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Nanotechnology, the art of engineering structures on a molecular level, offers the opportunity to implement new strategies for the diagnosis and management of pregnancy-related disorders. Although nanotechnology has been on the bench for many years, most of the studies in obstetrics are preclinical. Ongoing research spans from the development of diagnostic tools, including optimized strategies to selectively confine contrast agents in the maternal bloodstream and approaches to improve diagnostics tests to be used in obstetrics, to the synthesis of innovative delivery nanosystems for therapeutic interventions. Using nanotechnology to achieve spatial and temporal control over the delivery of therapeutic agents (e.g., commonly used drugs, more recently defined formulations, or gene therapy-based approaches) offers significant advantages, including the possibility to target specific cells/tissues of interest (e.g., the maternal bloodstream, uterus wall, or fetal compartment). This characteristic of nanotechnology-driven therapy reduces side effects and the amount of therapeutic agent used. However, nanotoxicology appears to be a significant obstacle to adopting these technologies in clinical therapeutic praxis.
- nanotechnology
- nanoparticle
- pregnancy
- fetal therapy
- preterm birth
- preterm labor
- preeclampsia
- fetal growth restriction
- fetal growth
- diabetes
1. Introduction
Over the previous decades, significant advances in obstetrics have led to a reduction in mortality and morbidity associated with pregnancy complications [1,2]. Fundamental advances in neonatology have also ameliorated pregnancy outcomes and improved the survival rate of newborns delivered at earlier gestational ages, although not without an economic impact [1,3,4]. Fetal growth restriction, preterm birth, and cancer management during pregnancy still require research advancements to improve the quality of life of mothers and newborns, and possibly to reduce the costs of the postnatal management of newborns resulting from particularly problematic pregnancies.
The advancement of precision medicine strategies to manage these pathologies relies on a cornerstone that requires a more comprehensive understanding of the pathogeneses of these conditions, which is expected to lead to the implementation of current strategies and the development of new ones, with diagnostic and therapeutic applications [18,19]. As the science of engineering structures on a molecular level, nanotechnology offers a significant opportunity to achieve this goal [18,20].
Conceptually introduced in the 1950s, nanotechnology refers to the use of nanoscopic particles and devices with the potential to specifically integrate electronic, optical, fluid, and mechanical functions. In the biological field, these approaches are primarily applied in diagnostics and therapy [21,22]. The main purpose of nanotechnologies in the medical field is to improve the biodistribution, specificity, and targeting of bioactive molecules, in order to induce a desired therapeutic outcome while reducing potentially threatening side effects [22].
3. Nanotechnologies and Pregnancy
The use of drugs during pregnancy has increased significantly over time, probably due to the greater confidence that modern pharmacology has allowed us to acquire regarding the use of specific medication classes [25,26,27]. In spite of the greater awareness of medication use in pregnancy and lactation, information about indications and contraindications is not always available, especially in the case of newly introduced active principles or formulations. This paucity of information somewhat depends on the fact that trials seeking to ascertain drug effects on the fetus are performed solely in particular cases (e.g., treatments targeted explicitly for pregnancy or fetal in utero therapy), and pregnant women are willingly excluded in most studies due to ethical issues [28].
From this perspective, nanotechnology has only recently been applied to pregnancy and lactation, resulting in a new branch of medicine known as “nano-obstetrics”. Nanomedicine-based therapies are currently gaining great interest for what concerns the treatment of conditions affecting the mother, the placenta, and the fetus, and to improve the prognosis for both mothers and newborns [29]. A common fear of potentially damaging gametes, embryos, and fetuses, or even negatively impacting a woman’s reproductive potential, affects the development of innovative therapeutics in reproductive medicine and obstetrics. Modern delivery systems may provide alternative targeted intervention strategies by precisely targeting the source of the disease while minimizing short- and long-term consequences for the mother and the progeny [18,30,31].
Despite the evident success of nanotechnologies in the last few decades and the growing interest in the development of strategies which are able to temporally and spatially deliver drugs and retain them at the targeted site, pregnancy still represents a challenge for the application of these novel medications [31]. On the one hand, as introduced above, there is often a lack of data regarding the possible adverse effects on the mother and fetus, as for classical drugs [28,31]. Consequently, only phase IV observations allow us subsequently to draw definitive conclusions relating to any secondary effects in the female gender or specific conditions such as pregnancy. On the other hand, specific design and chemical features make nanoparticles capable of overcoming physiological barriers, such as the blood–placental barrier [32], and potentially to be active also on the fetus.
4. The Placental Barrier, Therapeutic Perspectives of Nanoparticles, and Nanotoxicology
During pregnancy, the blood–placental barrier regulates the transport of oxygen, nutrients, and residual products between the maternal and fetal bloodstreams. It also prevents fetal exposure to possibly harmful molecules from the maternal circulation. Therefore, the essential role that the blood–placental barrier plays in supporting the interaction between the mother and the fetus represents an interesting opportunity for the delivery of nanotherapeutics to treat various pathologies (e.g., targeting a drug specifically to the maternal compartment only, without entering the fetal compartment) [33].
During its intrauterine development, the fetus is vulnerable to chemicals and other substances that can impair its development [34]. A major limitation for the application of nanomedicine in the field of maternal and fetal health is the lack of established and reliable in vitro and ex vivo models which are available to adequately simulate the pregnant patient scenario [29]. Experimental models of the placenta have been developed to address the function of the placental barrier, which can be classified into in vivo, ex vivo, and in vitro models [35,36,37]. As expected, any of these models presents some strengths and some limitations.
Nanoparticles can transit through the ordinary placental trans-cellular transport mechanisms such as pinocytosis, active transport, facilitated diffusion, and passive diffusion. The exact pathway is likely to be dependent on the particle size and the surface chemistry [36,39]. For example, gold nanoparticles could cross the placenta, arriving at the fetal circulation employing endocytosis, whether clathrin-mediated or caveolin-mediated [40]. Meanwhile, polystyrene nanoparticles were found to cross the placenta through passive diffusion [41]. Furthermore, polyethylene glycol-coated liposomes were shown to be mostly impermeable to the placental barrier [36,42]. Additionally, the CNKGLRNK peptide-coated liposomes specifically target the placental interface [43].
High concentrations of polystyrene nanoparticles reduced in vitro the cell viability of choriocarcinoma cells (BeWo cell line) [45]. The authors attributed the effect to a previously known positive association between a high polystyrene dosage and a pro-inflammatory effect [45,46]. The in vivo administration of cobalt and chromium 80 nm nanoparticles resulted in neurodevelopmental abnormalities, and increased DNA damage in the fetal hippocampus [47]. Maternal–fetal oxygen transfer and the production of human chorionic gonadotropin were not modified by polyamidoamine dendrimer exposure in an ex vivo placenta perfusion experiment [48].
Nanoparticle permeability through the placental barrier may be affected by the disruption of tight junctions, which can compromise its physiological regulatory processes.
Different organic, inorganic, or hybrid nanoparticles have been previously tested (Table 2) [36,37,44,45,47,48,49,51,58]. Shojaei and coworkers reviewed the literature in detail on different placental models and the fetal risk assessment, considering various organic and inorganic nanoparticles [36]. Inorganic nanoparticles have been demonstrated to easily cross the blood–placental barrier and induce several toxicological effects [59]. In contrast, organic nanoparticles can be more selective in their target potential and show less toxicological effects [18,59]. However, additional studies are still required in order to broaden their application in the obstetric field [18,59].
Surface-functionalized nanoparticles can prevent transplacental passage and promote placental-specific drug delivery, thus enhancing medication safety and efficacy. Optimal results have been achieved, for instance, by combining nanoparticles with specific proteins which are exclusively expressed in the placenta, such as the placental chondroitin sulfate A-binding peptide or oxytocin receptor [60,61,62,63,64,65].
Although the characteristics of nanoparticles could be predictive of their maternal, placental, or fetal uptake, the achievement of a comprehensive understanding of nanoparticle uptake, accumulation, and translocation, as well as of how their size, shape, surface chemistry, and charge affect biodistribution and therapeutic efficacy through predictive placental transfer models, is absolutely mandatory in order to determine how the timing and route of nanoparticle administration impact their distribution, effectiveness, and safety [72].
5. Point-of-Care Testing and Other Applications in Diagnostics
Along with therapeutic nanoparticles, novel nanotechnologies have been designed to improve diagnostic accuracy. Point-of-care testing is a medical concept to describe diagnostic testing at or near the point of care, which is the place and time of the patient care. This kind of advanced testing can be used in remote locations or outpatient facilities, reducing the costs of traditional medical laboratories, specialized operators, and complex equipment. One of the most prominent examples in obstetrics is the introduction of the home pregnancy test in the 1970s [73]. Through the years, the test has been modified, opening the way to the paper-based diagnostic technologies [74,75]. Generally, paper-based diagnostics, including lateral flow assays and microfluidic paper-based analytical devices, are affordable, user-friendly, rapid, robust, and scalable for manufacturing [74]. These diagnostics are optimal for the improvement of clinical pathways in remote settings and resource-limited areas. Nanotechnology was proposed to strengthen test performance in lateral flow assays or microfluidic paper-based analytical devices [74]. As previously mentioned, the introduction of a point-of-care test for pregnancy has modified the clinical management of early pregnancy, allowing the wide spread of the prompt detection of early pregnancy and the better planning of the following management. Moreover, using a β-HCG point-of-care test while assessing fertile women with low abdominal pain in outpatient facilities allows us, with low resources, to rapidly exclude from the possible causes of pain a life-threatening situation such as extra-uterine pregnancy. The widespread use of these types of test has changed clinical management, and has the potential to change clinical pathways further. Nanotechnology has recently been applied to human chorionic gonadotropin testing to improve detection sensitivity and widen the application of these tests in clinical management [76,77,78,79].
Nanotechnology-based approaches were also used to retrieve and isolate trophoblasts from the human cervix during pregnancy, allowing an early attempt at prenatal diagnosis starting from 5 weeks of gestation [80,81]. In particular, Bolnick and coworkers collected a cervical specimen with a brushing system for liquid-based cytology [80]. The cells were marked with an antibody specific for trophoblastic cells (anti-HLA-G) [80]. A secondary antibody conjugated with magnetic nanoparticles was used for the immunomagnetic isolation of the trophoblastic cells [80]. Other applications in the field of diagnostics include cell-free fetal DNA isolation for prenatal screenings [82,83,84,85].
Nanoparticles have been designed to improve imaging techniques which are traditionally considered off-limits during pregnancy. For example, the classical contrast medium of magnetic resonance imaging, gadolinium, is blamed for possible teratogenic and chromosomal damages. In order to overcome this issue, the use of superparamagnetic iron oxide nanoparticle ferumoxytol has been tested, with encouraging results and no impact at the maternal–fetal interface in pregnant rhesus macaques [86]. Moreover, liposomal gadolinium has also been proposed as a promising tool in the obstetrics field [87].
6. Preterm Birth
The use of nanotechnology has been proposed for the treatment of preterm labor. This technology was suggested to improve the accuracy and cost-effectiveness of preterm delivery diagnosis by implementing a fibronectin test using magnetic nanoparticles coated with anti-fibronectin antibodies [91]. Furthermore, it was also applied to improve drug treatment. In the current practice, the use of drugs to reduce uterine contractions and prevent preterm birth is limited due to the systemic or fetal effects of currently available medications such as ritodrine or indomethacin [7,92]. Nanotechnology-based approaches have been developed to prevent the drug’s passage in the fetal bloodstream, and to target its localization at the uterine-wall level [60,61,62,63,64,65]. To this end, liposomes coated with antibodies or specific receptor antagonists were developed (e.g., placental chondroitin sulfate A-binding peptide, oxytocin receptor antagonist, or oxytocin receptor antibody) [60,61,62,63,64,65]. Moreover, nanotechnology was also used to improve the effectiveness of preterm-delivery-preventive drugs via the vaginal administration of progesterone, significantly reducing the prevalence of preterm birth in a mouse model and lengthening the time-to-delivery outcome by 39% [93]. In addition to the implementation of new devices for the administration of already known drugs, nanotechnology has also been exploited to optimize the delivery of innovative medicines, in order to counteract the mechanisms of inflammation known to be involved in preterm labor and offspring complications (e.g., improving the delivery of N-acetylcysteine) [94,95].
7. Preeclampsia and Fetal Growth Restriction
Both preeclampsia and fetal growth restriction are associated with aging and dysfunctional placentae [96]. In this field, nanotechnology was also applied with different intents: (1) to improve diagnostic management and (2) to implement treatment strategies. New nanotechnology-based point-of-care tests are being developed to improve the assessment of preeclampsia development risk [97,98,99]. For instance, recent advancements have been made in the development of electrochemical immunosensors for the early clinical diagnosis of preeclampsia within the 18–20th gestational weeks [100]. In particular, the aim would be to establish a high-specificity immuno-diagnostic platform which is able to detect and analyze multiple molecules simultaneously (at the picomolar resolution), which could be highly predictive for preeclampsia onset to anticipate and improve its further treatment. There is also a tremendous effort in the development of nanotechnology-based approaches to target the placental tissue in order to prevent or mild the consequences of preeclampsia and fetal growth restriction [101,102,103,104,105,106,107]. Another field of interest was the development of new disease-specific models [108]. In a recent article, Yu and coworkers precisely silenced a long non-coding RNA (lncRNA H19) in the placental tissue of a mouse model, obtaining in vivo the occurrence of pre-eclampsia-like symptoms [108]. This result is extremely important, and opens the path to future discoveries. First, the previous models of pre-eclampsia were mainly established by the systemic administration of drugs or surgery, hence inducing unwanted systemic toxicity and limiting the possible understanding of pre-eclampsia. Pre-eclampsia is supposed to be an obstetric pathology of placental origin [96].
8. Diabetes Mellitus
Nanotechnology has been proposed for the implementation of highly accurate tests for the diagnosis and monitoring of diabetes mellitus [109]. Recently, a nanotechnology-based point-of-care test was developed with the intent to monitor glycated albumin in gestational diabetic pregnancies [110]. In addition, different approaches (e.g., Cerium nanoparticles or zinc oxide resveratrol encapsulated in Chitosan) were also developed to treat gestational diabetes and its comorbidities [109,111,112,113].
9. In Utero Gene Therapy
In 2019, a viral-vector-based gene therapy for spinal muscular atrophy that delivers a functional copy of the survival of motor neuron gene cDNA was approved by the FDA. Since then, the interest in this field has grown [115], and nanoparticles have been exploited as carriers of nucleic acids in utero during embryonic or fetal life [116,117,118,119]. Although no human studies have been carried out until now for in utero gene therapy, many in vitro and in vivo studies have been performed [120]. In utero gene therapy is a potential game-changer for monogenic diseases because the treatment can prevent disease inception, avoiding early damage to the tissues. Another advantage is the prevention of immune system reactions to the gene therapy approach, limiting or overcoming its effectiveness, as it occurs in post-natal genetic therapy. Other potential benefits are the capacity to cross the blood–brain barrier or deliver the treatment with a high vector-to-target-cell ratio [120].
10. Assisted Reproductive Technology
Another fascinating application field of nanomedicine related to pregnancy is assisted reproductive technology. With the progressive delay of first pregnancies due to contemporary social and working habits, modern society is now experiencing its highest infertility rate [15,122]. Novel techniques have been consequently developed to improve the conception rate in couples utilizing assisted reproductive technology. Exploring nanotechnology in non-human models is stimulating, as they make it possible to optimize newly developed protocols using nanomaterials against the impairments still faced by reproductive medicine [123,124].
11. Cancer in Pregnancy
The increase of pregnancy-related cancer prevalence is a critical issue, partly due to the progressive delay of first pregnancies in high-income countries for work and social reasons [15]. Pregnant cancer patients represent a major concern in the modern maternal and fetal health field [125,126]. However, nowadays, many intervention options exist which can dramatically change patients’ prognosis, and consequently positively improve the therapeutic outcomes [19,127]. In most cases, patients require a personalized and integrated treatment which is necessarily drawn within a multidisciplinary setting in order to prevent the iatrogenic pregnancy complications which could be caused by cancer treatment, such as preterm delivery or impaired fetal growth [125].
The most frequent malignancy diagnosed during pregnancy is breast cancer [125,126]. Nanomedicine improvements can allow the safe administration of antiblastic agents during pregnancy, avoid improper therapeutic delays, and enable highly effective and safe treatment for the mother and the offspring [126].In addition, several monoclonal antibodies have been developed that target the Her2 protein, expressed in several breast cancer patients, and with a notoriously poor prognosis [134]. The efficacy of these drugs in both the neoadjuvant and adjuvant setting has been one of the greatest successes of the last few decades against this frequent and life-threatening disease. Monoclonal antibodies represent a prime example of the most efficient modalities of targeted drug delivery we have today against malignancies, and probably represent the future of personalized medicine in the oncological field. Unfortunately, there is insufficient evidence to justify their use during pregnancy, which is why their administration is generally delayed in the puerperium. However, we can imagine that in the future, we will likely be able to offer monoclonal antibodies in formulations which are capable of sparing the fetus while battling the pregnant woman’s neoplastic disease. In fact, targeted liposomal carriers are an emerging field of research, and are capable of targeting a compartment or tissue specifically [63,64,65,132]. For example, Refuerzo and coworkers demonstrated in a mouse model that delivering indomethacin within multilamellar liposomes prevents the drug from passing the placental barrier, significantly reducing fetal exposure [132].
This entry is adapted from the peer-reviewed paper 10.3390/jpm12081324
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