Nanotechnology for the understanding and prevention of preterm birth

Preterm birth (PTB) affects nearly 15 million infants each year. Of these PTBs, more than 25% are a result of inflammation or infection. One way in which the uterus can become inflamed is via bacterial ascension from the vaginal environment into the uterine environment. The cervicovaginal mucus (CVM) barrier serves to prevent ascension, however if the CVM barrier is compromised during pregnancy, pathogens and bacteria are more likely to cause infection in the vagina leading to inflammation in the uterus, which can result in PTB. Here, we describe changes to the CVM barrier during pregnancy, and observe that women who are at high risk for PTB have decreased CVM barrier properties, compared to women who are not at high risk for PTB. We next developed an animal model to improved our understanding of the mechanisms leading to PTB. Prior work has described induction of intrauterine inflammation in mice with a single injection of LPS. Here, we have improved the reproducibility and potency of LPS in the model using two injections distal to the cervix. We observed more uniform distribution of the injection using a double distal injection (DDI) approach compared to a single proximal injection (SPI). At equivalent LPS doses, DDI consistently induced more PTB than SPI, and DDI showed a linear dose response, whereas SPI did not. The more reliable PTB induction and uniform uterine exposure provided by this new model were useful for further studying fetal outcomes and potential therapeutics for the prevention of inflammation-induced PTB. Using this model, we tested both clinical and novel therapies for the prevention of PTB. We observed that neither systemic hydroxyprogesterone caproate (17-OHPC) nor vaginal progesterone gel (Crinone®) were sufficient to prevent inflammation-induced PTB. However, we found that vaginal delivery of mucoinert nanosuspensions combining progesterone (P4) with histone deacetylase (HDAC) inhibitors, prevented PTB and resulted in delivery of live pups, with neurotypical development. To our knowledge, this is the first description of vaginally delivered drugs preventing intrauterine inflammation-induced PTB with birth of live offspring in a preclinical animal model. This work highlights the benefits of local delivery, as well as the importance of rationally designed therapies. We believe that this work will aid in the understanding of mechanisms that contribute to PTB, as well as the effective design of therapies for other women’s health issues