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Spray-dried powders enhance vaginal siRNA delivery by potentially modulating the mucus molecular sieve structure.

Wu N, Zhang X, Li F, Zhang T, Gan Y, Li J - Int J Nanomedicine (2015)

Bottom Line: Highly dispersed dry powders with diameters of 5-15 μm were produced.These powders showed effective siRNA protection and sustained release.The mucus-penetrating properties of the powders differed depending on their compositions.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.

ABSTRACT
Vaginal small interfering RNA (siRNA) delivery provides a promising strategy for the prevention and treatment of vaginal diseases. However, the densely cross-linked mucus layer on the vaginal wall severely restricts nanoparticle-mediated siRNA delivery to the vaginal epithelium. In order to overcome this barrier and enhance vaginal mucus penetration, we prepared spray-dried powders containing siRNA-loaded nanoparticles. Powders with Pluronic F127 (F127), hydroxypropyl methyl cellulose (HPMC), and mannitol as carriers were obtained using an ultrasound-assisted spray-drying technique. Highly dispersed dry powders with diameters of 5-15 μm were produced. These powders showed effective siRNA protection and sustained release. The mucus-penetrating properties of the powders differed depending on their compositions. They exhibited different potential of opening mesh size of molecular sieve in simulated vaginal mucus system. A powder formulation with 0.6% F127 and 0.1% HPMC produced the maximum increase in the pore size of the model gel used to simulate vaginal mucus by rapidly extracting water from the gel and interacting with the gel; the resulting modulation of the molecular sieve effect achieved a 17.8-fold improvement of siRNA delivery in vaginal tract and effective siRNA delivery to the epithelium. This study suggests that powder formulations with optimized compositions have the potential to alter the steric barrier posed by mucus and hold promise for effective vaginal siRNA delivery.

No MeSH data available.


Related in: MedlinePlus

Frequency dependence of the viscoelastic moduli.Notes: Viscoelastic moduli of 0.5% HEC, solutions of F1 (A), F2 (B), F3 (C), and F4 (D) powder carriers (eg, F1-sol), 0.5% HEC after the addition of F1–F4 powders (containing no nanoparticles) (eg, F1/HEC), and 0.5% HEC after the addition of F1–F4 powder carrier solutions at 37.2°C. The arrows indicate the degree of shift of the crossover points for the 0.5% HEC solution, after being mixed with powder formulations (the blue arrows), or the same solution formulations (the green arrows).Abbreviations: F, formulation; HEC, hydroxyethyl cellulose; sol, solution.
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f7-ijn-10-5383: Frequency dependence of the viscoelastic moduli.Notes: Viscoelastic moduli of 0.5% HEC, solutions of F1 (A), F2 (B), F3 (C), and F4 (D) powder carriers (eg, F1-sol), 0.5% HEC after the addition of F1–F4 powders (containing no nanoparticles) (eg, F1/HEC), and 0.5% HEC after the addition of F1–F4 powder carrier solutions at 37.2°C. The arrows indicate the degree of shift of the crossover points for the 0.5% HEC solution, after being mixed with powder formulations (the blue arrows), or the same solution formulations (the green arrows).Abbreviations: F, formulation; HEC, hydroxyethyl cellulose; sol, solution.

Mentions: In order to discriminate between the curves, we moved them to distinguishable areas and labeled the ordinates with arbitrary units. As shown in Figure 7, all the curves showed a crossover point, where G′ = G″, and G″ increased at higher frequencies. The crossover point for the 0.5% HEC solution was at 2.045 Hz. After being mixed with any formulations, the crossover points of the mixtures shifted to a lower frequency region, which meant that the elastic behavior was prevailing over the viscous behavior. When they were mixed with HEC, F2 and F4 caused a larger shift to 0.298 Hz and 0.332 Hz, respectively, while F3 showed the smallest shift to 0.692 Hz. The shifts caused by the same solution formulations were relatively smaller and there was little difference between the formulations. The degree of shift of the crossover points coincided with the alterations in gel structures. Comparison of the corresponding scanning electron micrographs (Figure 6) showed that formulations producing the larger/smaller rheological shift produced greater/lesser (respectively) changes in the gel structure. These results validated that the addition of the formulation caused alterations of model gel rheological properties, which might partly explain the alterations of the structures.


Spray-dried powders enhance vaginal siRNA delivery by potentially modulating the mucus molecular sieve structure.

Wu N, Zhang X, Li F, Zhang T, Gan Y, Li J - Int J Nanomedicine (2015)

Frequency dependence of the viscoelastic moduli.Notes: Viscoelastic moduli of 0.5% HEC, solutions of F1 (A), F2 (B), F3 (C), and F4 (D) powder carriers (eg, F1-sol), 0.5% HEC after the addition of F1–F4 powders (containing no nanoparticles) (eg, F1/HEC), and 0.5% HEC after the addition of F1–F4 powder carrier solutions at 37.2°C. The arrows indicate the degree of shift of the crossover points for the 0.5% HEC solution, after being mixed with powder formulations (the blue arrows), or the same solution formulations (the green arrows).Abbreviations: F, formulation; HEC, hydroxyethyl cellulose; sol, solution.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554414&req=5

f7-ijn-10-5383: Frequency dependence of the viscoelastic moduli.Notes: Viscoelastic moduli of 0.5% HEC, solutions of F1 (A), F2 (B), F3 (C), and F4 (D) powder carriers (eg, F1-sol), 0.5% HEC after the addition of F1–F4 powders (containing no nanoparticles) (eg, F1/HEC), and 0.5% HEC after the addition of F1–F4 powder carrier solutions at 37.2°C. The arrows indicate the degree of shift of the crossover points for the 0.5% HEC solution, after being mixed with powder formulations (the blue arrows), or the same solution formulations (the green arrows).Abbreviations: F, formulation; HEC, hydroxyethyl cellulose; sol, solution.
Mentions: In order to discriminate between the curves, we moved them to distinguishable areas and labeled the ordinates with arbitrary units. As shown in Figure 7, all the curves showed a crossover point, where G′ = G″, and G″ increased at higher frequencies. The crossover point for the 0.5% HEC solution was at 2.045 Hz. After being mixed with any formulations, the crossover points of the mixtures shifted to a lower frequency region, which meant that the elastic behavior was prevailing over the viscous behavior. When they were mixed with HEC, F2 and F4 caused a larger shift to 0.298 Hz and 0.332 Hz, respectively, while F3 showed the smallest shift to 0.692 Hz. The shifts caused by the same solution formulations were relatively smaller and there was little difference between the formulations. The degree of shift of the crossover points coincided with the alterations in gel structures. Comparison of the corresponding scanning electron micrographs (Figure 6) showed that formulations producing the larger/smaller rheological shift produced greater/lesser (respectively) changes in the gel structure. These results validated that the addition of the formulation caused alterations of model gel rheological properties, which might partly explain the alterations of the structures.

Bottom Line: Highly dispersed dry powders with diameters of 5-15 μm were produced.These powders showed effective siRNA protection and sustained release.The mucus-penetrating properties of the powders differed depending on their compositions.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.

ABSTRACT
Vaginal small interfering RNA (siRNA) delivery provides a promising strategy for the prevention and treatment of vaginal diseases. However, the densely cross-linked mucus layer on the vaginal wall severely restricts nanoparticle-mediated siRNA delivery to the vaginal epithelium. In order to overcome this barrier and enhance vaginal mucus penetration, we prepared spray-dried powders containing siRNA-loaded nanoparticles. Powders with Pluronic F127 (F127), hydroxypropyl methyl cellulose (HPMC), and mannitol as carriers were obtained using an ultrasound-assisted spray-drying technique. Highly dispersed dry powders with diameters of 5-15 μm were produced. These powders showed effective siRNA protection and sustained release. The mucus-penetrating properties of the powders differed depending on their compositions. They exhibited different potential of opening mesh size of molecular sieve in simulated vaginal mucus system. A powder formulation with 0.6% F127 and 0.1% HPMC produced the maximum increase in the pore size of the model gel used to simulate vaginal mucus by rapidly extracting water from the gel and interacting with the gel; the resulting modulation of the molecular sieve effect achieved a 17.8-fold improvement of siRNA delivery in vaginal tract and effective siRNA delivery to the epithelium. This study suggests that powder formulations with optimized compositions have the potential to alter the steric barrier posed by mucus and hold promise for effective vaginal siRNA delivery.

No MeSH data available.


Related in: MedlinePlus