Chronic lung allograft dysfunction (CLAD) and interstitial lung disease associated with collagen tissue diseases (CTD-ILD) are two end-stage lung disorders in which different chronic triggers induce activation of myo-/fibroblasts (LFs). Everolimus, an mTOR inhibitor, can be adopted as a potential strategy for CLAD and CTD-ILD, however it exerts important side effects. This study aims to exploit nanomedicine to reduce everolimus side effects encapsulating it inside liposomes targeted against LFs, expressing a high rate of CD44. PEGylated liposomes were modified with high molecular weight hyaluronic acid and loaded with everolimus (PEG-LIP(ev)-HA400kDa). Liposomes were tested by in vitro experiments using LFs derived from broncholveolar lavage (BAL) of patients affected by CLAD and CTD-ILD, and on alveolar macrophages (AM) and lymphocytes isolated, respectively, from BAL and peripheral blood. PEG-LIP-HA400kDa demonstrated to be specific for LFs, but not for CD44-negative cells, and after loading everolimus, PEG-LIP(ev)-HA400kDa were able to arrest cell cycle arrest and to decrease phospho-mTOR level. PEG-LIP(ev)-HA400kDa showed anti-inflammatory effect on immune cells. This study opens the possibility to use everolimus in lung fibrotic diseases, demonstrating that our lipids-based vehicles can vehicle everolimus inside cells exerting the same drug molecular effect, not only in LFs, but also in immune cells.

Background: The strategic development of therapeutic agents capable of being targeted at their active sites has been a major goal in the treatment of cancer. The delivery of drugs for tumors has as its main challenge the development of safe and effective drugs, since the goal of chemotherapy is to eliminate the tumor completely without reaching healthy cells. The aim of the present study was to investigate the antioxidant, anticancer activitie of zidovudine and its α-O-glycosylated derivative obtained by biosynthesis using the filamentous fungi Cunninghamela echinulata. Methods: Was performed an evaluation of the cytotoxic potential zidovudine and its α-O-glycosylated in fibroblasts and melanoma cells by the tetrazolium reduction method (MTT), and the antioxidant activity of this derivative. Results: The antioxidant activity of zidovudine demonstrated an electrochemical oxidation potential of 0.91V while the α-glycosylated derivative did not exhibit any antioxidant activity. The zidovudine exhibited low cytotoxicity for melanoma and fibroblast cells while the αglycosylated derivative presented better cytotoxicity on melanoma cells at a concentration of 10mg. mL-1. Conclusion: This, demonstrate the specific cytotoxicity of the glycoconjugate and suggest that glycosylation by biosynthesis can be a useful strategy for obtaining new anticancer compounds.

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