SELECTION OF TARGETING MOIETIES DRIVING NANOPARTICLE PENETRATION THROUGH SQUAMOUS PLURISTRATIFIED EPITHELIA

Drug delivery through stratified squamous epithelia is crucial for treating various local and systemic conditions. Nevertheless, the administration through these kinds of epithelia, like the skin, the esophageal membrane, and the corneal membrane, poses significant challenges due to their complex structure and barrier properties restricting drug absorption. Therefore, overcoming these barriers requires innovative approaches tailored to the target tissue's specific anatomical and physiological complexities, with the use of nanoparticle drug delivery systems together with absorption-enhancing techniques posing a significant role in addressing this challenge. This thesis thus explored the design of advanced drug delivery systems decorated with targeting moieties to enhance local drug delivery through stratified squamous epithelia, namely the skin, the esophageal mucosa, and the corneal membrane. In particular, regarding skin delivery, low molecular weight hyaluronic acid (HA) was used to prepare some HA-decorated deformable liposomes to target resveratrol (RSV) within the skin, assessing the effect of the preparation method, the lipid anchor’s nature for the preparation of the HA conjugates, and the HA content on liposomes deformability properties and performances. Intriguingly, depending on the lipid anchor nature, different HA contents in the liposomal formulations were obtained, and a parabolic trend was identified, with the optimal amount to favor skin permeation that was an approximately 30 HA/phospholipid (µg/mmol) ratio. The study therefore demonstrates the ability to modulate drug delivery in the skin by adjusting the amount of HA on the vesicle surface, thereby providing insights into optimizing topical drug administration strategies. To investigate the possibility of obtaining a tailored absorption enhancer molecule and its potential to promote NPs delivery, in a second study phage display screening was used as a novel mucosa penetrating peptide (MPP) screening technique to facilitate targeted drug release in the esophagus of MPP-conjugated liposomes. In this case, curcumin (CUR) was used as a model drug in reason of its application for esophageal pathologies. Through several rounds of screening, we identified three peptides capable of crossing the esophageal mucosa with the peptide SLENKGP (PEP3) which demonstrated significant efficacy in ex vivo and in vivo studies, facilitating both esophageal retention and the translocation of CUR-loaded liposomal cargo through the esophageal mucosa, compared to control pegylated liposomes. Further investigation revealed that PEP3 may mask PEG-mucus interactions, promoting liposome partitioning into the epithelium and enhancing permeation without significantly affecting cell uptake. While the precise mechanism of action of PEP3 remains unclear, both ex vivo and in vivo studies validate its effectiveness for esophageal drug delivery. As last, in the context of ocular drug delivery, the thesis was focused in addressing the challenges posed by the complex anatomy and physiology of the eye, particularly the corneal mucosa's barrier properties. Nanosystems (NSs) indeed, including liposomes and micelles, have emerged as promising tools to achieve a significant transcorneal delivery, even though the physicochemical properties influencing their penetration through the cornea remain unclear. Therefore, we investigated the impact of non-ionic surfactant agents, charge, size, and PEG2000 on liposomes and micelles corneal penetration performances by confocal laser scanning microscopy. Surprisingly, formulations with cationic charge and small size exhibit superior penetration performances, highlighting the intricate interplay between formulation properties and tissue barriers. Subsequent research will concentrate on screening various targeting agents to enhance the penetration capabilities of these formulated nanoparticles, potentially creating an advanced drug delivery system for treating chronic eye conditions. Overall, this study offers insights into novel strategies for enhancing skin, esophageal, and corneal drug delivery, with surface decoration of lipid-based nanoparticles with targeting moieties resulting in a highly promising one to facilitate topical administration through stratified squamous epithelia.