(498f) Nanoparticle Optimization for Improved Vaginal Drug Delivery during Pregnancy
Methods: 250 CVM samples (spaced monthly) were self-collected by 70 pregnant women. CVM microstructure was characterized by a quantitative multiple particle tracking method. Fluorescently-labeled nanoparticles with and without mucoinert coatings were added to CVM. Particle motions due to thermal energy were recorded and quantified to estimate the mesh spacing of mucin proteins comprising CVM. Trichostatin A (TSA), a histone deacetylase inhibitor that has been shown to delay parturition at term , and progesterone (P4), the âpregnancy hormoneâ, were formulated as nanosuspensions (NS) via wet milling. To investigate the efficacy of these particles, pregnant mice were challenged with an intra-uterine (IU) lipopolysaccharide (LPS) injection on embryonic day 15 (E15, out of 19 day gestation). Sham animals received IU saline and no treatment. LPS animals received no treatment, TSA, P4, or TSA+P4. Treatment was dosed vaginally daily from E15-18. Mice were checked every 12 h for signs of PTB.
Results: Similar to what was observed previously in CVM from non-pregnant women, nanoparticles with mucoinert coatings have increased mobility in CVM from pregnant women. However, CVM from pregnant women causes a significant reduction in mobility of nanoparticles, particularly for nanoparticles 500 nm in size or greater, as pregnancy progresses. Mucoinert nanoparticles ~250 nm in size were slowed, but a significant fraction were still highly mobile in CVM. This inferred reduction in pore size in CVM is likely due to increasing progesterone levels throughout pregnancy. The TSA NS had average size of 207 nm with an average PDI of 0.25, and an average zeta potential of -0.38 mV. The P4 NS had average size of 301 nm with a PDI of 0.22, and an average zeta potential of -2.01 mV. These nanoparticles were shown to bypass the vaginal mucus barrier in mice, and have mobility in human CVM. They further showed efficacy in the model of inflammation induced PTB. The percentage of pregnant animals that went to full term were as follows: sham animals (100%), LPS only (10%), LPS + P4 NS (15%), LPS + TSA NS (30%), LPS + TSA/P4 NS (40%) (p=0.003 compared to LPS only). There was no significant loss of pups in litters that went to term. Analysis of cervical and myometrial tissues revealed anti-inflammatory effects from the combination dosing.
Conclusion: Here, we gained valuable insight for engineering targeted vaginal drug treatments for pregnant women. Further studies will use human myometrial and cervical biopsies to confirm the mechanism of action, and expand the delivery platform to other potential drugs for the prevention of PTB.
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