Structure and Fate of Nanoparticles Designed for the Nasal Delivery of Poorly Soluble Drugs

Abstract

Nanoparticles are promising mediators to enable nasal systemic and brain delivery of active compounds. However, the possibility of reaching therapeutically relevant levels of exogenous molecules in the body is strongly reliant on the ability of the nanoparticles to overcome biological barriers. In this work, three paradigmatic nanoformulations vehiculating the poorly soluble model drug simvastatin were addressed: (i) hybrid lecithin/chitosan nanoparticles (LCNs), (ii) polymeric poly-ε-caprolactone nanocapsules stabilized with the nonionic surfactant polysorbate 80 (PCL_P80), and (iii) polymeric poly-ε-caprolactone nanocapsules stabilized with a polysaccharide-based surfactant, i.e., sodium caproyl hyaluronate (PCL_SCH). The three nanosystems were investigated for their physicochemical and structural properties and for their impact on the biopharmaceutical aspects critical for nasal and nose-to-brain delivery: biocompatibility, drug release, mucoadhesion, and permeation across the nasal mucosa. All three nanoformulations were highly reproducible, with small particle size (∼200 nm), narrow size distribution (polydispersity index (PI) < 0.2), and high drug encapsulation efficiency (>97%). Nanoparticle composition, surface charge, and internal structure (multilayered, core–shell or raspberry-like, as assessed by small-angle neutron scattering, SANS) were demonstrated to have an impact on both the drug-release profile and, strikingly, its behavior at the biological interface. The interaction with the mucus layer and the kinetics and extent of transport of the drug across the excised animal nasal epithelium were modulated by nanoparticle structure and surface. In fact, all of the produced nanoparticles improved simvastatin transport across the epithelial barrier of the nasal cavity as compared to a traditional formulation. Interestingly, however, the permeation enhancement was achieved via two distinct pathways: (a) enhanced mucoadhesion for hybrid LCN accompanied by fast mucosal permeation of the model drug, or (b) mucopenetration and an improved uptake and potential transport of whole PCL_P80 and PCL_SCH nanocapsules with delayed boost of permeation across the nasal mucosa. The correlation between nanoparticle structure and its biopharmaceutical properties appears to be a pivotal point for the development of novel platforms suitable for systemic and brain delivery of pharmaceutical compounds via intranasal administration.

Using the Intranasal Route to Administer Drugs to Treat Neurological and Psychiatric Illnesses: Rationale, Successes, and Future Needs

“…Nanoparticles 20 nm in size had twice the penetration rate of 100 nm nanoparticles, which themselves were twice as effective in penetration than 500–1,000 nm particles (3.25%:2%:1.25% of particles, respectively, reach systemic circulation). Coating the PS nanoparticles with poloxamine 908 (a PEG-like polymer) reduced cellular interactions and thus decreased penetration, while coating with mucoadhesive chitosan doubled particle delivery into systemic circulation (0.3–0.6%) [ 122 ]; similar results were shown comparing polysorbate 80 and chitosan-coated lecithin nanoparticles [ 119 ].…”

“…For nanoparticles of similar size, the surface chemistry of the nanoparticle primarily dictates its primary transport pathway; introducing hydrophobic surface chemistry (e.g. using lipid nanoparticles) can help increase transcellular transport while the introduction of hydrophilic groups and penetration enhancers can improve paracellular travel [ 119 ]. Cationic surface charge in particular can govern two key biological responses to nanoparticles: (1) disrupt tight junctions to allow for increased binding to, and subsequent penetration through, the nasal epithelium; and (2) complex with the highly anionic nasal mucus to promote transmucosal transport [ 16 ].…”

Safety and Toxicity Implications of Multifunctional Drug Delivery Nanocarriers on Reproductive Systems In Vitro and In Vivo

“…This process could be further assessed by the ex vivo fluorescent bio-imaging and confocal microscopic techniques. On the basis of this extensive in vivo and ex vivo research, these implications of nanoparticle toxicities were found to be size-dependent ( Anton et al, 2008 ; Clementino et al, 2021 ).…”

Development of Eudragit® Nanoparticles for Intranasal Drug Delivery: Preliminary Technological and Toxicological Evaluation

“…Several features may hamper drug absorption through the nasal mucosa, such as molecular weight and permeability. The amount of drug transported from nose to the systemic circulation can be quite variable, ranging from almost 100% to less than 1% of the administered dose [34].…”