Development of Microfluidic-Based Liposomes for Ocular Administration of Nutlin-3a

The effective ocular delivery of therapeutic agents is hindered by the eye's natural barriers, necessitating advanced drug delivery systems. Novel drug-delivery technologies such as liposomes are increasingly studied as potential ophthalmic drug delivery systems able to encapsulate and efficiently deliver also highly lipophilic drugs. In this regard, the present study aims to develop and produce liposomes formulation able to encapsulate and allow the ocular delivery of Nutlin-3a, a small non-genotoxic inhibitor of the MDM2/p53 interaction, that shows interesting therapeutic potential against retinal disease. Liposomes were produced via a microfluidic approach and their size distribution was evaluated by photon correlation spectroscopy, and centrifugal field flow fractionation. Nutlin-3a entrapment capacity was evaluated via ultrafiltration and HPLC. Moreover, morphological, and structural characterization were conducted using transmission electron microscopy and Fourier-transform infrared spectroscopy, respectively. The microfluidic formulative study enabled the selection of LIPO constituted of phosphatidylcholine at concentrations of 5.4 and ethanol 10% ethanol, exhibiting a roundish vesicular structure with mean diameters around 150 nm, polydispersity index values always below 0.2, as well as high Nutlin-3a entrapment capacity [1]. Viability, proliferation, apoptosis, and migration assays were conducted to evaluate the biological effectiveness of Nutlin-3a. Nutlin-3a loaded in liposomes was able to induce a significant reduction of viability and migration in RPE cell models. This work paves the way for future applications of liposomes in the ocular delivery of Nutlin-3a.

[1] E. Esposito, E. Pozza, C. Contado, W. Pula, O. Bortolini, D. Ragno, … E. Melloni. Microfluidic Fabricated Liposomes for Nutlin-3a Ocular Delivery as Potential Candidate for Proliferative Vitreoretinal Diseases Treatment. International Journal of Nanomedicine, 2024, 19, 3513–3536.