Targeted nanoparticles for placenta-specific drug delivery in pregnant rhesus macaques

Rationale: To reduce the risks associated with systemic drug administration in pregnancy and create new therapies for placental dysfunction, we have previously developed targeted liposomes capable of selective delivery of payloads to the placentas of pregnant mice. In this study, we assessed whether these liposomes selectively accumulated in the placentas of nonhuman primates and evaluated the maternal systemic response to liposome infusion. Methods: Liposomes were produced using the thin-film method, decorated with the placental homing peptide CRGDKGPDC (iRGD) or non-targeting peptide ARALPSQRSR (ARA) and loaded with 5(6)carboxyfluorescein. Liposomes were infused intravenously into pregnant rhesus macaques early in gestation, at days 45-64 (iRGD, n = 4; ARA, n = 1) or mid-gestation, at days 84-100 (iRGD, n = 4; ARA, n = 2; term = 165 days). After 24 h, maternal blood and maternal, uteroplacental and fetal tissues were collected for evaluation. Results: Liposome infusions were well tolerated, with no adverse clinical reactions or abnormal placental or fetal pathology. Maternal plasma hormone, cytokine and chemokine levels, and complete blood cell counts remained broadly stable for the duration of the treatment period. iRGD-decorated liposomes accumulated in both placental discs of each animal, varying in intensity and tissue distribution. Limited fluorescence was noted in some sections of maternal liver, spleen, kidney and mesenteric lymph nodes, but no visible signal was observed in other maternal or fetal tissues examined. In contrast, ARA-decorated liposomes exhibited a widespread tissue distribution, with fluorescence observed in the majority of maternal, uteroplacental and fetal tissues examined. Conclusions: This study confirms that iRGD-decorated liposomes selectively accumulate in the rhesus macaque placenta in vivo, but are not transferred to the fetus. Their composition is compatible with short term courses of treatment, indicating that this nanoparticle formulation may be suitable for targeted placental delivery of therapeutic payloads in human pregnancy.