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Nano Research 2021, 14(8): 2749-2761 https://doi.org/10.1007/s12274-020-3280-0
Research Article | Issue | Published: 05 January 2021

Non-invasive delivery of levodopa-loaded nanoparticles to the brain via lymphatic vasculature to enhance treatment of Parkinson’s disease

Show Author's Information Tianqi Nie1,§,  Zhiyu He2,§( ),  Jinchang Zhu3,  Kuntao Chen3,  Gregory P. Howard4,5,  Jesus Pacheco-Torres6,  Il Minn5,6,  Pengfei Zhao1,  Zaver M. Bhujwalla6,  Hai-Quan Mao3,4,5,7( ),  Lixin Liu1,  Yongming Chen1( )
School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou 510275, China
Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, Ocean University of China, Qingdao 266100, China
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Translational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA

§ Tianqi Nie and Zhiyu He contributed equally to this work.

Keywords:
Parkinson’s disease, levodopa, brain delivery, cerebral lymphatic vasculature
Topics:
BiocompatibilityControlled drug deliveryHydrogen bonds NanoparticlesNeuronsTargeted drug delivery
Cite this article:
Nie T, He Z, Zhu J, et al. Non-invasive delivery of levodopa-loaded nanoparticles to the brain via lymphatic vasculature to enhance treatment of Parkinson’s disease. Nano Research, 2021, 14(8): 2749-2761. https://doi.org/10.1007/s12274-020-3280-0
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Abstract Full text Electronic supplementary material About this article

Levodopa (L-DOPA), a precursor of dopamine, is commonly prescribed for the treatment of the Parkinson’s disease (PD). However, oral administration of levodopa results in a high level of homocysteine in the peripheral circulation, thereby elevating the risk of cardiovascular disease, and limiting its clinical application. Here, we report a non-invasive method to deliver levodopa to the brain by delivering L-DOPA-loaded sub-50 nm nanoparticles via brain-lymphatic vasculature. The hydrophilic L-DOPA was successfully encapsulated into nanoparticles of tannic acid (TA)/polyvinyl alcohol (PVA) via hydrogen bonding using the flash nanocomplexation (FNC) process, resulting in a high L-DOPA-loading capacity and uniform size in a scalable manner. Pharmacodynamics analysis in a PD rat model demonstrated that the levels of dopamine and tyrosine hydroxylase, which indicate the dopaminergic neuron functions, were increased by 2- and 4-fold, respectively. Movement disorders and cerebral oxidative stress of the rats were significantly improved. This formulation exhibited a high degree of biocompatibility as evidenced by lack of induced inflammation or other pathological changes in major organs. This antioxidative and drug-delivery platform administered through the brain-lymphatic vasculature shows promise for clinical treatment of the PD.


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Abstract
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Electronic supplementary material
About this article

Non-invasive delivery of levodopa-loaded nanoparticles to the brain via lymphatic vasculature to enhance treatment of Parkinson’s disease

Show Author's information Tianqi Nie1,§, Zhiyu He2,§( ), Jinchang Zhu3, Kuntao Chen3, Gregory P. Howard4,5, Jesus Pacheco-Torres6, Il Minn5,6, Pengfei Zhao1, Zaver M. Bhujwalla6, Hai-Quan Mao3,4,5,7( ), Lixin Liu1, Yongming Chen1( )
School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou 510275, China
Key Laboratory of Marine Chemistry Theory and Technology, Ministry of Education, Ocean University of China, Qingdao 266100, China
Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Translational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA

§ Tianqi Nie and Zhiyu He contributed equally to this work.

Abstract

Levodopa (L-DOPA), a precursor of dopamine, is commonly prescribed for the treatment of the Parkinson’s disease (PD). However, oral administration of levodopa results in a high level of homocysteine in the peripheral circulation, thereby elevating the risk of cardiovascular disease, and limiting its clinical application. Here, we report a non-invasive method to deliver levodopa to the brain by delivering L-DOPA-loaded sub-50 nm nanoparticles via brain-lymphatic vasculature. The hydrophilic L-DOPA was successfully encapsulated into nanoparticles of tannic acid (TA)/polyvinyl alcohol (PVA) via hydrogen bonding using the flash nanocomplexation (FNC) process, resulting in a high L-DOPA-loading capacity and uniform size in a scalable manner. Pharmacodynamics analysis in a PD rat model demonstrated that the levels of dopamine and tyrosine hydroxylase, which indicate the dopaminergic neuron functions, were increased by 2- and 4-fold, respectively. Movement disorders and cerebral oxidative stress of the rats were significantly improved. This formulation exhibited a high degree of biocompatibility as evidenced by lack of induced inflammation or other pathological changes in major organs. This antioxidative and drug-delivery platform administered through the brain-lymphatic vasculature shows promise for clinical treatment of the PD.

Keywords: Parkinson’s disease, levodopa, brain delivery, cerebral lymphatic vasculature

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Publication history
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Acknowledgements

Publication history

Received: 22 September 2020
Revised: 27 November 2020
Accepted: 02 December 2020
Published: 05 January 2021
Issue date: August 2021

Copyright

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020

Acknowledgements

This work was partially supported by Natural Science Foundation of China (No. 51533009), the Guangdong Innovative and Entrepreneurial Research Team Program (No. 2013S086) and the key Area Research and Development of Guangzhou (No. 202007020006).

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