MRJF22

(±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viability in a comparable manner to bevacizumab. Moreover, (±)-2 was able to significantly reduce viable cells count, endothelial cell migration, and tube formation in vascular endothelial growth factor A (VEGF-A) stimulated HREC cultures.

Among the eye tumors, uveal melanoma is one of the most diffuse and aggressive, affecting mainly the choroid, but also the ciliary body and the iris.Promising pharmaceutical therapies involve histone deacetylase inhibitors and sigma-ligands: these targets were combined in a new-synthesized prodrug, namely (±)-MRJF22, which demonstrated to perform antiangiogenic activity, as well as its (R)- and (S)-enantiomers.Since this cancer mainly occurs in the posterior segment of the eye, the therapeutical use of this prodrug is limited by the presence of ocular barriers.Herein, lipid nanoparticles were selected for their potential ophthalmic application to encapsulate (±)-MRJF22 prodrug and its (R)- and (S)-enantiomers.The prepared nanoparticles demonstrated to be suitable for the intended ophthalmic administration in terms of size, homogeneity, zeta potential, pH and osmolality.DSC and FTIR analyses were performed on the formulations, and their long-term stability was confirmed by accelerated stability studies.Mucoadhesive studies suggested a potential good interaction with ocular surface epithelia, thus enhancing the ocular residence time of the formulations.In vitro release studies demonstrated a sustained and prolonged release of the prodrugs loaded in the colloidal suspensions.Cytocompatibility and proliferation assays were performed on uveal melanoma 92-1 cell line, confirming the suitability of the formulations and their potential application in the treatment of uveal melanoma.