Rational Design of Nanomedicine for Placental Disorders: Birthing a New Era in Women's Reproductive Health

Abstract

The placenta is a transient organ that forms during pregnancy and acts as a biological barrier, mediating exchange between maternal and fetal circulation. Placental disorders, such as preeclampsia, fetal growth restriction, placenta accreta spectrum, and gestational trophoblastic disease, originate in dysfunctional placental development during pregnancy and can lead to severe complications for both the mother and fetus. Unfortunately, treatment options for these disorders are severely lacking. Challenges in designing therapeutics for use during pregnancy involve selectively delivering payloads to the placenta while protecting the fetus from potential toxic side effects. Nanomedicine holds great promise in overcoming these barriers; the versatile and modular nature of nanocarriers, including prolonged circulation times, intracellular delivery, and organ-specific targeting, can control how therapeutics interact with the placenta. In this review, nanomedicine strategies are discussed to treat and diagnose placental disorders with an emphasis on understanding the unique pathophysiology behind each of these diseases. Finally, prior study of the pathophysiologic mechanisms underlying these placental disorders has revealed novel disease targets. These targets are highlighted here to motivate the rational design of precision nanocarriers to improve therapeutic options for placental disorders.

Keywords: drug delivery; nanomedicine; nanoparticles; placenta; placental disorders; pregnancy.

Figure 1.. Overview of placental disorders and potential of nanomedicine platforms to treat placental disorders occurring during pregnancy.

The four main placental disorders include preeclampsia, fetal growth restriction, placenta accreta spectrum, and gestational trophoblastic disease. Nanocarriers studied during pregnancy have ranged from polymeric nanoparticles (NPs) and gold NPs to drug conjugates and viral vectors. Nanocarriers have encapsulated growth factors, small molecules, and nucleic acids for the treatment of placental disorders during pregnancy.

Figure 2.. The biology of the placenta.

(A) The placenta mediates transfer between maternal and fetal circulation during pregnancy. (B) During placental development, CTBs differentiate into the STB layer, forming the exterior of placental villi functional units for biochemical processes to support fetal development. CTBs can burst open placental villi and migrate towards vasculature. Here, CTBs differentiate into EVTs and invade maternal spiral arteries to create high-flow vasculature for enhanced blood supply to the placenta and fetus. CTB, cytotrophoblast; STB, syncytiotrophoblast; EVT, extravillous trophoblast.

Figure 3.. Design considerations of nanomedicine platforms for use during pregnancy.

Physiological changes in pregnancy may alter pharmacokinetics of nanocarriers, and limited knowledge regarding how nanocarrier physicochemical properties impact placental transcytosis may present as a challenge when designing nanocarrier platforms for use during pregnancy. Nanocarriers should be designed to preferentially target maternal circulation, fetal circulation, or the placenta based on the desired application. Further, nanocarriers should not exacerbate the pro-inflammatory conditions present in many obstetric complications, and off-target effects must be minimized, as they may be detrimental to not only maternal health, but also fetal development. Cellular crosstalk at the maternal-fetal interface is complex and remains only partially understood; interactions between nanocarriers and the local immune environment must be considered. Nanomedicine platforms should be designed for use with IV administration, as intra-placental injections are not common in the clinic. Finally, human pregnancy is unique and proper recapitulation in in vitro, in vivo, or ex vivo models will be important in assessing nanocarrier efficacy and safety in pregnancy.

Figure 4.. Schematic of preeclampsia.

In stage 1, abnormal placentation is characterized by impaired spiral artery remodeling. In stage 2, deficient vascular remodeling manifests in maternal syndrome characterized by widespread endothelial activation and multi-organ disease.​ VEGFR-1, vascular endothelial growth factor receptor 1; sFLT-1, soluble fms-like tyrosine kinase 1; VEGF, vascular endothelial growth factor; PlGF, placental growth factor; sENG, soluble Endoglin; TGF-β1, transforming growth factor beta 1.

Figure 5.. Schematic of placental dysfunction that occurs in FGR.

Following improper remodeling of the uterine spiral arteries, impaired placental perfusion leads to a subsequent hypoxic environment, imbalance in angiogenic and anti-angiogenic growth factors and impairment of nutrient exchange, ultimately leading to a decrease in fetal growth. ROS, reactive oxygen species; sFLT-1, soluble fms-like tyrosine kinase-1; sENG, soluble Endoglin; VEGF, vascular endothelial growth factor; PlGF, placental growth factor; IGF-1, insulin like growth factor-1; IGF-2, insulin like growth factor-2.

Figure 6.. Schematic of placenta accreta spectrum.

(A) PAS can be divided into three subtypes, placenta accreta, placenta increta and placenta percreta, depending on the degree of placental invasion into the maternal myometrium. (B) Factors impacting aberrant trophoblast invasion that occurs during PAS. VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; sFLT-1, soluble fms-like tyrosine kinase-1.

Figure 7.. Flow chart describing benign and malignant forms of gestational trophoblastic disease.

Complete and partial hydatidiform moles lead to benign clumps of trophoblast cells in place of a fetus; these moles can be evacuated surgically. Invasive moles are biologically benign, but deep invasion into the myometrium can occur, leading to metastasis and a malignant classification. Choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor are all classified as malignant, as tumor metastasis can occur in various distal organ systems.

Figure 8.. Schematic of Gestational Trophoblastic Diseases.

In molar pregnancy, abnormal trophoblast differentiation and proliferation results in an absent or nonviable fetus. The pregnancy hormone hCG and oncogenes c-MYC, c-ERB-2, c-FMS, and BCL-2 are upregulated during molar pregnancy. Invasive moles form when trophoblasts invade deep into the myometrium during molar pregnancy. Molar pregnancy often leads to development of malignant gestational trophoblastic neoplasia. Risks of invasive mole and gestational trophoblastic neoplasia include cancer metastasis and chemotherapeutic resistance. hCG, human chorionic gonadotropin; p53, p53 tumor suppressor protein; MDM2, mouse double minute 2; HLA-G, human leukocyte antigen G; EGFR, epidermal growth factor receptor; MMP, matrix metalloproteinases.