https://orcid.org/0000-0002-8416-3629
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Abstract
Purpose
Proliferative vitreoretinal diseases (PVDs) represent a heterogeneous group of pathologies characterized by the presence of retinal proliferative membranes, in whose development retinal pigment epithelium (RPE) is deeply involved. As the only effective treatment for PVDs at present is surgery, we aimed to investigate the potential therapeutic activity of Nutlin-3a, a small non-genotoxic inhibitor of the MDM2/p53 interaction, on ARPE-19 cell line and on human RPE primary cells, as in vitro models of RPE and, more importantly, to formulate and evaluate Nutlin-3a loaded liposomes designed for ophthalmic administration.
Methods
Liposomes were produced using an innovative approach by a microfluidic device under selection of different conditions. Liposome size distribution was evaluated by photon correlation spectroscopy and centrifugal field flow fractionation, while the liposome structure was studied by transmission electron microscopy and Fourier-transform infrared spectroscopy. The Nutlin-3a entrapment capacity was evaluated by ultrafiltration and HPLC. Nutlin-3a biological effectiveness as a solution or loaded in liposomes was evaluated by viability, proliferation, apoptosis and migration assays and by morphological analysis.
Results
The microfluidic formulative study enabled the selection of liposomes composed of phosphatidylcholine (PC) 5.4 or 8.2 mg/mL and 10% ethanol, characterized by roundish vesicular structures with 150–250 nm mean diameters. Particularly, liposomes based on the lower PC concentration were characterized by higher stability. Nutlin-3a was effectively encapsulated in liposomes and was able to induce a significant reduction of viability and migration in RPE cell models.
Conclusion
Our results lay the basis for a possible use of liposomes for the ocular delivery of Nutlin-3a.
Graphical Abstract
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Acknowledgments
The authors are grateful to Lorenza Marvelli (Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Italy) for FTIR analysis, Paola Boldrini (Electron Microscopy Center, University of Ferrara, Italy) for TEM analyses and Francesca Bompan (Department of Environmental Sciences and Prevention, University of Ferrara, Italy) for the support for primary HRPE experiments.
Disclosure
The authors report there are no competing interests to declare in this work.