revealed that PEG-UK could reduce microthrombus in distal microcirculation, and its destructive effect was also less than that of free UK. The PEG-UK+UK formulation actually provided a "dual targeting" delivery of UK to both the large vessels and the microcirculation, which was beneficial to the treatment of cerebral ischemic stroke both within and beyond the therapeutic time window | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a Acute ischemic stroke | |
650 | 4 | |a Microcirculation | |
650 | 4 | |a Nanodrug | |
650 | 4 | |a Targeted release | |
650 | 4 | |a Thrombolysis | |
650 | 7 | |a Nanogels |2 NLM | |
650 | 7 | |a Polyethylene Glycols |2 NLM | |
650 | 7 | |a 3WJQ0SDW1A |2 NLM | |
650 | 7 | |a Urokinase-Type Plasminogen Activator |2 NLM | |
650 | 7 | |a EC 3.4.21.73 |2 NLM | |
700 | 1 | |a Jin, Haiqiang |e verfasserin |4 aut | |
700 | 1 | |a Yang, Di |e verfasserin |4 aut | |
700 | 1 | |a Yu, Weiwei |e verfasserin |4 aut | |
700 | 1 | |a Jia, Jingjing |e verfasserin |4 aut | |
700 | 1 | |a Yu, Zemou |e verfasserin |4 aut | |
700 | 1 | |a Tan, Hui |e verfasserin |4 aut | |
700 | 1 | |a Sun, Yongan |e verfasserin |4 aut | |
700 | 1 | |a Hao, Hongjun |e verfasserin |4 aut | |
700 | 1 | |a Qu, Xiaozhong |e verfasserin |4 aut | |
700 | 1 | |a Huang, Yining |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Translational stroke research |d 2010 |g 12(2021), 5 vom: 16. Okt., Seite 844-857 |w (DE-627)NLM198739184 |x 1868-601X |7 nnns |
773 | 1 | 8 | |g volume:12 |g year:2021 |g number:5 |g day:16 |g month:10 |g pages:844-857 |
856 | 4 | 0 | |u http://dx.doi.org/10.1007/s12975-020-00865-2 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 12 |j 2021 |e 5 |b 16 |c 10 |h 844-857 |