Liposomal encapsulation of L-arginine and L-citrulline enhances pharmacokinetics and therapeutic effects in a model of preeclampsia and fetal growth restriction

Abstract L-arginine and L-citrulline improve vascular health in preeclampsia (PE) and fetal growth restriction (FGR), but their short half-life limits efficacy. This study evaluated pharmacokinetics, delivery, and therapeutic outcomes of liposomal encapsulation of these amino acids in a rat model of PE and FGR. Pharmacokinetics of liposome-encapsulated L-arginine were compared with free L-arginine (Free L-arg) in normal pregnant (NP) dams. Therapeutic effect on maternal blood pressure and fetal weight were studied in NP rats and the reduced uterine perfusion pressure (RUPP) model. Treatment groups received Encapsulated L-arginine and L-citrulline (Encapsulated AAs); ratio 1:1, Free L-arginine and L-citrulline (AAs), or PBS. Blood and organs were analyzed for amino acid concentrations and liposome distribution. Nitrite and nitrate were measured to assess endogenous nitric oxide production in the pharmacokinetic study. Encapsulation increased blood arginine exposure > 120-fold and increased plasma and placental concentrations than free forms. In RUPP, Encapsulated AAs reduced maternal blood pressure without affecting fetal weight. Both encapsulated groups developed splenomegaly. Liposomal encapsulation markedly improved pharmacokinetics and placental delivery, thereby reducing maternal hypertension. However, it provided limited benefit for FGR. Optimized encapsulated AAs may represent a promising therapeutic strategy for PE and FGR, although the maternal splenomegaly observed requires further investigation before clinical translation.