Mucoadhesive Nanoemulsion Enhances the Antineoplastic Potential of Naringenin in Bladder Cancer Cell Lines

Naringenin exhibits anticancer properties against various types of cancer. Bladder cancer is among the most prevalent cancers worldwide and is characterized by a high recurrence rate because of resistance to standard chemotherapy. Nanotechnology represents a prospective approach to counteracting the challenges associated with the therapeutic application of naringenin in the treatment of bladder cancer. The aim of this study was to evaluate the antineoplastic activity of naringenin in high-grade bladder cancer cell lines (J82 and UM-UC-3) and to develop nanoemulsions. The assessment of cellular toxicity was conducted using the sulforhodamine B method, clonogenic survival using crystal violet staining, cell migration by the wound healing assay, changes in the cell cycle using flow cytometry, and expression of the specific long noncoding RNAs RP11-363E7.4 and SBF-AS1 by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Nanoemulsions with and without chitosan were developed using the phase inversion method and characterized by measuring particle size as well as release profile, encapsulation efficiency, and mucoadhesion in vitro and ex vivo. Naringenin significantly inhibited cell proliferation, viability, clonogenic survival, and migration and altered the cell cycle in both bladder cancer cell lines. Moreover, naringenin increased the expression of the long noncoding RNA RP11-363E7.4 in the UM-UC-3 cell line. The nanoemulsions were found to be nanometric, monodisperse, stable, sustained-release systems, and exhibited adequate encapsulation efficiency. In addition, the formulations increased the cytotoxicity of naringenin, and the chitosan-containing nanoemulsion demonstrated mucoadhesion without ex vivo toxicity. Consequently, naringenin and nanoemulsions may represent promising alternatives for the development of therapeutic agents for the treatment of bladder cancer.