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]
Jin, Haiqiang [VerfasserIn]
Yang, Di [VerfasserIn]
Yu, Weiwei [VerfasserIn]
Jia, Jingjing [VerfasserIn]
Yu, Zemou [VerfasserIn]
Tan, Hui [VerfasserIn]
Sun, Yongan [VerfasserIn]
Hao, Hongjun [VerfasserIn]
Qu, Xiaozhong [VerfasserIn]
Huang, Yining [VerfasserIn]

Links:

Volltext

Themen:

3WJQ0SDW1A
Acute ischemic stroke
EC 3.4.21.73
Journal Article
Microcirculation
Nanodrug
Nanogels
Polyethylene Glycols
Research Support, Non-U.S. Gov't
Targeted release
Thrombolysis
Urokinase-Type Plasminogen Activator

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