Investigating Liquid Crystal Nanoparticles for Placental Drug Delivery

Abstract

Pregnancy disorders, such as preeclampsia and fetal growth restriction, are associated with compromised blood flow to the placenta. The consequence is that fetuses in affected pregnancies are at immediate risk of health complications and even death. Conventional therapeutic approaches are failing to manage these conditions and can cause unpleasant side effects in the mother and even harm the developing fetus. The administration of drugs in pregnancy is further complicated by a lack of evidence-based research on the efficacy and safety of drugs in pregnancy. We therefore sought to apply modern drug delivery strategies to better understand how they may interact with the placenta to potentially enhance blood flow and improve fetal outcomes. Liquid crystal nanoparticles (LCNPs) have emerged as promising drug delivery vehicles with the potential to overcome several of the limitations of conventional therapy. In this project, the physicochemical properties of LCNPs were optimised and thoroughly characterised. The encapsulation and release of vasoactive compounds in the LCNPs were studied and assessed for the potential of these formulations to dilate placental arteries. Finally, the placental homing peptides CGKRK and iRGD were attached to the surface of the LCNPs to study their binding and uptake in healthy human and mouse placentas, and to assess their in vivo biodistribution in pregnant mice. Anionic LCNPs of small size (< 200 nm) were formulated and their physicochemical properties were shown to be significantly affected by changing the nanomaterial composition, drug loading and peptide association. Additionally, model and vasoactive drugs were successfully encapsulated and released. LCNP encapsulated sodium nitroprusside was then shown to induce vasodilation of isolated human placental arteries. Attaching placental homing peptides to the surface of the LCNPs demonstrated preferential uptake by the syncytiotrophoblast of human placental explants and accumulation in the maternal spiral arteries in mice. Targeted LCNPs were not observed in maternal organs, apart from the clearance organs; liver, kidney and spleen. However, they were detected in fetal tissue which requires further investigation to demonstrate what effects this may have. As a result of the work presented in this thesis, it is concluded that LCNPs are a suitable drug carrier for placental drug delivery. However, they may be unsuitable for the delivery of fetotoxic drugs, although they could be potentially exploited for fetal drug delivery.

Date of Award	31 Dec 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Richard Campbell (Supervisor) & Lynda Harris (Supervisor)