Date of Award

2025

Document Type

Dissertation

Degree Name

Pharmaceutical Sciences (Ph.D.)

Department

Pharmaceutical Sciences

First Advisor

Sandra E Reznik

Second Advisor

John Wurpel

Third Advisor

Ketankumar Patel

Abstract

With no available treatment for preterm birth, the field of reproductive medicine has been repurposing small molecule candidates into vaginal nanoformulations as potential treatments for the condition. The commercial solvent N,N-Dimethylacetamide (DMA) has previously been shown to delay and prevent inflammation-induced preterm birth in a mouse model. A vaginal nanoformulation of DMA loaded into a self-nanoemulsifying drug delivery system (SNEEDS) was studied to see if it can also be efficacious. A side by-side histological comparison was done in the more pertinent tissues of the reproductive tract between the traditional formulation of DMA given intraperitoneally (IP) and the vaginal nanoformulation of DMA when given at a lower dose. SNEDDS DMA was shown to have comparable efficacy to IP DMA in delaying and preventing preterm birth altogether in an inflammation-induced mouse model. Histological sections of the placental labyrinth revealed IP DMA causes the vascular channels to be engorged with red blood cells while this phenomenon is ameliorated when using SNEDDS DMA. Quantitative analysis revealed villous congestion is reduced by approximately 25% with SNEDDS DMA. IP DMA also showed lower CD31 content in the placental labyrinth implicating a potential adverse effect in the development of fetal blood vessels while loss of CD31 was reduced by about 20% when mice were given SNEDDS DMA. Quantitative analysis also showed that adverse effects seen in mice following IP DMA administration are more severe in implantation sites closer to the ovaries than implantation sites closer to the cervix while this phenomenon is absent in mice given SNEDDS DMA illustrating differences in hemodynamics when comparing intraperitoneal and vaginal administration. DMA levels in the plasma were reduced by more than 50% when mice were given SNEDDS DMA, limiting the amount of DMA in the systemic circulation and the likelihood of causing adverse effects in other tissues. Overall, this study demonstrates the vaginal nanoformulation of DMA is efficacious for treating preterm birth in pregnant mice while minimizing damage in the sensitive tissues of the reproductive tract.

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