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: 10378977
• 负责人: Olena Taratula
• 金额: $ 7.43万
• 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/10378977
• 关键词: Address; 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; 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; Role; Site; Surface; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Translations; Uterus; Visualization; Work; adverse outcome; adverse pregnancy outcome; angiogenesis; anticancer research; base; biomaterial compatibility; clinical translation; contrast enhanced; diagnostic accuracy; experimental study; fetal; imaging agent; imaging modality; improved; intravenous injection; maternal risk; nanocarrier; nanoparticle; 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） 人类胎盘发挥着多种重要作用，许多导致不良妊娠结局的情况 与胎盘功能障碍有关。在美国，每年约有 500,000 名准妈妈及其后代 面临这些危及生命的并发症。每年孕产妇死亡率为每10万人中17.4人 怀孕（约 700 名母亲），围产期死亡率为每 160 名新生儿（约 24,000 名婴儿）中就有 1 人死亡。其中许多 母亲还患有长期心血管和代谢并发症，许多新生儿 成年后容易患病。因此，迫切需要改善胎盘的可视化，并 评估和改善其功能，并有可能治疗和预防这些产生不良后果的情况。这 评估胎盘的主要方法是超声检查和 MRI 作为附加方式。对比度增强 MRI 可以显着改善胎盘的检测和功能评估，但使用造影剂 怀孕期间不鼓励使用，因为低分子量化合物会穿过胎盘并可能导致胎儿 毒性。因此，迫切需要生物相容性载体来特异性递送MRI造影剂 至胎盘，胎儿暴露量可忽略不计。还需要此类载体来输送造影剂 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。这将解决一个主要障碍（胎儿暴露于 对比剂和治疗剂）转化为治疗期间胎盘并发症的新方法 怀孕。 PI 将利用 KL-2 期间开发的聚合物纳米粒子的最新发现 支持癌症研究，静脉注射后积聚在胎盘中，但不会积聚在胎儿中。原来是 验证了这些纳米颗粒可以负载各种成像和治疗剂，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，研究团队在目标 1 中提出， 优化全身给药后所开发的纳米颗粒在胎盘中的积累。这 拟议的实验将确定最佳尺寸和表面修饰（PEG 链长度），以最大化 胎盘积聚已发育的纳米颗粒，同时减少它们向胎儿的运输。在目标 2 中， 研究小组将测试用靶向肽修饰优化纳米颗粒的假设 VEGF 受体 2 (KDR) 在胎盘内皮细胞和绒毛外滋养层细胞中过度表达， 可以增强它们在胎盘中的积累和保留。生物分布概况以及胎盘和 将在怀孕期间评估优化的非靶向和主动靶向纳米粒子的胎儿积累 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 用于治疗异位妊娠的新型纳米平台，并建立一个独立的外部资助 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。