胶质细胞源性神经生长因子
神经营养因子
多巴胺能
黑质
化学
原癌基因蛋白质c-ret
受体
GDNF配体家族
药理学
帕金森病
生物物理学
多巴胺
神经科学
生物化学
医学
生物
内科学
疾病
作者
Wei Li,Ermei Mäkilä,Jarno Salonen,Märt Saarma,Yulia Sidorova,Hélder A. Santos
标识
DOI:10.1016/j.nano.2017.11.290
摘要
Parkinson’s disease is neurodegenerative movement disorder caused byprogressive degeneration of dopaminergic neurons in substantia nigra. Currently, there are no treatments to slow down, stop or reverse the loss of dopaminergic neuros. Glial cell line-derived neurotrophic factor (GDNF) is a protein that has been shown to prevent the death and help to repair the damaged neurons. However, GDNF is a large molecule (about 32 kDa) that cannot cross the blood brain barrier (BBB), and therefore needs to be delivered by intracranial administration, which requires complex and expensive stereotactic surgery. Generally, small molecules are easier to across the BBB than largemolecules. Thus, small molecules with similar biological activity to GDNF(named GDNF mimetics) might be a better approach to translate into the clinic.Several GDNF mimetics (molecular weight 500-600 g/mol), which are able to activate GDNF receptors and support the survival of dopaminergic neurons, have been found, but they have limited aqueous solubility. Porous silicon nanoparticles (PSi NPs) have the ability to improve the solubility and dissolution rate of poorly water-soluble drugs, as well as to enhance the drug permeation across biological barriers. In our study,GDNF mimetics were loaded into thermally oxidized-PSi (TOPSi) NPs, by which the solubility and dissolution rate of GDNF mimetics were considerably enhanced. Luciferase assay, GDNF receptor RET phosphorylation and internal signalling assay showed that the GDNF mimetics delivered by the TOPSi NPs exhibit higher activity than pristine GDNF mimetics, even in the absence of organic solvents.
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