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Promoting Vaginal Distribution of E7 and MCL-1 siRNA-Silencing Nanoparticles for Cervical Cancer Treatment

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‡ †Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM and ‡Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, 4000 Liège, Belgium
*E-mail: [email protected]. Phone: +32 4 366 43 07. Fax: +32 4 366 43 02.
Cite this: Mol. Pharmaceutics 2017, 14, 5, 1706–1717
Publication Date (Web):March 28, 2017
https://doi.org/10.1021/acs.molpharmaceut.6b01154
Copyright © 2017 American Chemical Society
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    Abstract

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    There is an urgent need to develop a less aggressive and more effective treatment against cervical lesions induced by different high-risk human papillomavirus (HR-HPV). We investigated the potential of a cocktail of small interfering RNA (siRNA) directed against the oncoprotein E6 (E6), the oncoprotein E7 (E7), or the antiapoptotic protein MCL-1 (MCL-1). The combination of siRNA anti-E7 and anti-MCL-1 demonstrated high efficacy on multiple HPV16 and HPV18 cell lines and no effects on healthy keratinocytes. This gene therapy has been considered for a vaginal administration since this route of application holds high potential for the treatment of diseases in the female reproductive tracts. Therefore, PEGylated lipoplexes have been designed and characterized to protect siRNA and to diffuse in the mucosal environment before they reach the cervico/vaginal epithelium. This new nanovector complexed to the combination of active siRNA induced an efficient mRNA knockdown since biological effects were obtained in vitro. This work also provided evidence that the PEGylated lipoplexes had appropriate physicochemical properties to diffuse into a mucin network according to size measurement experiments in artificial mucus. After demonstrating the distribution and the efficacy of siRNA into a 3D-cervical model lesion and through porcine vaginal mucosa, in vivo experiments in mouse have been performed under physiological conditions. This study revealed a complete and sustained coverage of the mucosal epithelium following an unique vaginal administration of fluorescent PEGylated lipoplexes. Overall, our results showed the potential of the PEGylated lipoplexes for the prolonged delivery of active siRNA to treat HPV-induced lesions.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.6b01154.

    • SVF composition, KNCC medium composition, expression of MCL-1 in cervical HPV-induced lesions and in normal tissue, in vitro evaluation of E6/E7/MCL-1 mRNA knockdown on CaSki cells, transfection capacity of siRNA on CaSki and SiHa cells (PDF)

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