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.

Design, Fabrication, and In Vitro Evaluation of Nanoceria-Loaded Nanostructured Lipid Carriers for the Treatment of Neurological Diseases.

Neurodegenerative diseases comprise a large group of disorders characterized by a dramatic synaptic connections loss, occurring as a result of neurodegeneration, which is closely related to the overproduction of reactive oxygen and nitrogen species. Currently, the treatment of neurodegenerative diseases has been limited mainly because of the inability of the synthesized delivery systems to cross the blood-brain barrier and to successfully deliver their therapeutic cargo to the diseased tissue. Taking into consideration the aforementioned limitations, we designed a lipid-based nanotherapeutic vector composed of biomimetic lipids and CeO2 nanoparticles (nanoceria, NC). NC have shown to be a promising tool for the treatment of several pathological conditions ranging from cancer to neurological diseases, mainly because of their antioxidant properties, while lipid-based structures have been shown to have an inherent ability to cross the blood-brain barrier. The lipid-based nanotherapeutics were successfully fabricated using a combination of ultrasonication and high-pressure homogenization techniques, and they were fully characterized morphologically and physicochemically. Their antioxidant ability was demonstrated using electron paramagnetic resonance spectroscopy and antioxidant assays. These innovative nanotherapeutics demonstrated a higher colloidal stability with respect to free NC, preserving at the same time their antioxidant properties. Finally, the ability of the lipid carriers to cross a model of the blood-brain barrier and to be internalized by neurons, acting both as neuroprotective and pro-neurogenic agents, was demonstrated using single- and triple-culture systems.