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SC79 promotes efficient entry of GDNF liposomes into brain parenchyma to repair dopamine neurons through reversible regulation of tight junction proteins

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An Erratum to this article was published on 14 March 2023

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Abstract

Glial cell line-derived neurotrophic factor (GDNF), a disease-modifying drug for Parkinson’s disease (PD) is in Phase 2 clinical trials (EudraCT number: 2011-003866-34), however it is administered by direct intrastriatal delivery via stereotaxy, which is accompanied with intracranial infection, brain tissue damage, and other complications. In addition, because of complex administration routes, clinical trials of GDNF have yielded contrary results, largely due to differences in dose and concentration brought by intracranial device. Herein, a small molecular agonist SC79 was screened to open blood-brain barrier (BBB) and promote GDNF liposomes to get into brain. SC79 reversibly reduces the expression of claudin-5, one of dominant tight junctions of BBB. Animal study showed SC79 promoted liposomes to enter into brain parenchyma 2.43 times more than that of the control. Motor deficits of PD mice receiving SC79 and brain-targeted GDNF liposomes were recovered by 36.70% and tyrosine hydroxylase positive neurons in striatum were restored by 39.90%. Our combination therapy effectively avoids the side effects such as secondary infection and uneven delivery caused by intracranial injection, improving patients’ compliance and providing valuable research ideas for the clinic.

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Acknowledgements

We thank Jingyao Chen and Qiong Huang from the public technology platform of Zhejiang University School of Medicine for their help in immunohistochemical experiments on brain slices. We thank Hangjun Wu in the Center of Cryo-Electron Microscopy (CCEM), Zhejiang University for their technical assistance on two photon imaging. This work was supported by the National Natural Science Foundation of China (No. 81973267) and Natural Science Foundation of Zhejiang Province (No. LD19H300001).

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Authors and Affiliations

  1. College of Pharmaceutical Science, Zhejiang University, Hangzhou, 310058, China

    Xiaomei Wu, Li Wang, Kai Wang, Sufen Li, Tingting Meng, Hong Yuan, Qirui Zhang & Fuqiang Hu

  2. College of Pharmaceutical Science, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Jia Ke

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  1. Xiaomei Wu
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Correspondence to Fuqiang Hu.

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SC79 promotes efficient entry of GDNF liposomes into brain parenchyma to repair dopamine neurons through reversible regulation of tight junction proteins

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Wu, X., Wang, L., Wang, K. et al. SC79 promotes efficient entry of GDNF liposomes into brain parenchyma to repair dopamine neurons through reversible regulation of tight junction proteins. Nano Res. 16, 2695–2705 (2023). https://doi.org/10.1007/s12274-022-4857-6

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  • DOI: https://doi.org/10.1007/s12274-022-4857-6

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