Freeze-dried mucoadhesive polymeric system containing pegylated lipoplexes: Towards a vaginal sustained released system for siRNA

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• 作者：Tania Furst^a ; ^{tania.furst@ulg.ac.be" class="auth_mail" title="E-mail the corresponding author} ; George R. Dakwar^b ; Elisa Zagato^b ; Anna Lechanteur^a ; Katrien Remaut^b ; Brigitte Evrard^a ; Kevin Braeckmans^b ; Geraldine Piel^a
• 关键词：Ceramide-PEG2000 ; N-octanoyl-sphingosine-1-{succinyl[methoxy(polyethylene glycol)2000]} ; DSPE-PEG2000 ; 1 ; 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] ; DSPE-PEG750 ; 1 ; 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-750] ; FCS ; fluorescence correlation spectroscopy ; fluo-siRNA ; fluorescent small interfering RNA ; fSPT ; fluorescence single particle tracking ; HEC ; hydroxyethyl cellulose ; PdI ; polydispersity index ; PEG ; polyethylene g
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：28 August 2016
• 年：2016
• 卷：236
• 期：Complete
• 页码：68-78
• 全文大小：1562 K

文摘

Topical vaginal sustained delivery of siRNA presents a significant challenge due to the short residence time of formulations. Therefore, a drug delivery system capable to adhere to the vaginal mucosa is desirable, as it could allow a prolonged delivery and increase the effectiveness of the therapy. The aim of this project is to develop a polymeric solid mucoadhesive system, loaded with lipoplexes, able to be progressively rehydrated by the vaginal fluids to form a hydrogel and to deliver siRNA to vaginal tissues.

To minimize adhesive interactions with vaginal mucus components, lipoplexes were coated with different derivatives of polyethylene glycol: DPSE-PEG₂₀₀₀, DPSE-PEG₇₅₀ and ceramide-PEG₂₀₀₀. Based on stability and diffusion properties in simulated vaginal fluids, lipoplexes containing DSPE-PEG₂₀₀₀ were selected and incorporated in hydroxyethyl cellulose (HEC) hydrogels. Solid systems, called sponges, were then obtained by freeze-drying. Sponges meet acceptable mechanical characteristics and their hardness, deformability and mucoadhesive properties are not influenced by the presence of lipoplexes. Finally, mobility and stability of lipoplexes inside sponges rehydrated with vaginal mucus, mimicking in situ conditions, were evaluated by advanced fluorescence microscopy. The release rate was found to be influenced by the HEC concentration and consequently by the viscosity after rehydration.

This study demonstrates the feasibility of entrapping pegylated lipoplexes into a solid matrix system for a prolonged delivery of siRNA into the vagina.