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） 人胎盘扮演多个至关重要的角色，许多不良怀孕结果的情况是 与胎盘功能障碍相关。每年在美国，约有500,000名准妈妈及其后代 暴露于这些威胁生命的并发症。每年的孕产妇死亡率为每10万人17.4 怀孕（约700名母亲），围产期死亡率为160个出生（约24,000个婴儿）。其中许多 母亲还遭受长期的心血管和代谢并发症，许多新生儿都是 在成人生活中易于疾病。因此，迫切需要改善胎盘的可视化和 评估和改善其功能，并有可能以不利的结果来治疗并防止这些情况。这 评估胎盘的主要阶段是超声检查，MRI是另一种方式。对比增强 MRI可以实质上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，并且会产生胎儿 毒性。因此，迫切需要生物相容性载体专门提供MRI对比剂 到胎盘接触可忽略的胎盘。还需要此类载体以交付造影剂 新兴成像方式（例如，光声成像）和用于治疗胎盘疾病的治疗剂。 该项目的目的是开发生物相容性载体，用于特定于胎盘的成像和成像交付 不同胎龄的治疗剂。这将解决一个主要的障碍（胎儿暴露于 对比度和治疗剂）在转化新方式用于管理胎盘并发症的新方式 怀孕。 PI将利用最近的发现，即在KL-2期间开发的聚合物纳米颗粒 静脉注射后，支持癌症研究，积累在胎盘中，但没有胎儿。是 确认这些纳米颗粒可以装有各种成像和治疗剂，并且是安全的 当注射到各种动物中时。为了进一步推进这项技术，研究小组在AIM 1中建议 全身给药后，要优化发达的纳米颗粒的积累。这 提出的实验将确定最大化的最佳尺寸和表面修饰（PEG链长） 发达的纳米颗粒的胎盘积聚，同时减少其运输到胎儿。在AIM 2中， 研究团队将检验以下假设，即用靶肽修改优化的纳米颗粒 VEGF受体2（KDR），它在胎盘内皮细胞和额外滋养细胞细胞中过表达 可以增强其在胎盘中的积累和保留率。生物分布轮廓和胎盘和 在怀孕中将评估优化的非靶向和主动靶向纳米颗粒的胎儿积累 老鼠。获得的数据将允许PI准备一个竞争性的R01应用程序，以开发为重点 用于治疗异位妊娠并建立独立外部资助的新型纳米植物。 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。