Abstract
Purpose Bronchiolitis Obliterans Syndrome (BOS), major clinical phenotype of chronic lung allograft dysfunction (CLAD), is responsible of poor long-term survival after lung transplantation (LTx). Once BOS starts can at best be halted for some months and no pharmacological treatment is able to revert it. Main actors of BOS are aberrantly activated mesenchymal cells (MCs), which proliferate and obliterate the small airways. Based on previous encouraging results with CD44 coated-drug loaded gold nanoparticles (Cova, 2014 and 2017) aiming to engineer more biocompatible nanocarriers to be delivered by inhalation route, we designed hyaluronic acid (HA)- decorated liposomes (LIP-HA) to be loaded with an antiproliferative drug, targeting CD44 receptor on BOS patient-derived MCs Methods We preliminarily evaluated the efficiency of liposomes functionalized with HA of different molecular weight (MW 4800, 14800 kDa), possibly associated to different targeting efficiency and pro-inflammatory activity. Results Using confocal microscopy and flow cytometry, we assessed that LIP decorated with higher MW HA were able to be internalized by MCs more (89 ± 15%) than LIP carrying HA with lower MW (45 ± 7.8%). In order to confirm that our nanovehicles are specific only for CD44-expressing cells, we incubated CD44-negative cell line (16HBE) with both MW HA-liposomes which were poorly internalized (confocal microscopy). We also studied the influence of LIP-HA on cytokine release from macrophages. We observed that 14800 kDa LIP-HA did not alter the release of TNF-α, IL-1β, VEGF and TGF-β, in contrast to 4800 kDa LIP-HA that exerted a 2-fold increase of the release of TGF-β respect to untreated cells (p Conclusion In conclusion 14.800- HA decorated liposomes are more efficient in entering primary BOS MCs and do not induce macrophage activation, thus they are promising biocompatible nanovectors for local targeted drug delivery. The efficacy of drug loaded 14.800 HA decorated liposomes is now under investigation.
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