Poster X9 - Vaginal delivery of nanocrystal therapeutics in a mouse model of cervical insufficiency.

Introduction: Preterm birth (PTB), or birth prior to 37 weeks of gestation, is one of the leading causes of infant morbidity and mortality. Previously, our lab has shown that vaginal dosing of nanocrystal drug formulations is more effective than systemic dosing for preventing PTB in mouse models of intrauterine inflammation and progesterone withdrawal. However, one of the only clinical predictors of PTB is sonographic short cervix, affecting 12.5% of all pregnancies, but there are no mouse models available to test potential therapeutics. Here, we describe the development of a mouse model of short cervix based on the critical role of prostaglandins (PGE2/PGE1) in the initiation of cervical remodeling. We then test vaginal nanoformulations containing the tocolytic indomethacin, which is used to treat preterm labor and has been tested in some contexts of cervical shortening and insufficiency. We then demonstrate that vaginal treatment with indomethacin can promote cervical sufficiency and delay PTB caused by a loss of cervical integrity.

Materials and

Methods: Pregnant CD-1 dams were dosed vaginally at gestation day 15 (E15) with an intraperitoneal solution containing dimethyl prostaglandin E2 (dmPGE2) to induce cervical remodeling. The effects of dmPGE2 on the myometrium and cervix were characterized using total calcium quantification at varying time points within the myometrium, and hydroxyproline quantification to define collagen density of the cervix. Mice were then treated with indomethacin nanocrystals vaginally, and therapeutic effect was determined through PTB outcome and changes to the cervix and myometrium after treatment at various time points.

Results, Conclusions, and Discussions: Intraperitoneal injection with dmPGE2 was effective in causing preterm cervical remodeling, with higher doses causing complete evacuation of the uterus. Dose titration allowed for a less severe phenotype with signs of labor that halted and then leading to the delivery of live pups at full term. Vaginal indomethacin treatment resulted in slowing of the labor process and reduction of cervical remodeling and PTB.
Induction of preterm cervical remodeling with dmPGE2 may be a suitable model of short cervix and cervical insufficiency. The tocolytic indomethacin was more effective when dosed vaginally and may prevent preterm cervical remodeling when applied at effective local doses.
Due to indomethacin’s action as a COX inhibitor, it holds promise of being a viable therapeutic option for this model at an appropriate dose, though the therapeutic window may be narrow. The lack of selectivity for either COX 1 or COX 2 may also contribute to some of the adverse side effects, due to COX 1 inhibition resulting in lack of platelet aggregation and heavy bleeding. The model will be tested with other therapeutics that may have more specificity for the molecular mechanisms involved in preterm cervical remodeling.

Acknowledgements (Optional): Dr. Laura Ensign, Sa'ed Abassi, Davell Carter