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Pregnancy complications such as fetal growth restriction (FGR) are often attributed to poor uteroplacental blood flow, but the risk of systemic side-effects hinders therapeutic intervention. We have utilised novel placental-specific homing peptides to overcome this and have conjugated these to biocompatible liposomes. Peptide-conjugated liposomes were found to selectively bind to the outer syncytiotrophoblast layer of the human placenta and to the uteroplacental vasculature and labyrinth region of the mouse placenta. The novel vasodilator SE175 was selected as a nitric oxide donor with a favourable stability and release profile, to encapsulate in peptide-conjugated liposomes in an attempt to restore impaired uteroplacental blood flow in a mouse model of FGR, the endothelial nitric oxide synthase knockout mouse. Liposomes containing SE175 or PBS were prepared by lipid film hydration and targeting peptides coupled to the liposomal surface. Vehicle control, free SE175, PBS- or SE175-containing liposomes were intravenously injected on embryonic (E) days 11.5, 13.5, 15.5 and 17.5. Animals were sacrificed at E18.5 and fetal and placental weights recorded. Targeted delivery of SE175 significantly increased fetal weight compared to vehicle control but no other treatment groups, whilst significantly decreasing placental weight, indicating improved placental efficiency. Treatment was well tolerated, having no impact on litter size or resorptions. Targeted delivery of SE175, but no other treatment group, reduced a marker of lipid peroxidation in the placenta, indicating a reduction in oxidative stress. These data suggest that selective delivery of SE175 to the uteroplacental vasculature in peptide decorated liposomes may represent a novel treatment for FGR.

During pregnancy the placenta is responsible for ensuring sufficient nutrient transfer and gaseous exchange between the maternal and fetal circulations. Fetal growth restriction (FGR), defined as the inability of the fetus to grow to its genetically determined potential, is often the result of a poorly functioning placenta. Unfortunately there is currently no treatment for FGR except to deliver the fetus early, which has a high risk of morbidity and mortality. Several drugs have previously been shown to enhance placental function and in doing so have improved fetal growth and viability in both human and animal studies. However, the risk of teratogenesis prevents these drugs from reaching the clinic. We have developed a way of targeting drugs specifically to the placenta with the aim of enhancing placental function, increasing fetal growth and improving fetal outcome, whilst minimising off target side effects. Biocompatible nanoparticles called liposomes were prepared to display the homing peptide sequences iRGD and CGKRK, both of which bind to the human and mouse placental exchange regions, to created targeted liposomes. We report that these peptide-decorated liposomes bound to the mouse and human placenta and were able to deliver a fluorescent cargo to the area. Insulin-like growth factors-I and -II (IGF-I and IGF-II) were separately incorporated inside of the targeted liposomes and administered as a biological cargo to pregnant mice. IGFs are particularly important for placental and fetal growth and can improve fetal growth and viability. Treatment in healthy pregnant C57/BL6J mice increased placental weight, but not fetal weight. Treatment in mice displaying an FGR phenotype (P0+/-) increased the weight of the lightest fetuses, but did not affect normally grown fetuses. Treatment was well tolerated and did not cause any gross pathology in mothers or fetuses. These data provide proof of principle for targeted delivery of drugs to the placenta and are a novel platform for the development of placental-specific therapeutics to treat conditions such as FGR.