Examining nanoparticle based systems for applications in maternal/fetal health

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University of Delaware
The presence of pregnancy complications poses significant challenges for both the mother and the developing fetus, as available treatment options are limited due to safety and ethical considerations. Conditions like preeclampsia, fetal growth restriction (FGR), and placenta accreta exemplify pregnancy-induced disorders that lack effective remedies. As pregnancy progresses, these conditions worsen, leading to adverse consequences on the health of both the mother and the fetus. Consequently, emergency cesarean section delivery is often necessary, resulting in additional complications associated with premature birth for the newborns. Addressing the pressing need for enhanced maternal and fetal health during pregnancy, it is imperative to develop therapeutic advancements that can effectively treat pregnancy-related conditions while ensuring the well-being of the developing baby. ☐ In recent years, significant progress has been made in engineering nanocarrier systems for targeting various diseases, including cancers. The behavior of these nanocarriers in the body following systemic delivery is known to depend on factors such as size, shape, and surface chemistry. While researchers have harnessed this knowledge to develop powerful systems for treating ailments like cervical cancer, endometriosis, and HIV, the exploration of nanomedicine for pregnancy complications remains limited. The unique state of pregnancy introduces additional variables that influence NP distribution and design, including the dynamic physiology of the maternal reproductive system, the transport of nutrients and drugs through the placenta, and the development of the fetus. It is crucial to comprehend the impact of these factors on NP distribution to develop effective treatments that can support full-term pregnancies and improve the health of both mother and fetus. ☐ First, the biodistribution of gold-based nanoparticles (NPs) in pregnant mice was investigated following systemic delivery. Two different sizes of NPs, namely 15 nm gold nanoparticles and 150 nm diameter silica core/gold nanoshells coated with poly(ethylene) glycol (PEG), were intravenously administered to pregnant mice at gestational days (E)9.5 or 14.5. After twenty-four hours, the distribution of NPs in tissues was analyzed using inductively coupled plasma-mass spectrometry and silver staining of histological samples. The findings revealed a higher accumulation of NPs in the placentas compared to the embryos, with a greater delivery to these tissues observed at E9.5 than E14.5. Additionally, no adverse effects on fetal or placental weight were observed, indicating minimal short-term toxicity during early to mid-stage pregnancy. These results underscore the potential of further developing NPs as safe tools for targeted therapeutics delivery to reproductive tissues. ☐ The following study delved into the distribution of PEG-coated poly(lactic-co-glycolic) acid nanoparticles (PEG-PLGA NPs) in pregnant mice through vaginal delivery, as well as their short-term toxicity. Two types of NPs were employed: DiD-PEG-PLGA NPs loaded with fluorophores for cargo tracking, and Cy5-PEG-PLGA NPs incorporating tagged polymer for distribution analysis. DiD-PEG-PLGA NPs were administered on either gestational day (E)14.5 or 17.5, and after 24 hours, the distribution of cargo was examined in excised tissues and histological sections using fluorescence imaging. Interestingly, no variations in DiD distribution were found between the gestational periods. Therefore, Cy5-PEG-PLGA NPs were exclusively administered on E17.5 to assess polymer distribution in reproductive organs. The results showed the presence of Cy5-PEG-PLGA NPs in the vagina, placentas, and embryos, while DiD cargo was limited to the vagina. Furthermore, maternal, fetal, and placental weights remained unaffected by the NPs, indicating no immediate adverse effects on maternal or fetal growth. These findings suggest the potential of exploring vaginally delivered NP therapies for managing vaginal conditions during pregnancy. ☐ Lastly, the effectiveness of clindamycin-loaded PEG-PLGA nanoparticles (CLN-PEG-PLGA NPs) with different L:G ratios (50:50, 75:25, and 85:15) in inhibiting the growth of G. vaginalis, a pathogenic bacteria associated with bacterial vaginosis (BV) infections, was examined. G. vaginalis was cultured in suspension and on agar plates and treated with CLN-PEG-PLGA NPs of each L:G ratio. The growth of G. vaginalis was monitored using spectrophotometry or imaging at regular intervals over a 12-hour treatment period. The experiments demonstrated the effective inhibition of G. vaginalis growth in both suspension and on surfaces by CLN-PEG-PLGA NPs, irrespective of the L:G ratio. Interestingly, the bacterial growth inhibition did not significantly differ among the three L:G ratios, indicating that the ratio had minimal impact on short-term antibacterial treatment, likely due to similar total drug release from each formulation within the 12-hour period. While freely delivered clindamycin exhibited greater potency against G. vaginalis, it is important to note that CLN-PEG-PLGA NPs were able to decrease G. vaginalis growth in vitro. ☐ The foundational knowledge provided in this thesis holds utmost importance for the initial advancement of nanomedicines designed to address maternal-fetal health conditions. By incorporating the additional experiments mentioned earlier, researchers can assess the prolonged impacts of NP injections on pup development and growth. This comprehensive understanding will guide researchers in optimizing NP delivery and treatment efficacy while safeguarding the well-being of both the mother and the fetus. Such insights can aid in determining the most suitable administration routes, be it systemic or vaginal, to enhance NP delivery and promote successful treatment outcomes without compromising maternal or fetal health.
Drug delivery, Fetal health, Maternity, Nanomedicine, Nanoparticles, Pregnancy