In Vitro and In Vivo Testing and Validation for Intranasal Nanotechnology Solutions in Neurological Disorders

Brain diseases such as Parkinson's (PD) or Glioblastoma (GB) represent significant health challenges given I) the lack of definitive cures (or highly efficient palliative treatments), and II) the increasing incidence driven by progressive societal aging. There are many challenges that Science faces in finding solutions, starting with a lack of deep understanding of the biological mechanisms underlying these diseases. However, when it comes to treatment, there is undoubtedly one predominant challenge: the limited accessibility of the drugs to the brain via conventional oral or intravenous routes, due to the protective but restrictive nature of the blood-brain barrier (BBB). Thus, it is necessary to establish new and innovative approaches that enable the effective liberation of drugs to the brain, addressing these challenges through three interconnected hypotheses: Hypothesis 1: intranasal administration as a direct and efficient solution The olfactory and trigeminal nerves within the nasal mucosa can facilitate direct, non-invasive, and rapid drug entry into the brain with high cerebral bioavailability. Despite the growing number of publications in the field, only a few formulations have been tested in clinical trials with limited success to date. Challenges for its implementation include limited drug penetration into the mucosa, rapid mucociliary clearance and enzymatic degradation, as well as interindividual variability. Additional challenges are the restricted surface area of the nasal cavity and its limited drug-loading capacity. Hypothesis 2: nanoparticles can overcome these limitations. Nanoparticles provide a powerful platform to enhance drug delivery by improving mucosal penetration, cellular uptake, and bioavailability through the optimization of their surface charge, content and hydrophobicity. They also enable: I) the co-encapsulation of multiple therapeutic and imaging agents (e.g., fluorescent/MRI), II) protection of the drug from chemical inactivation while minimizing side effects, and III) controlled release/activation triggered by predesigned external stimulus. Despite encouraging results from preclinical studies, their transition to clinical practice remains limited. Hypothesis 3: bio-/bioinspired nanosystems will facilitate clinical implementation This project proposes the use of nanoparticles, coatings and bioinspired formulations. As nanosystems, it explores the use of lipid droplets, nanoparticles inspired by neuromelanin, proteins or ellipsoidal capsules mimicking bacteria. These nanosystems will be designed to: I) encapsulate multiple drugs and/or imaging agents for monitoring by optical or resonance techniques, and II) combine chemotherapy with thermal therapies or immunotherapy. To further enhance functionality, these nanosystems will be coated and formulated with bio-/bioinspired coatings/hydrogels such as polyphenols, glycans or chitosan. Finally, the optimized nanosystems will be evaluated at the cellular level and especially in preclinical studies using murine GB and PD models. This is an ambitious and completely transversal approach that can only be tackled with a multidisciplinary consortium of knowledge and experiences as complementary as the one presented in this project.