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Intranasal Administration of TAT-Conjugated Lipid Nanocarriers Loading GDNF for Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder (ND), characterized by the loss of dopaminergic neurons, microglial activation, and neuroinflammation. Current available treatments in clinical practice cannot halt the progression of the disease. During the last few years, growth factors (GFs) have been raised as a promising therapeutic approach to address the underlying neurodegenerative process. Among others, glial cell-derived neurotrophic factor (GDNF) is a widely studied GF for PD. However, its clinical use is limited due to its short half life, rapid degradation rate, and difficulties in crossing the blood-brain barrier (BBB). Lately, intranasal administration has appeared as an alternative non-invasive way to bypass the BBB and target drugs directly to the central nervous system (CNS). Thus, the aim of this work was to develop a novel nanoformulation to enhance brain targeting in PD through nasal administration. For that purpose, GDNF was encapsulated into chitosan (CS)-coated nanostructured lipid carriers, with the surface modified with transactivator of transcription (TAT) peptide (CS-nanostructured lipid carrier (NLC)-TAT-GDNF). After the physiochemical characterization of nanoparticles, the in vivo study was performed by intranasal administration to a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The CS-NLC-TAT-GDNF-treated group revealed motor recovery which was confirmed with immunohistochemistry studies, showing the highest number of tyrosine hydroxylase (TH+) fibers in the striatum and TH+ neuron levels in the substantia nigra. Moreover, ionizing calcium-binding adaptor molecule 1 immunohistochemistry was performed, revealing that CS-NLC-TAT-GDNF acts as a modulator on microglia activation, obtaining values similar to control. Therefore, it may be concluded that the intranasal administration of CS-NLC-TAT-GDNF may represent a promising therapy for PD treatment.

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Acknowledgements

This project was partially supported by the “Ministerio de Economía y Competitividad” (SAF2013-42347-R), the University of the Basque Country (UPV/EHU) (UFI 11/32), and the FEDER funds. The authors thank SGIker of UPV/EHU and European funding (ERDF and ESF) for technical and human support. The authors also wish to thank the intellectual and technical assistance from the ICTS “NANBIOSIS”, more specifically by the Drug Formulation Unit (U10) of the CIBER-BBN at the UPV/EHU.

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  1. Sara Hernando and Enara Herran contributed equally to this work.

Authors and Affiliations

  1. NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006, Vitoria-Gasteiz, Spain

    Sara Hernando, Enara Herran, José Luis Pedraz, Manoli Igartua & Rosa Maria Hernandez

  2. Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006, Vitoria-Gasteiz, Spain

    Enara Herran, José Luis Pedraz, Manoli Igartua & Rosa Maria Hernandez

  3. Neuroscience Laboratory, Research Institute, Hospital 12 de Octubre, Madrid, Spain

    Joana Figueiro-Silva & Eva Carro

  4. Neurodegenerative Diseases Biomedical Research Centre (CIBERNED), Madrid, Spain

    Joana Figueiro-Silva & Eva Carro

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  1. Sara Hernando
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  3. Joana Figueiro-Silva
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Correspondence to Rosa Maria Hernandez.

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Hernando, S., Herran, E., Figueiro-Silva, J. et al. Intranasal Administration of TAT-Conjugated Lipid Nanocarriers Loading GDNF for Parkinson’s Disease. Mol Neurobiol 55, 145–155 (2018). https://doi.org/10.1007/s12035-017-0728-7

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