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Emerging nanomedicine approaches in obstetrics

      Related article, page 283
      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.
      • Blencowe H.
      • Cousens S.
      • Oestergaard M.Z.
      • et al.
      National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.
      • Goldenberg R.L.
      • Culhane J.F.
      • Iams J.D.
      • Romero R.
      Epidemiology and causes of preterm birth.
      Among survivors, there is a high incidence of neurological impairment including cerebral palsy, deafness, blindness, cognitive disabilities, and behavioral dysfunction including autism spectrum disorders.
      • Rogers E.E.
      • Hintz S.R.
      Early neurodevelopmental outcomes of extremely preterm infants.
      • Joseph R.M.
      • Korzeniewski S.J.
      • Allred E.N.
      • et al.
      ELGAN Study Investigators
      Extremely low gestational age and very low birthweight for gestational age are risk factors for autism spectrum disorder in a large cohort study of 10-year-old children born at 23-27 weeks' gestation.
      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.
      • Stoll B.J.
      • Hansen N.I.
      • Bell E.F.
      • et al.
      Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network.
      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.
      • Valenzuela G.J.
      • Sanchez-Ramos L.
      • Romero R.
      • et al.
      Maintenance treatment of preterm labor with the oxytocin antagonist atosiban. The Atosiban, PTL-098 Study Group.
      • Romero R.
      • Sibai B.M.
      • Sanchez-Ramos L.
      • et al.
      An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue.
      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 β2 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)
      • Hammers A.L.
      • Sanchez-Ramos L.
      • Kaunitz A.M.
      Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis.
      and magnesium has been associated with increased fetal/neonatal mortality.
      • Hammers A.L.
      • Sanchez-Ramos L.
      • Kaunitz A.M.
      Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis.
      • Agustín C.A.
      • Romero R.
      • Kusanovic J.P.
      Nifedipine in the management of preterm labor: a systematic review and metaanalysis.
      • Crowther J.E.
      • Hiller L.
      • Doyle W.
      Magnesium sulfate for preventing preterm birth in threatened preterm labor.
      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
      • Paul J.W.
      • Hua S.
      • Ilicic M.
      • et al.
      Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor.
      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.

      Potential of nanotechnology-based treatments in the neonatal period

      Nanotechnology can also offer significant promise to treat the consequences of preterm birth. Although the traditional thought has been that preventing premature birth by stopping uterine contractions and allowing the fetus more time to grow and mature would improve neonatal outcomes, it is not clear whether this is adequate to change the prognosis of preterm birth. This may be because preterm labor is a syndrome that involves multiple pathological processes and underlying factors, such as maternal inflammation or immune dysregulation that could also affect the fetal immune function, have not been addressed.
      • Romero R.
      • Mazor M.
      • Wu Y.K.
      • Sirtori M.
      • et al.
      Infection in the pathogenesis of preterm labor.
      • Romero R.
      • Mazor M.
      • Munoz H.
      • et al.
      The preterm labor syndrome.
      • Romero R.
      • Dey S.K.
      • Fisher S.J.
      Preterm labor: one syndrome, many causes.
      • Leviton A.
      • Allred E.N.
      • Fichorova R.N.
      • et al.
      ELGAN Study Investigators
      Systemic inflammation on postnatal days 21 and 28 and indicators of brain dysfunction 2 years later among children born before the 28th week of gestation.
      • Kuban K.C.
      • O'Shea T.M.
      • Allred E.N.
      • et al.
      ELGAN Study Investigators
      The breadth and type of systemic inflammation and the risk of adverse neurological outcomes in extremely low gestation newborns.
      The presence of neuroinflammation and immune dysregulation appear to have a strong role to play in the neurological outcomes in extremely low-gestational-age neonates.
      • Leviton A.
      • Allred E.N.
      • Fichorova R.N.
      • et al.
      ELGAN Study Investigators
      Systemic inflammation on postnatal days 21 and 28 and indicators of brain dysfunction 2 years later among children born before the 28th week of gestation.
      • Kuban K.C.
      • O'Shea T.M.
      • Allred E.N.
      • et al.
      ELGAN Study Investigators
      The breadth and type of systemic inflammation and the risk of adverse neurological outcomes in extremely low gestation newborns.
      The presence of immune dysregulation may not only lead to brain injury perinatally, but also prevent normal development in the postnatal period. Preclinical models have shown that intrauterine inflammation results in microglial activation along with hypomyelination and neuronal injury leading to a phenotype of cerebral palsy in the newborn.
      • Balakrishnan B.
      • Dai H.
      • Janisse J.
      • Romero R.
      • Kannan S.
      Maternal endotoxin exposure results in abnormal neuronal architecture in the newborn rabbit.
      • Saadani-Makki F.
      • Kannan S.
      • Lu X.
      • et al.
      Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy.
      Novel drug delivery mechanisms that target neuroinflammation antenatally or postnatally may improve neonatal outcomes.
      The future for successful neonatal outcomes would be in not only targeting uterine contractions but also in changing the milieu to control maternal and fetal immune dysregulation for both prevention of preterm births and allowing for normal development. Recent studies have shown that nanotechnology can address these aspects. It has been shown that targeting and appropriately manipulating neonatal neuroinflammation with dendrimer nanoparticles can be highly beneficial for treating neonatal brain injury in preclinical models. Systemically administered hydroxyl poly(amidoamine) dendrimers have been shown to target activated glia in multiple brain injury models.
      • Kannan S.
      • Dai H.
      • Navath R.S.
      • et al.
      Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model.
      • Nance E.
      • Porambo M.
      • Zhang F.
      • et al.
      Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.
      • Mishra M.K.
      • Beaty C.A.
      • Lesniak W.G.
      • et al.
      Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest.
      When the dendrimer was conjugated to N-acetyl cysteine, a single, systemic dose of 10 mg/kg of N-acetyl cysteine in the conjugated form was effective in preclinical models representing 3 of the major etiologies of cerebral palsy (maternal-fetal inflammation, hypoxic-ischemia, and necrotizing enterocolitis).
      • Kannan S.
      • Dai H.
      • Navath R.S.
      • et al.
      Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model.
      • Nance E.
      • Porambo M.
      • Zhang F.
      • et al.
      Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.
      Targeted, local manipulation of the inflammatory response from systemic administration is likely to have potential, considering the recent recognition of the importance of glial cells in the pathogenesis of neurological disorders.
      • Perry V.H.
      • Nicoll J.A.
      • Holmes C.
      Microglia in neurodegenerative disease.
      In preclinical models, it has been shown that the dendrimer formulation could be administered intraamniotically to target fetal neuroinflammation,
      • Zhang F.
      • Nance E.
      • Zhang Z.
      • et al.
      Surface functionality affects the biodistribution and microglia-targeting of intra-amniotically delivered dendrimers.
      and could be applied topically in the cervical endometrium to prevent intraamniotic infection and reduce preterm birth.
      • Wang B.
      • Navath R.S.
      • Menjoge A.R.
      • et al.
      Inhibition of bacterial growth and intramniotic infection in a guinea pig model of chorioamnionitis using PAMAM dendrimers.
      Furthermore, in preclinical models, it could be administrated to the mother, without appreciable crossover to the fetal compartment, potentially enabling treatment to the mother without affecting the fetus.
      • Menjoge A.R.
      • Rinderknecht A.L.
      • Navath R.S.
      • et al.
      Transfer of PAMAM dendrimers across human placenta: prospects of its use as drug carrier during pregnancy.
      This dendrimer-based platform is undergoing clinical translation for the treatment of childhood cerebral adrenoleukodystrophy patients, an orphan pediatric brain disorder with no viable therapies for those who do not qualify for bone-marrow transplant.
      The perinatal period is a crucial period in the life of the mother, fetus, and newborn. In many cases, debilitating disorders arising from perinatal brain injury, such as cerebral palsy and autism spectrum disorders, are diagnosed well past the time of birth, when therapeutic interventions, even if successful, cannot fully reverse the problem. Appropriate diagnosis and treatment of health issues during the perinatal period can have significant positive consequences for the long-term well-being of all concerned, preventing debilitating neurological disorders in children. This is a high-risk high-reward approach, where nanotechnology can play a key role in reducing the risk associated with drug side effects, while increasing the reward (drug benefit) by improving the treatment response time and efficacy through targeting, as illustrated by the work of Paul et al.
      • Paul J.W.
      • Hua S.
      • Ilicic M.
      • et al.
      Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor.
      Even though these and other efforts are in early stages, they represent an increasing interest from nanotechnology researchers to address long-standing challenges in perinatal medicine. Careful, collective consideration of these approaches in the context of pregnancy can lead to new therapies positively impacting major health issues in newborns around the world. The successes of liposomal and nanoparticle delivery systems (eg, Doxil and Abraxane) for cancer therapies, and the many nanotechnology-based therapies that are undergoing trials, provides a positive impetus for these approaches to be adapted to the perinatal period, after careful scrutiny.
      • Anselmo A.C.
      • Mitragotri S.
      Nanoparticles in the clinic.

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      Linked Article

      • Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor
        American Journal of Obstetrics & GynecologyVol. 216Issue 3
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          The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is hampered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs.
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