Risultato Progetto: FFC#25/2018
Veicolazione polmonare di siRNA nel trattamento dell’infiammazione polmonare in fibrosi cistica: potenziale terapeutico di nanoparticelle ibride a base di lipidi e polimeri

I ricercatori hanno sviluppato nanoparticelle a base di polimeri biodegradabili e fosfolipidi endogeni (nanoparticelle ibride) per trasportare un insieme di siRNA (corti frammenti di RNA) in grado di inibire NF-kB. NF-kB è una complessa proteina, presente all’interno del nucleo delle cellule, che agisce come segnale di attivazione dell’infiammazione. Le nanoparticelle veicolanti SiRNA contro NF-kB sono state sperimentate in vitro su modelli diversi di epitelio polmonare e in vivo su modelli animali. Gli studi in vitro hanno mostrato la loro capacità di penetrare attraverso il muco con le caratteristiche della malattia FC e di trasportare lo specifico siRNA all’interno delle cellule polmonari. L’efficacia di SiRNA veicolato dalle nanoparticelle è risultata maggiore rispetto al siRNA somministrato libero sia in vitro che in vivo. I risultati del progetto illustrano il vantaggio delle nuove nanoparticelle come vettori e più in generale la potenzialità dei siRNA come strategia terapeutica in fibrosi cistica.

In vitro studies demonstrated that the developed siRNA-loaded hybrid nanoparticles (hNPs) may penetrate lung extracellular barriers, as CF mucus, allowing a significantly higher uptake in human bronchial epithelial cells as compared to both free siRNA and siRNA/lipofectamine complexes. As a result, significant nuclear factor-kB(NF-kB) downregulation up to 72h was observed in human bronchial epithelial cells treated with optimised siRNA-loaded hNPs. Moreover, preliminary efficacy studies upon intratracheal administration in LPS-challenged rats highlighted the potential of the developed siRNA-loaded to downregulate NF-kB also in vivo. The perspective is that optimized nanoparticles could move to further in vivo preclinical studies, which are essential to translate the technology under development from labs to the clinics. The development of a siRNA delivery system already engineered for in vivo inhalation and transfection might shorten the time to translation to patients, providing a therapeutic platform to address multiple targets that are still considered “undruggable” in CF.

Congress abstracts

• Ungaro F, Overcoming lung barriers to siRNA delivery in cystic fibrosis through tailored lipid/polymer hybrid nanoparticles, 11th Annual RNA Therapeutics Conference Focus Day – Oligonucleotide Delivery Systems, 18th February 2020, London, UK
• Baldassi D, Costabile G, Conte G et al. In vitro evaluation of siRNA loaded hNPs for the treatment of cystic fibrosis, International Conference on Nanomedicine and Nanobiotechnology 2019 (ICONAN 2019), October 16th – 18th, 2019, Munich, Germany
• D’Angelo I, Conte G, Costabile G et al. Enabling pulmonary delivery of siRNA in cystic fibrosis lung inflammation through hybrid lipid/polymer nanoparticles, International Society for Aerosol in Medicine e.V., 22nd ISAM Congress, Montreaux, Switzerland, May 25-29, 2019
• D’Angelo I, Conte G, Costabile G et al. Tailored hybrid lipid/polymer nanoparticles for pulmonary delivery of siRNA in cystic fibrosis, IV International Caparica Symposium on Nanoparticles/Nanomaterials and Applications 2020 (ISN2A2020), January 20th-23rd, 2020, Caparica, Portugal
• Costabile G, Buroni S, Provenzano R et al. Elongated mucus-penetrating nanocrystals for lung delivery of a new anti-Burkholderia agent in cystic fibrosis, International Society for Aerosol in Medicine e.V., 22nd ISAM Congress, Montreaux, Switzerland, May 25-29, 2019
• Costabile G, Provenzano R, Mitidieri E et al. Repurposing Gallium for local treatment of P. aeruginosa lung infections through sustained-release dry powders for inhalation, International Society for Aerosol in Medicine e.V.”, 22nd ISAM Congress, Montreaux, Switzerland, May 25-29, 2019
• D’Angelo I, Casciaro B, Zhang X et al. Biodegradable nanoparticles for prolonged therapeutic efficacy of antimicrobial peptides against Pseudomonas aeruginosa lung infections, International Society for Aerosol in Medicine e.V.”, 22nd ISAM Congress, Montreaux, Switzerland, May 25-29, 2019