Costabile, Gabriella (2016) New strategies to deliver drugs for the local treatment of severe pulmonary diseases. [Tesi di dottorato]

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Although dated back of some years, the opportunity to selectively target a drug to lungs remains a fascinating option to strongly limit ubiquitous distribution of systemically, and often chronically, administered drugs used to treat severe and chronic lung diseases, such as cystic fibrosis (CF). The main research focus is to combine the advanced, and often “nanotechnology-based”, delivery strategies with the pulmonary route of administration. In this scenario, the general aim of this work is the design and development of advanced nano- and micro-carriers for pulmonary delivery of drugs potentially useful in the local treatment of CF-related chronic lung infection and inflammation. This objective has been pursued through the development of four different formulation strategies, driven by both technological and biological design rules. Through the adequate combination of the most appropriate materials and available technologies, inhalable formulations allowing repositioning of two distinct old drugs, namely niclosamide and flucytosine, for local therapy of lung infections have been successfully developed. Then, biodegradable large porous particles have been especially designed for combined and sustained release of two bioactive macromolecules, namely a decoy oligonucleotide and poly(ethylenimine) with antinflammatory and antimicrobial properties. Finally, novel hybrid lipid/polymer nanoparticles are proposed to face the current challenge of siRNA delivery on the human airway epithelial barrier. The most appropriate formulation approach was selected taking into account the distinct physico-chemical profile of the drug under investigation (e.g., solubility, stability, molecular weight) and the peculiarities of CF lung. In vitro/in vivo studies represented a critical step before selection of the best formulation to candidate for further development. Special attention was paid to the optimization of the lung deposition profile of the drug. Nevertheless, in vitro studies aimed to acquire knowledge on what happens after the particles have landed were considered crucial for formulation choice. An important challenge that has been taken into account is the toxicity of the selected materials to the lung cell/tissues and its biodistribution and persistence in the lung in vivo.

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