Project Portugal 2030

Summary

The long-term objective of the NasalSteP project is to improve the treatment of MDD and TRD through the production of nose-to-brain drug-device products with fast-acting antidepressant effect. The main objective of the NasalSteP project is to develop safe antidepressant-device products with fast onset of action, which promote a sustained delivery that reduces the frequency of administration comparatively to oral routes. To enable the non-invasive direct delivery system of neurosteroids and neuropeptides into the CNS and overcome their poor systemic bioavailability, short half-life time and limited uptake into the brain, NasalStep team will develop biodegradable in situ gels entrapping functionalized nanoparticles, to be administered through the nasal olfactory mucosa. Envisioning a multitarget antidepressant effect, these systems will be loaded with fast antidepressant neurosteroids and enriched with GDF11 neuropeptide and tryptophan, which are considerably reduced in TRD. This is an innovative multi-target synergistic approach, which is expected to increase treatment efficacy in TRD and fulfil some nutritional needs of depressed patients. NasalSteP aims to ensure an accurate and reproducible deposition of the formulation on the human olfactory mucosa for a sustained and direct delivery to the brain. To attain this objective, a double innovative strategy is herein proposed: (i) to create functionalized nanostructured lipid carriers (NLCs) integrated in in situ gelling formulations, and (ii) to aerosolize the formulations with different nasal devices. In this regard, nanopeptides (eg. arginine-glycine-aspartic acid) or small peptides (eg. lactoferrin and odorronalectine) will be incorporated on the NLC’s surface to promote site-specific drug delivery into olfactory mucosa – a small and hard-to-reach target area located at the upper end of the nasal cavity. Since lactoferrin receptor in highly expressed in olfactory neurons and brain endothelial cells, we expect a more efficient and specific nose-to-brain delivery of the active therapeutics. Environmentally friendly and renewable natural polymers (namely chitosan and cellulose derivatives) will be used to produce biodegradable in situ gelling formulations and different nasal devices will be tested in human nasal casts to select the one that more accurately deliver the formulations into olfactory mucosa. Importantly, all the excipients herein proposed are eco-friendly, safe and biodegradable, already approved for clinical use, promoting a safe and sustainable production of NasalSteP drug-device systems. Through a sustainable structured step-by-step technological development, the NasalSteP project will start with in vitro cell screening model and end in proof-of-concept pre-clinical validation studies, carried out under GLP conditions, to open an avenue to start clinical validation. At the end, we expect to develop an innovative nose-to-brain drug-device prototype that bypasses the BBB through direct brain delivery of fast-acting antidepressants with a special medical device. This will bring to the market an improved non-invasive antidepressant therapy, able to reduce drug resistance, suicide ideation and premature death, improving patients and families’ well-being at all ages. NasalSteP systems will be safely and easily self-administered at home, avoiding hospitalization, with important economic improvements for patients and health units.