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. 2017 Aug 24;3(1):102-109.
doi: 10.1016/j.bioactmat.2017.08.001. eCollection 2018 Mar.

In vivo evaluation of urokinase-loaded hollow nanogels for sonothrombolysis on suture embolization-induced acute ischemic stroke rat model

Yuming Teng  1 , Haiqiang Jin  1 , Ding Nan  1 , Mengnan Li  2 , Chenghe Fan  1 , Yuanyuan Liu  1 , Pu Lv  1 , Wei Cui  1 , Yongan Sun  1 , Hongjun Hao  1 , Xiaozhong Qu  3 , Zhenzhong Yang  2 , Yining Huang  1
Affiliations

In vivo evaluation of urokinase-loaded hollow nanogels for sonothrombolysis on suture embolization-induced acute ischemic stroke rat model

Yuming Teng et al. Bioact Mater. .

Abstract

The urokinase-type plasminogen activator (uPA) loaded hollow nanogels (nUK) were synthesized by a one-step reaction of glycol chitosan and aldehyde capped poly (ethylene oxide). The resultant formulation is sensitive to diagnostic ultrasound (US) of 2 MHz. Herein, we evaluated the in vivo sonothrombolysis performance of the nUK on acute ischemic stroke rat model which was established by suture embolization of middle cerebral artery (MCA). Via intravenous (i.v.) administration, the experimental data prove a controlled release of the therapeutic protein around the clots under ultrasound stimulation, leading to enhanced thrombolysis efficiency of the nUK, evidenced from smaller infarct volume and better clinical scores when compared to the i.v. dose of free uPA no matter with or without US intervention. Meanwhile, the preservation ability of the nanogels not only prolonged the circulation duration of the protein, but also resulted in the better blood-brain barrier protection of the nUK formulation, showing no increased risk on the hemorrhagic transformation than the controls. This work suggests that the nUK is a safe sonothrombolytic formulation for the treatment of acute ischemic stroke.

Keywords: BBB, blood-brain barrier; CCA, common carotid artery; EB, evens blue; ELIP, echogenic liposomes; HT, hemorrhagic transformation; Hb, hemoglobin; Hollow nanogel; In vivo evaluation; MCA, middle cerebral artery; MCAO, middle cerebral artery occlusion; MRI, magnetic resonance imaging; SD, Sprague-Dawley; TCD, Transcranial Doppler; TTC, 2,3,5-triphenyltetrazolium chloride; Thrombolysis; UK+US, ultrasound and free urokinase; UK, urokinase; US, ultrasound; Ultrasound responsive; Urokinase delivery; nUK+US, ultrasound and uPA-loaded nanogels; nUK, uPA-loaded nanogels.

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Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
SEM and TEM (inset) images of the synthesized uPA loaded hollow nanogels.
Fig. 2
Fig. 2
Peripheral blood concentration of uPA in stoke rats after the formulations were administrated via i.v. injection.
Fig. 3
Fig. 3
The dynamic levels of D-dimer in the rats (Statistics: 6 h, PnUK+USvsUK = 0.021; PnUK+USvsUK+US = 0.05; 10 h, PnUK+USvsUK = 0.009, PnUK+USvsUK+US = 0.010).
Fig. 4
Fig. 4
(a) Representative TTC and T2 images on the infraction area where the infarction brain tissue was stained in white. (b) Relative infraction volume after the treatment.
Fig. 5
Fig. 5
The clinical scores of rats treated by different formulations.
Fig. 6
Fig. 6
(a) Concentration of EB in rats after treated by different formulations 30 min post-MCA occlusion. (b) The concentration of Hb in the brain tissue on days 1, 3 and 7 after MCA occlusion. No statistic difference among the formulations on each day in (b).
Fig. 7
Fig. 7
HT (a) and survival rate (b) of different groups of animals after treated for 1 week. (c) H&E staining on heart, liver and kidney sections isolated two weeks after the treatment by nUK.
See this image and copyright information in PMC

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