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Abstract
Nowdays, neurodegenerative diseases represent a great challenge from both the therapeutic and diagnostic points of view. Indeed, several physiological barriers of the body, including the blood brain barrier (BBB), nasal, dermal, and intestinal barriers, interpose between the development of new drugs and their effective administration to reach the target organ or target cells at therapeutic concentrations. Currently, the nose-to-brain delivery with nanoformulations specifically designed for intranasal administration is a strategy widely investigated with the goal to reach the brain while bypassing the BBB. To produce nanosystems suitable to study both in vitro and/or in vivo cells trafficking for potential nose-to-brain delivery route, we prepared and characterized two types of fluorescent poly(ethylene glycol)-methyl-ether-block-poly(lactide-co-glycolide) (PLGA–PEG) nanoparticles (PNPs), i.e., Rhodamine B (RhB) dye loaded- and grafted- PNPs, respectively. The latter were produced by blending into the PLGA–PEG matrix a RhB-labeled polyaspartamide/polylactide graft copolymer to ensure a stable fluorescence during the time of analysis. Photon correlation spectroscopy (PCS), UV-visible (UV-vis) spectroscopies, differential scanning calorimetry (DSC), atomic force microscopy (AFM) were used to characterize the RhB-loaded and RhB-grafted PNPs. To assess their potential use for brain targeting, cytotoxicity tests were carried out on olfactory ensheathing cells (OECs) and neuron-like differentiated PC12 cells. Both PNP types showed mean sizes suitable for nose-to-brain delivery (<200 nm, PDI < 0.3) and were not cytotoxic toward OECs in the concentration range tested, while a reduction in the viability on PC12 cells was found when higher concentrations of nanomedicines were used. Both the RhB-labelled NPs are suitable drug carrier models for exploring cellular trafficking in nose-to-brain delivery for short-time or long-term studies.
Highlights
The intranasal (IN) drug administration route represents an intriguing strategy for obtaining the rapid delivery of the drugs to the central nervous systems (CNS), by allowing the drugs to reach the brain directly
Matrix, a relevant question to solve was the determination of Rhodamine B (RhB) release profile from the nanosystems in physiological conditions to prove that the fluorescence determined during the in vitro and in vivo experiments was due to the cargo and not to the dye released during the experiment
Nanoprecipitation allowed to obtain NPs based on PLGA–PEG with a core constituted by the PLGA portion, the while PEG portion forms a hydrophilic corona, resulting in a core/corona structure
Summary
The intranasal (IN) drug administration route represents an intriguing strategy for obtaining the rapid delivery of the drugs to the central nervous systems (CNS), by allowing the drugs to reach the brain directly. Despite there being several studies on the use of free drugs through nose-to-brain delivery, it has been demonstrated that most molecules do not have suitable properties to reach therapeutic doses in the brain Such reduced bioavailability can be due to the low instilled volumes that can be given intranasally, and/or to the local physiological mechanisms that reduce the drug’s access to the target site, such as the mucociliary clearance (which does not allow long residence time in the nose), or enzymatic degradation, besides temporary local disfunction (allergies, influenzae) altering the physiological function
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