Innovative formulations for pharmacological targeting: local and inhalation approaches for oncological and pulmonary applications

Targeted drug delivery represents one of the most ambitious and promising frontiers of modern pharmaceutical sciences. The constant search for more effective, safer, and patient-tailored therapies has driven the development of advanced formulations able to concentrate drugs at the desired site of action while minimizing systemic exposure. Despite remarkable progress in nanomedicine and materials science, achieving precise localization of therapeutic agents within complex biological environments remains a major challenge. The design of drug delivery systems capable of overcoming biological barriers, prolonging residence time at the target site, and ensuring stability and reproducibility is therefore a central focus of current pharmaceutical research. The present doctoral thesis aims to explore different formulation strategies for achieving localized drug action. The research integrates various technological and biological perspectives, investigating how specific formulation approaches can be adapted to the pathological and anatomical features of the target tissue. The first part of the thesis focuses on biological targeting through biomimetic nanocarriers. In this study, Inula viscosa extract, a natural source of anticancer compounds, was incorporated into self-nanoemulsifying systems (SNEDDS) subsequently camouflaged with melanoma cell membranes. The resulting biomimetic nanosystems exploited homotypic recognition to selectively interact with tumor cells, enhancing intracellular uptake and cytotoxicity while preserving safety toward non-cancerous cells. The second part addresses physical targeting using thermosensitive injectable gels. The developed formulation, based on Pluronic® F127 and carboxymethyl chitosan, forms an in situ gel depot at body temperature, enabling the sustained local release of protein therapeutics. The system was optimized for mechanical and thermal properties, sterilization feasibility, and cytocompatibility, providing a practical approach for intratumoral administration. Such a formulation enhances drug persistence at the injection site, reducing clearance and supporting localized immunotherapy applications. The third part of the thesis focuses on aerodynamic targeting through pulmonary administration. In the oncological context, nanogels based on octenyl succinic anhydride-modified hyaluronic acid (OSA-HA) were developed via microfluidic technology for gefitinib encapsulation and subsequently processed into inhalable dry powders. These nanogel-based aerosols demonstrated aerodynamic properties suitable for deep lung deposition and preserved the pharmacological activity of gefitinib, highlighting their potential in non-small cell lung cancer therapy. The pulmonary targeting section also includes a series of studies on aerosolized plasminogen (PLG) as a protein biopharmaceutical for the treatment of acute respiratory distress syndrome (ARDS). The first work assessed the biopharmaceutical and physicochemical stability of mesh-nebulized PLG, confirming the preservation of fibrinolytic activity and structural integrity. Subsequent in vivo studies demonstrated the ability of aerosolized PLG to modulate inflammation and restore fibrinolytic balance in experimental ARDS models. To further improve protein stability under oxygen-enriched nebulization, a new formulation based on hydroxypropyl-β-cyclodextrin (HP-β-CD) complexation was developed, preserving over 95% enzymatic activity and maintaining fibrinolytic efficacy.