Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth

Abstract

Inflammation contributes to nearly 4 million global premature births annually. Here, we used a mouse model of intrauterine inflammation to test clinically used formulations, as well as engineered nanoformulations, for the prevention of preterm birth (PTB). We observed that neither systemic 17a-hydroxyprogesterone caproate (Makena) nor vaginal progesterone gel (Crinone) was sufficient to prevent inflammation-induced PTB, consistent with recent clinical trial failures. However, we found that vaginal delivery of mucoinert nanosuspensions of histone deacetylase (HDAC) inhibitors, in some cases with the addition of progesterone, prevented PTB and resulted in delivery of live pups exhibiting neurotypical development. In human myometrial cells in vitro, the P4/HDAC inhibitor combination both inhibited cell contractility and promoted the anti-inflammatory action of P4 by increasing progesterone receptor B stability. Here, we demonstrate the use of vaginally delivered drugs to prevent intrauterine inflammation–induced PTB resulting in the birth of live offspring in a preclinical animal model.

Landscape of Preterm Birth Therapeutics and a Path Forward

“…These mucoinert nanosuspensions have been shown to improve the vaginal administration of progesterone and prevent progesterone withdrawal (RU486)-induced preterm birth in mice, while avoiding stimulating myometrial expression of inflammatory cytokines [286]. Other studies have demonstrated successful vaginal administration of the histone deacetylase inhibitors trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA) via mucoinert nanosuspensions [287]. Nanosuspensions of TSA in combination with progesterone had anti-inflammatory effects on myometrial gene expression and were effective in significantly reducing rates of LPS-induced preterm birth in mice, whereas nanosuspensions of progesterone alone were not effective [287].…”

“…Other studies have demonstrated successful vaginal administration of the histone deacetylase inhibitors trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA) via mucoinert nanosuspensions [287]. Nanosuspensions of TSA in combination with progesterone had anti-inflammatory effects on myometrial gene expression and were effective in significantly reducing rates of LPS-induced preterm birth in mice, whereas nanosuspensions of progesterone alone were not effective [287]. Similarly, nanoformulations of the sphingosine kinase (SphK) inhibitor (SKI II) were developed, as SphK inhibition was previously shown to prevent LPS-induced preterm birth in mice [288].…”

“…Neither of the landmark studies detected fetal transfer of non-targeted or OTR-targeted nanoliposomes [281,282]. For the vaginal nanoformulations, nanosuspensions of progesterone were found to produce no significant inflammation or toxicity and actually avoided the cervical and myometrial inflammatory signaling induced by a clinical progesterone gel, while nanosuspensions of TSA and progesterone led to delivery of live pups that exhibited neurotypical development [286,287]. Moreover, vaginal delivery of SKI II via SNEDDS had no toxic effect on cultured human cervical cells (HeLa) after 24 h, and a teratogenicity study revealed no effect on birth weight or the prevalence of congenital anomalies among pups born to treated dams.…”

An ion‐paired moxifloxacin nanosuspension eye drop provides improved prevention and treatment of ocular infection

“…Penetration enhancers may also be used, though frequent and chronic dosing can lead to ocular irritation and toxicity 24 . An alternative approach that has been demonstrated for a wide variety of mucosal surfaces, including the eye, female reproductive tract, gastrointestinal tract, and airways is to formulate nanoparticles with mucoinert surface coatings 25,26 . These so‐called mucus‐penetrating particles (MPP) are nonadhesive to the sticky mucin proteins and small enough in size to fit through the net‐like pores, leading to enhanced delivery of small‐molecule drugs and nucleic acids alike 25 .…”

“… 24 An alternative approach that has been demonstrated for a wide variety of mucosal surfaces, including the eye, female reproductive tract, gastrointestinal tract, and airways is to formulate nanoparticles with mucoinert surface coatings. 25 , 26 These so‐called mucus‐penetrating particles (MPP) are nonadhesive to the sticky mucin proteins and small enough in size to fit through the net‐like pores, leading to enhanced delivery of small‐molecule drugs and nucleic acids alike. 25 In the context of eye drops, MPP provide rapid and enhanced intraocular drug absorption, leading to the Food and Drug Administration (FDA) approval of two loteprednol etabonate (LE)‐based products for treating ocular inflammation and pain.…”