Major advances in obstetrics and neonatology over the last few decades have led to significant improvements in the mortality and morbidity associated with preterm births. However, with >15 million preterm deliveries worldwide, preterm birth remains one of the leading causes of neonatal mortality resulting in ∼1 million deaths annually. Among survivors, there is a high incidence of neurological impairment including cerebral palsy, deafness, blindness, cognitive disabilities, and behavioral dysfunction including autism spectrum disorders. Morbidity among survivors is reported to be as high as 91% of neonates born at 24 weeks of gestational age and remains high at 56% even at 27 weeks of gestation.

Therapeutic strategies to prevent and treat preterm labor have ranged from suppression of uterine contractions using systemically administered tocolytics to treatment of maternal infection/inflammation and use of vaginal progesterone in at-risk patients. Although advances in prenatal care and identification and treatment of at-risk patients have decreased morbidities from preterm births over the last decade, therapies to stop preterm labor once uterine contractions have started have not proven to be effective. Unfortunately, the drugs currently used for tocolysis have systemic side effects that affect the mother and/or the fetus. Drugs such as β ₂ adrenergic receptor agonists and calcium channel blockers have maternal cardiovascular side effects, while prostaglandin inhibitors such as indomethacin have fetal effects (closure of ductus arteriosus) and magnesium has been associated with increased fetal/neonatal mortality.

Therefore, there is an urgency to develop strategies to address preterm labor in a specific and targeted manner. Novel developments in nanotechnology have been slow to be adapted to perinatal health since it is often viewed as a high-risk high-reward arena for therapeutics development by the pharmaceutical industry. Therapies that address obstetric complications such as preterm birth or postpartum hemorrhage should ideally be localized to prevent side effects to the mother or the fetus, short acting to elicit a rapid response, and targeted to improve efficacy and reduce drug side effects.

The study by Paul et al describes a novel liposome-based, targeted drug delivery approach, making important strides in addressing these challenges. The “immunoliposomes” (∼200 nm) are prepared by conjugating the liposome with an antibody to target the “overexpressed” oxytocin receptors and are loaded with different drugs to elicit different desired responses. The use of a poly(ethylene glycol) (PEG) spacer to attach the targeting antibody is a key aspect that provides conformational flexibility for superior receptor binding. The liposomal platform and use of PEG are well described, and the significant body of literature and clinically approved platform provides a sound basis for translation into perinatal medicine. The PEGylation can enhance the circulation time in the maternal compartment, providing opportunities for target localization, while reducing the chance for potential transport across the placenta to the fetus. The specific issue that the authors seek to address, especially relating to the manipulation of contractions in the myometrium, is a very intriguing application for nanoparticle approaches. Using strips of human myometrial tissue and mouse uterine tissue, the authors show several promising results. (1) Using appropriate agents, they can significantly increase or decrease contraction times. The effect of the liposomal formulation is relatively rapid (within minutes). This is interesting and suggests that the liposomes release the drug rapidly to exert the effect. (2) The contraction times can be reversed following a simple washout. This suggest that the released drug is present only in the local environment where it is needed, reducing the chance of drug-related side effects to other tissues. This also indicates that the relatively large liposome may be bound to the oxytocin receptor, without being taken up into cells over this period, with the drug being released in the extracellular environment. The relatively rapid, reversible effect of the therapy is a novel application of nanoparticle drug delivery, which has typically been utilized for sustained, long-lasting drug delivery.

To move these interesting findings further toward translation, several important aspects have to be addressed. First, establishing the efficacy of the liposomal formulations with appropriate free drug controls, both ex vivo and in vivo, will be important. Second, additional studies have to be conducted in vivo to show that the liposomal formulation is efficacious and safe in animal models that are considered appropriate for a path toward investigational new drug filing. Third, scaling up the production of the liposomal formulation, as designed here, requires significant specialized expertise. Even though liposomal manufacturing under good manufacturing practices (as regulated by Food and Drug Administration) is already established, further PEGylation and targeting antibody conjugation are likely to require a combination of manufacturing expertise in liposomal formulation and PEG-antibody conjugation. Fourth, a close collaboration with the regulatory agencies to define the product specification and clinical trial outcomes would be required. Given the aversion of the traditional pharmaceutical companies to this space, novel approaches and partnerships may be required to translate such technologies.