Nanocarriers for placenta-specific delivery of imaging and therapeutic agents

点击翻译按钮获取中文摘要

Summary/Abstract (30 lines) The human placenta performs several vital roles, and many conditions with adverse pregnancy outcomes are associated with placental dysfunction. Every year in the USA, ~500,000 expectant mothers and their offspring are exposed to these life-threatening complications. The annual maternal mortality rate is 17.4 per 100,000 pregnancies (~ 700 mothers) and the perinatal mortality rate is 1 in 160 births (~24,000 babies). Many of these mothers also suffer long-term cardiovascular and metabolic complications, and many of the newborns are predisposed to illness in adult life. Hence, there is a critical need to improve visualization of the placenta, and to assess and improve its function and potentially treat and prevent these scenarios with adverse outcomes. The mainstay for assessment of the placenta is ultrasound with MRI as an additional modality. Contrast-enhanced MRI can substantially improve detection and functional assessment of the placenta, but use of contrast agents during pregnancy is discouraged as low molecular weight compounds cross the placenta and can incur fetal toxicity. Therefore, there is an urgent need for biocompatible carriers to specifically deliver MRI contrast agents to the placenta with negligible fetal exposure. Such carriers are also needed for delivery of contrast agents for emerging imaging modalities (e.g., photoacoustic imaging) and therapeutics for treating placenta disorders. The goal of this project is to develop biocompatible carriers for placenta-specific delivery of imaging and therapeutic agents at different gestational ages. This will address a major roadblock (exposure of the fetus to contrast and therapeutic agents) in translation of new modalities for managing placental complications during pregnancy. The PI will capitalize on the recent discovery that polymeric nanoparticles, developed during KL-2 supported cancer research, accumulate in the placenta, but not the fetus, after intravenous injection. It was verified that these nanoparticles can be loaded with various imaging and therapeutic agents, and they are safe when injected into various animals. To further advance this technology, the research team proposes in Aim 1, to optimize accumulation of the developed nanoparticles in the placenta following systemic administration. The proposed experiments will identify optimal sizes and surface modification (PEG chain lengths) that maximize placenta accumulation of the developed nanoparticles while diminishing their transport to the fetus. In Aim 2, the research team will test the hypothesis that modifying optimized nanoparticles with a targeting peptide to the VEGF receptor 2 (KDR), which is overexpressed in placenta endothelial cells and extravillous trophoblast cells, can enhance their accumulation and retention in the placenta. Biodistribution profiles and both placental and fetal accumulation of the optimized non-targeted and actively targeted nanoparticles will be evaluated in pregnant mice. The obtained data will allow the PI to prepare a competitive R01 application focused on the development of novel nanoplatforms for management of ectopic pregnancy and establish an independent extramurally funded research program to provide clinicians with novel tools for diagnosis and treatment of pregnancy complications.