Development of a New Local Therapeutic Approach for BOS: Efficacy of Imatinib Loaded -antiCD44 Coated Gold Nanoparticles In Vitro and In Vivo

Abstract

Purpose The use of gold nanoparticles (GNPs) as local targeted drug delivery system are a promising issue for several orphan diseases. Bronchiolitis obliterans syndrome (BOS) represents about 70% of cases of chronic lung allograft dysfunction limiting long term survival after lung transplant, and occurs also as chronic pulmonary involvement in the context of GVHD. To now treatment strategies in BOS are scarce and poorly effective. In the present work, we investigated the effect of GNP decorated with the half chain of monoclonal antibody against CD44 (GNP-HC), surface receptor overexpressed by primary BOS derived mesenchymal cells (MCs) that cause the partial or total occlusion of alveolar tract. We loaded GNP-HC with imatinib (GNP-HCim), an cAbl inhibitor used in the management of chronic GVHD. Methods In vitro experiments were performed on MCs derived from BOS patients evaluating cell cytotoxicity after incubation with GNP-HC, GNP-HCim and Imatinib alone. We further performed a mouse heterotopic trachea transplantation model modified by the subcutaneous placement of Alzet Model 2004 miniosmotic pumps used to deliver into the trachea different solutions at a constant rate for 28 days. This was performed in order to assess the efficacy of the local intratracheal administration of our nanovectors. Results Thanks to MTT and apoptosis assay we observed that GNP-HCim decrease MCs viability more than GNP-HC and Imatinib alone, due to an induction of apoptosis (50 ± 0.5 % for GNP-HCim in contrast to GNP-HC 40 ± 0.35 % and Imatinib alone 30 ± 1.2 %). Moreover, animal model data confirmed the in vitro results: GNP-HCim significantly reduced the percentage of tracheal obliterative area (12.99 ± 2.5%) respect to GNP-HC (46.79± 5.7%) and vehicle treated mice (30.92 ± 5.8%). Conclusion We conclude that this approach by newly developed nano-based strategies for BOS treatment and especially targeted imatinib gold nanoparticles are promising candidates for further development.