Nanocarriers for placenta-specific delivery of imaging and therapeutic agents

用于胎盘特异性递送成像和治疗剂的纳米载体

• 批准号: 10542781
• 负责人: Olena Taratula
• 金额: $ 6.68万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542781
• 关键词: Adult; Animals; Binding; Biodistribution; Birth; Blood Vessels; Blood flow; Cardiovascular system; Cell Surface Receptors; Cells; Contrast Media; Data; Death Rate; Detection; Development; Diagnosis; Diffusion; Disease; Ectopic Pregnancy; Encapsulated; Endothelial Cells; Exposure to; Extramural Activities; Extravasation; FDA approved; Fetal Growth Retardation; Fetus; Functional disorder; Funding; Gestational Age; Goals; Human; Image; Invaded; KDR gene; Length; Lesion; Life; Ligands; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Maternal Mortality; Metabolic; Modality; Modification; Molecular Weight; Mothers; Mus; Newborn Infant; Penetration; Peptides; Perinatal mortality demographics; Permeability; Placenta; Placenta Accreta; Placenta Diseases; Polyethylene Glycols; Polymers; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy loss; Pregnant Women; Premature Birth; Reproducibility; Research; Risk Reduction; Role; Site; Surface; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Translations; Uterus; Villous; Visualization; Work; adverse outcome; adverse pregnancy outcome; angiogenesis; anticancer research; biomaterial compatibility; clinical translation; contrast enhanced; diagnostic accuracy; experimental study; fetal; imaging agent; imaging modality; improved; intravenous injection; maternal risk; nanocarrier; nanoparticle; nanopolymer; nanotechnology platform; novel; offspring; overexpression; photoacoustic imaging; polycaprolactone; pregnant; prenatal exposure; prevent; programs; stillbirth; tool; translational potential; trophoblast; tumor; ultrasound; uptake

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.

摘要/摘要（30行） 人类胎盘起着几个重要的作用，许多具有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50万孕妇和她们的孩子 都暴露在这些危及生命的并发症中年产妇死亡率为17.4/100 000 围产期死亡率为1/160（约24 000名婴儿）。许多这些 母亲也遭受长期的心血管和代谢并发症，许多新生儿 在成年生活中容易生病。因此，迫切需要改善胎盘的可视化，并且 评估和改善其功能，并可能治疗和预防这些具有不良后果的情况。的 评估胎盘的主要方法是超声和MRI作为附加方式。对比增强 MRI可以显著改善胎盘的检测和功能评估，但使用造影剂 在怀孕期间，由于低分子量化合物穿过胎盘， 毒性因此，迫切需要生物相容性载体来特异性地递送MRI造影剂 胎儿接触量可以忽略不计也需要这样的载体用于递送造影剂， 新兴的成像模态（例如，光声成像）和用于治疗胎盘疾病的治疗剂。 该项目的目标是开发生物相容性载体，用于胎盘特异性成像和 不同胎龄的治疗药物。这将解决一个主要的障碍（胎儿暴露于 造影剂和治疗剂）在治疗胎盘并发症的新模式中的应用 怀孕PI将利用最近的发现，聚合物纳米粒子，在KL-2期间开发 支持癌症研究，在静脉注射后，积聚在胎盘中，但不会在胎儿中。这是 证实了这些纳米颗粒可以装载各种成像和治疗剂，并且它们是安全的 注射到各种动物体内为了进一步推进这项技术，研究小组在目标1中提出， 以优化全身给药后所开发的纳米颗粒在胎盘中的积累。的 提出的实验将确定最佳的尺寸和表面改性（PEG链长）， 胎盘积累的开发纳米粒子，同时减少其运输到胎儿。在目标2中， 研究小组将测试一种假设，即用靶向肽修饰优化的纳米颗粒， VEGF受体2（KDR），在胎盘内皮细胞和绒毛外滋养层细胞中过表达， 可以增加它们在胎盘中的积累和保留。生物分布特征以及胎盘和 将在孕妇中评价优化的非靶向和主动靶向纳米颗粒的胎儿蓄积 小鼠获得的数据将使PI能够准备一份竞争性R01申请，重点是开发 新的纳米平台管理异位妊娠，并建立一个独立的壁外资助 研究计划，为临床医生提供诊断和治疗妊娠并发症的新工具。