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Pretreatment of human cervicovaginal mucus with pluronic F127 enhances nanoparticle penetration without compromising mucus barrier properties to herpes simplex virus.

ABSTRACT: Mucosal drug delivery nanotechnologies are limited by the mucus barrier that protects nearly all epithelial surfaces not covered with skin. Most polymeric nanoparticles, including polystyrene nanoparticles (PS), strongly adhere to mucus, thereby limiting penetration and facilitating rapid clearance from the body. Here, we demonstrate that PS rapidly penetrate human cervicovaginal mucus (CVM), if the CVM has been pretreated with sufficient concentrations of Pluronic F127. Importantly, the diffusion rate of large polyethylene glycol (PEG)-coated, nonmucoadhesive nanoparticles (PS-PEG) did not change in F127-pretreated CVM, implying that F127 did not significantly alter the native pore structure of CVM. Additionally, herpes simplex virus type 1 (HSV-1) remains adherent in F127-pretreated CVM, indicating that the presence of F127 did not reduce adhesive interactions between CVM and the virions. In contrast to treatment with a surfactant that has been approved for vaginal use as a spermicide (nonoxynol-9 or N9), there was no increase in inflammatory cytokine release in the vaginal tract of mice after daily application of 1% F127 for 1 week. Pluronic F127 pretreatment holds potential as a method to safely improve the distribution, retention, and efficacy of nanoparticle formulations without compromising CVM barrier properties to pathogens.

SUBMITTER: Ensign LM

PROVIDER: S-EPMC4261994 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Self-nanoemulsifying systems (SNEs) have excellent ability to improve the solubility of poorly water-soluble drugs (PWSD). However, SNEs are likely to be degraded in gastrointestinal (GIT) when their surface is recognized by lipase/co-lipase enzyme complex, resulting in rapid release and precipitation of encapsulated drugs. The precipitates are then captured and removed by intestinal mucus, reducing the delivery efficacy of SNEs. Herein, the amphiphilic polymer Pluronic® F127 was incorporated into long and short-chain triglycerides (LCT, SCT) based SNEs to diminish the recognition and therefore minimized their degradation by enzymes and clearance by mucus. The SNEs were characterized in terms of particle size, zeta potential and stability. Ex vivo multiple particles tracking studies were performed by adding particle solution into fresh rat mucus. Cellular uptake of SNEs were conducted by using E12 cells, the absorption and distribution in small intestine were also studied after oral administration in male Sprague-Dawley (SD) rats. The in vitro digestion rate of SNEs were found to be in following order SCT-SNE > SCT-F127-SNE > LCT-SNE > LCT-F127-SNE. Moreover, the LCT-F127-SNE was found to be most effective in enhancing cellular uptake, resulting in 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE and SCT-F127-SNE, respectively. After incubating the SNE with E12 cells, the LCT-F127-SNE exhibited the highest amount regarding both mucus penetration and cellular uptake, with an uptake amount number (via bicinchoninic acid (BCA) analysis) of 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE and SCT-F127-SNE, respectively. The in vivo results revealed that orally administered LCT-F127-SNE could significantly increase the bioavailability of Cyclosporine A (CsA), which was approximately 2.43-fold, 1.33-fold and 1.80-fold higher than that of SCT-SNE, SCT-F127-SNE and LCT-SNE, respectively. We address in this work that F127-modified SNEs have potentials to improve oral drug absorption by significantly reducing gastrointestinal enzymatic degradation and simultaneously enhancing mucus penetration.

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Pretreatment of human cervicovaginal mucus with pluronic F127 enhances nanoparticle penetration without compromising mucus barrier properties to herpes simplex virus.

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