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|Autori: ||Bonaccorso, Angela|
|Titolo: ||Nanocarriers for nose-to-brain delivery: a novel strategy for the treatment of CNS disorders|
|Abstract: ||The number of neurodegenerative diseases is estimated to be a few hundred. Despite the high prevalence and incidence, central nervous system (CNS) disorders are still incurable.
The blood-brain-barrier (BBB) precludes the delivery of drugs to the brain, preventing the therapy of a number of neurological disorders. In the last 20 years, intranasal (IN) administration has gained great attention in research and has been investigated with regard to its feasibility to serve as a direct drug transport route to the CNS. Drugs can be transported directly from the nasal cavity to the brain through the olfactory epithelium by trigeminal nerve systems and olfactory nerve pathways thereby bypassing the BBB. The incorporation of drugs into nanoparticles (NPs) might be a promising approach to improve the amount of pharmaceuticals delivered to the CNS. The goal of my PhD thesis is to assess the effective molecule delivery to the brain by using a new approach: IN administration combined with the nanotechnology-based carriers. My aim was to investigate whether polymeric NPs can end up the brain after IN administration; which region of the brain can be reached; how does surface property affect NPs transport. Once NPs translocation to the brain via this route was determined, our nanosystems have been formulated to study their potential application in epilepsy and brain cancer. We investigate PLGA NPs, unmodified and surface modified by PEG and chitosan. In Paper I we studied PEGylated PLGA NPs to obtain nanosystems with simple composition and long-term storage suitable for nose-to-brain delivery. A screening to select the degree of PEGylation of PLGA was performed and the effects of sucrose as surfactant-like and cryoprotectant agent was evaluated. Mucoadhesive evaluations between NPs and mucin were assessed by the mucin particle method and differential scanning calorimetry. Our results suggest the use of sucrose for its double effect and PEG 5% to confer an uncharged hydrophilic surface to minimize mucin-NPs adhesive interactions. Our nanosystems did not show any cytotoxic effects. In Paper II we looked at the in vivo fate of PLGA NPs and PLGA NPs surface modified with chitosan after IN administration in rats. The formulations have been optimized in terms of mean size and stability and tested in vivo. Both NPs were loaded with Rhodamine B and in vitro release study was evaluated by dyalisis bag technique. Biodistribution studies were carried out in rats after IN administration of NPs at different time intervals. Fluorescent microscopy was conducted to value the localization of NPs in the CNS. Our results suggest that compounds encapsulated in NPs may have a direct access to the CNS following IN administration. Our findings led us to hypothesize that different pathways were involved in the transport of unmodified and modified NPs. Additional experiments, were reported to confirm our results. In particular, the investigation of DiR-loaded PLGA NPs biodistribution and bioavailability to the brain after IN administration in living mice by Fluorescence Molecular Tomography system. Once established that our NPs reach the brain, we aim to investigate whether NPs can enhance the efficacy of the drugs loaded. Oxcarbazepine was encapsulated in PLGA NPs aiming at direct nose-to-brain delivery to improve epileptic therapy, and to evaluate the possible neuroprotection of this drug against the seizures and brain damage induced by Pentylentetrazole. Nose-to-brain delivery and NPs were also studied for gene therapy. We investigate the use of homemade polymers as potential delivery carriers of siRNA. The polymer bind to siRNA through electrostatic interaction to form nanocomplexes that were characterized in terms of size, zeta potential and stability. Cell cytotoxicity of the nanocomplex was determined in A431 cell line. Transfection and silencing efficiency were evaluated in vitro and in vivo after IN administration in rats by using Western Blot.|
|In||Area 05 - Scienze biologiche|
|BNCNGL87R45C351S-PhD_Thesis_Angela_Bonaccorso .pdf||PhD Thesis Angela Bonaccorso||4,56 MB||Adobe PDF||Visualizza/apri
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