Bioinspired theranostic coordination polymer nanoparticles for intranasal dopamine replacement in parkinson's disease

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. Our methodology, in addition to being simple and inexpensive, 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 administrations with DA-NCPs equivalent to 200 μg of the free drug per day, the number and duration of apomorphine-induced rotations was significantly lower from that 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.This work was supported by grants RTI2018-098027-B-C21 and RTI2018-098027-B-C22 from the Spanish Government funds and by the European Regional Development Fund (ERDF). The ICN2 is funded by the CERCA program/Generalitat de Catalunya. The ICN2 is supported by the Severo Ochoa Centres of Excellence program, funded by the Spanish Research Agency (AEI, grant no. SEV-2017-0706). M.V. received funding from “la Caixa” Foundation (ID 1178 100010434, under the agreement LCF/PR/HR17/52150003) 1179, Ministry of Economy and Competitiveness (MINECO, Spain) (SAF2016-77541-R) and The Michael J. Fox Foundation for Parkinson’s Research 1180 (Grant ID: 15291.01). A.P.C. received funding from the ATTRACT project funded by the EC under Grant Agreement 777222. The authors thank the support from COST Action CA17121