Nanocarriers for placenta-specific delivery of imaging and therapeutic agents

摘要/摘要(30行) 人类胎盘发挥着几个重要的作用，许多不良妊娠结局的情况是 与胎盘功能障碍有关。在美国，每年约有500,000名孕妇及其后代 都暴露在这些危及生命的并发症中。年孕产妇死亡率为17.4/10万 怀孕(约700名母亲)和围产儿死亡率为每160名新生儿(约24,000名婴儿)中有1名。其中许多 母亲还患有长期的心血管和新陈代谢并发症，许多新生儿是 在成年后容易生病的。因此，迫切需要改善胎盘的可视化，并 评估和改善其功能，并潜在地治疗和预防这些具有不良后果的情况。这个 评估胎盘的主要手段是超声和核磁共振，作为辅助手段。对比度增强 MRI可以显著提高对胎盘的检测和功能评估，但使用造影剂 在怀孕期间被劝阻，因为低分子化合物穿过胎盘，可能导致胎儿 毒性。因此，迫切需要生物相容的载体来专门输送MRI造影剂 胎盘与胎儿的接触微乎其微。这样的载体也需要用于输送造影剂 新兴的成像方式(例如，光声成像)和治疗胎盘疾病的疗法。 该项目的目标是开发生物相容的载体，用于胎盘特异性的成像和 不同胎龄的治疗剂。这将解决一个主要障碍(胎儿暴露在 造影剂和治疗剂)用于治疗胎盘并发症的新方法的翻译 怀孕了。PI将利用最近的发现，在KL-2期间开发的聚合物纳米颗粒 支持癌症研究，静脉注射后积聚在胎盘，而不是胎儿。确实是 证实这些纳米粒子可以装载各种成像和治疗药物，并且它们是安全的 当注射到各种动物体内时。为了进一步推进这项技术，研究小组在目标1中提出， 为了优化全身给药后开发的纳米颗粒在胎盘中的积累。这个 拟议的实验将确定最佳的尺寸和表面修饰(聚乙二醇链的长度)，以最大限度地 胎盘积聚已开发的纳米颗粒，同时减少它们向胎儿的运输。在目标2中， 研究小组将测试这样的假设，即用靶向多肽来修饰优化的纳米颗粒 血管内皮生长因子受体2(KDR)在胎盘内皮细胞和绒毛外滋养层细胞中过表达， 可以增强它们在胎盘中的蓄积和滞留。生物分布图和胎盘和胎盘 优化的非靶向和主动靶向纳米粒在胎儿体内的蓄积将在怀孕期间进行评估 老鼠。获得的数据将使PI能够准备专注于开发的具有竞争力的R01应用程序 管理异位妊娠的新型纳米平台，并建立一个独立的外部资助的 为临床医生提供诊断和治疗妊娠并发症的新工具的研究计划。

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.