New paper in ACS Nano – Bioinspired Theranostic NCPs for Intranasal Dopamine Replacement in Parkinson’s Disease

New paper in ACS Nano – Bioinspired Theranostic NCPs for Intranasal Dopamine Replacement in Parkinson’s Disease

22 Apr 2021

New publication in ACS Nano entitled “Bioinspired Theranostic Coordination Polymer Nanoparticles for Intranasal Dopamine Replacement in Parkinson’s Disease” with Dr. Javier García-Pardo as the first author. This work has been done thanks to the strong collaboration between Nanosfun and with different research teams: the group of Dr. Ana Paula Candiota from the Biomedical Applications of Magnetic Resonance Group, the group of Dr. Miquel Vila from the Neurodegenerative Diseases Research Group (Vall d’Hebron Research Institute – VHIR and Center for Networked Biomedical Research on Neurodegenerative Diseases – CIBERNED) and the group of Dr. Julia Lorenzo from the Protein Engineering and Proteomics Group (Institut de Biotecnologia i Biomedicina – IBB).

In this work, the authors envisioned a new approach for the dopamine (DA) replacement in Parkinson’s disease that consisted in the formation of a tailor-made coordination polymer, where the central polymeric backbone was made of iron nodes linked to a bidentate ligand such as 1,4-bis(imidazol-1-ylmethyl)benzene (bix) and DA was used as a counter ligand to complete the coordination sphere. The composition of the resulting nanoparticles (DA-NCPs) resulted to have a structure inspired by neuromelanin (NM), but with the fundamental difference that the incorporation of DA to the nanoparticles was reversible inside the cell.
Interestingly, the in vivo experiments performed through the nasal administration of the nanoparticles into the living brain showed an efficient delivery of DA to the nigrostriatal pathway capable of attenuating motor alterations in a 6-OHDA-induced animal model of Parkinson’s disease. On top of that, the presence of iron ions was used to track the nanoparticles by magnetic resonance imaging. All in all, these results position this last generation of DA-based nanoparticles in the field of DA replacement therapy with nanoparticles.

ABSTRACT: Dopamine (DA) is one of the main neurotransmitters found in the central nervous system and has a vital role in the function of dopaminergic (DArgic) neurons. A progressive loss of this specific subset of cells is one of the hallmarks of age-related neurodegenerative disorders such as Parkinson’s disease (PD). Symptomatic therapy for PD has been centered in the precursor L-DOPA administration, an amino acid precursor of DA that crosses the blood–brain barrier (BBB) while DA does not, although this approach presents medium- to long-term side effects. To overcome this limitation, DA-nanoencapsulation therapies are actively being searched as an alternative for DA replacement. However, overcoming the low yield of encapsulation and/or poor biodistribution/bioavailability of DA is still a current challenge. Herein, we report the synthesis of a family of neuromelanin bioinspired polymeric nanoparticles. Our system is based on the encapsulation of DA within nanoparticles through its reversible coordination complexation to iron metal nodes polymerized with a bis-imidazol ligand. In addition to being simple and inexpensive, our methodology results in DA loading efficiencies of up to 60%. In vitro, DA nanoscale coordination polymers (DA-NCPs) exhibited lower toxicity, degradation kinetics, and enhanced uptake by BE(2)-M17 DArgic cells compared to free DA. Direct infusion of the particles in the ventricle of rats in vivo showed a rapid distribution within the brain of healthy rats, leading to an increase in striatal DA levels. More importantly, after 4 days of nasal administration with DA-NCPs equivalent to 200 μg of the free drug per day, the number and duration of apomorphine-induced rotations were significantly lower than in either vehicle or DA-treated rats performed for comparison purposes. Overall, this study demonstrates the advantages of using nanostructured DA for DA-replacement therapy.

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