Effects of Anionic Liposome Delivery of All–Trans–Retinoic Acid on Neuroblastoma Cell Differentiation

Author:

Minò Antonio12ORCID,Lopez Francesco3ORCID,Barbaro Roberto4,Barile Maria4ORCID,Ambrosone Luigi2ORCID,Colella Matilde4ORCID

Affiliation:

1. Department of Biosciences and Territory (DiBT), University of Molise, Contrada Lappone, 86090 Pesche, Italy

2. Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Via F. De Sanctis snc, 86100 Campobasso, Italy

3. Department of Agricultural, Environmental and Food Sciences (DiAAA), University of Molise, Via F. De Sanctis snc, 86100 Campobasso, Italy

4. Department of Biosciences, Biotechnology and Environment (DBBA), University of Bari “Aldo Moro”, Via Orabona 4, 70125 Bari, Italy

Abstract

All–trans–retinoic acid (ATRA) has long been known to affect cell growth and differentiation. To improve ATRA’s therapeutic efficacy and pharmacodynamics, several delivery systems have been used. In this study, free ATRA and anionic–liposome–encapsulated ATRA were compared for their effects on SK–N–SH human neuroblastoma cell growth and differentiation. Anionic liposomes made of L–α–phosphatidylcholine (PC) and L–α–phosphatidic acid (PA), empty (PC–PA) and loaded with ATRA (PC–PA–ATRA), were characterized by dynamic light scattering (DLS) and electrophoretic mobility measurements, and drug entrapment efficiency (EE%) was measured to evaluate the applicability of the new colloidal formulation. The results of brightfield microscopy and cell growth curves indicated that ATRA, whether free or encapsulated, reduced growth and induced differentiation, resulting in SK–N–SH cells changing from epithelioid to neuronal–like morphologies, and producing a significant increase in neurite growth. To further characterize the neuro-differentiation of SK–N–SH cells, the expression of βIII–Tubulin and synaptophysin and mitochondria localization were analyzed via immunofluorescence. Increased expression of neuronal markers and a peculiar localization of mitochondria in the neuritic extensions were apparent both in ATRA– and PC–PA–ATRA–differentiated cells. As a whole, our results strongly indicate that ATRA treatment, by any means, can induce the differentiation of parent SK–N–SH, and they highlight that its encapsulation in anionic liposomes increases its differentiation ability in terms of the percentage of neurite–bearing cells. Interestingly, our data also suggest an unexpected differentiation capability of anionic liposomes per se. This work highlights the importance of developing and carefully testing novel delivery nanocarriers, which are a necessary first “step” in the development of new therapeutic settings.

Publisher

MDPI AG

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