Hybrid Nanogels as Biostable Non-Toxic Multifunctional Imaging Agentsfor MRI

混合纳米凝胶作为生物稳定无毒多功能 MRI 成像剂

• 批准号: 10159940
• 负责人: uri samuni
• 金额: $ 11.55万
• 依托单位: QUEENS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-06 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159940
• 关键词: Acceleration; Address; Affect; Anatomy; Animals; Biochemical; Biodistribution; Biological Assay; Biomedical Research; Biomimetics; Cell Culture Techniques; Cell Survival; Collaborations; Communities; Contrast Media; Data Collection; Dependence; Development; Diagnostic tests; Dose; Drug Kinetics; Electron Spin Resonance Spectroscopy; Encapsulated; Environment; Evaluation; Exhibits; Exposure to; Extravasation; Fluorescence Spectroscopy; Formulation; Gadolinium; Gel; Generations; Grant; Histologic; Hybrids; Hydroxylamine; Image; Immobilization; In Vitro; Kinetics; Link; Lomustine; Magnetic Resonance Imaging; Measurement; Measures; Metals; Methods; Modification; Molecular; Mus; NanoGel; Nanotechnology; Nephrogenic Systemic Fibrosis; Patients; Performance; Periodicity; Polyethylene Glycols; Preparation; Procedures; Productivity; Proteins; Protocols documentation; Public Health; Publications; Reaction; Research; Resolution; Safety; Science; Shapes; Signal Transduction; Silicon Dioxide; Solubility; Spectrometry; Spectrum Analysis; Structure; Students; Surface; Testing; Time; Tissues; Toxic effect; Underrepresented Populations; United States National Institutes of Health; Water; Work; adduct; animal imaging; base; biological systems; college; density; dosage; experimental study; graduate student; hydrophilicity; improved; in vivo; innovation; instrumentation; mouse model; nanomedicine; nanoparticle; nitroxyl; novel; programs; skills; tetraethoxysilane; undergraduate student; zeta potential

PROJECT SUMMARY: The SCORE grant will combine the PI expertise in protein encapsulation within silica based sol-gel matrices and nanoparticles with his work with stable cyclic nitroxide radicals and his expertise in spectroscopic methods and allow him to develop and apply it to address important challenges in public health. The objective is to generate novel nitroxides hybrid nanogels that will serve as non-toxic contrast agents for MRI diagnostic tests replacing the commonly used gadolinium-based contrast agents (GBCA) that are linked to the development of nephrogenic systemic fibrosis in patients. Our approach is innovative in that we utilize the sol-gel nanoparticle matrix to enhance the relaxivity of embedded nitroxides radicals as well as to increase their in vivo stability and inhibit their bioreduction. This research will explore methods for generation of sol-gel based hybrid nanoparticles with entrapped nitroxides or nitroxide-protein conjugates resulting in improved biostability, hydrophilicity and 1H water relaxivity (r1). In collaboration with Dr. Krishna, a leading expert in the field, select nitroxide hybrid nanogels (NHN) exhibiting improved activity will be characterized and optimized using in vitro MRI. These studies will identify promising NHN that will be further extended to animal studies at NCI. Specific Aim 1. Fabrication of Sol-gel based nanoparticles (nanogels): We will use tetramethylorthosilicate and/or tetraethylorthosilicate and their derivatives for sol-gel synthesis optimizing the nanogels size and solubility. We will explore an emerging biomimetic approach for the fabrication of hybrid nanogels. Specific Aim 2. Immobilization of nitroxides and nitroxide-protein conjugates within the nanogels. Selected nitroxides will be tested including TEMPOL, 3-CP, TEMPO-Lomustine, spirocyclohexyl nitroxide 1-OH and tetraethyl nitroxide 2-OH sterically protected nitroxides that are less susceptible to bio-reduction, as well as nitroxide-protein conjugates. Specific Aim 3. Structural and functional characterization of the entrapped nitroxides: We will study the size distribution, solubility, aggregation and loading capacity of the modified nanogel as well as rates of their release/leakage. UV/vis spectroscopy, EPR spectroscopy, and biochemical assays will be used to characterize the embedded nitroxides, including determination of their reduction rates. Specific Aim 4. Testing of the nitroxide entrapped hybrid nanogels as contrast agents for MRI in vitro and in mouse models. Optimize the NHN for highest relaxivity (>5mM-1S-1) in vitro followed by in vivo pharmacokinetic and toxicity characterization. This grant will serve to enhance the PI's research program, through acceleration of data collection and an increase in publication productivity, the PI will develop his research competitiveness and transition to non-SCORE support. The results of this research will be used to apply to an NIH RO1 grant by the third year of the project. Queens College undergraduate and graduate students, many of which are from populations under-represented in the biomedical research community, could participate in the research. Students will be exposed to methods and instrumentation of the emerging fields of bio-nanotechnology and nanomedicine, thereby enhancing their biomedical sciences skills. This research will overcome a public health challenge by developing non-toxic MRI contrast agents replacing GBCA that are linked to nephrogenic systemic fibrosis.

项目摘要：分数赠款将结合基于二氧化硅的蛋白质封装方面的PI专业知识 Sol-Gel矩阵和纳米颗粒的作品，其稳定的环状氮氧化物自由基及其在光谱镜上的专业知识 方法并允许他开发并应用其以应对公共卫生中的重要挑战。目的是 生成新型硝酸杂化纳米凝胶，将作为MRI诊断测试的无毒对比剂替换 常用的基于Gadolinium的对比剂（GBCA），与肾病的发展有关 患者的纤维化。我们的方法具有创新性，因为我们利用Sol-Gel纳米粒子矩阵来增强 嵌入氮氧化物自由基的松弛性以及增加其体内稳定性并抑制其 生物护理。这项研究将探讨生成基于Sol-Gel的混合纳米颗粒的方法 硝基氧化物或氮氧化物蛋白偶联物，从而提高了生物稳定性，亲水性和1H水松弛度（R1）。在 与该领域的领先专家Krishna博士合作，选择了氮氧化物混合纳米凝胶（NHN） 活性将使用体外MRI进行表征和优化。这些研究将确定有希望的NHN 进一步扩展到NCI的动物研究。特定目的1。制造基于溶胶 - 凝胶的纳米颗粒（纳米凝胶）：我们 将使用四甲基硅酸盐和/或四乙基硅酸盐及其衍生物进行溶胶 - 凝胶合成，以优化 纳米凝胶尺寸和溶解度。我们将探索一种用于制造杂交纳米凝胶的新兴仿生方法。 具体目的2。纳米凝胶中硝基氧化物和氮氧化物蛋白结合物的固定。选定 氮氧化物将进行测试，包括tempol，3-CP，tempo-lomustine，螺旋环己基氮氧化物1-OH和四乙基 氮氧化物2-OH在空间保护的氮氧化物中不易生物降低，以及氮氧化物蛋白 共轭。特定目的3。被夹住的氮氧化物的结构和功能表征：我们将研究 修饰纳米凝胶的尺寸分布，溶解度，聚合和加载能力及其速率 释放/泄漏。 UV/VIS光谱，EPR光谱和生化测定将用于表征 嵌入氮氧化物，包括确定其还原率。特定目的4。氮氧化物的测试 将混合纳米凝胶置于体外和小鼠模型中MRI的对比剂。优化最高的NHN 放松性（> 5mm-1s-1）体外，然后体内药代动力学和毒性表征。这笔赠款将用于 通过加速数据收集并提高出版物生产率，增强PI的研究计划 PI将发展他的研究竞争力并过渡到非得分支持。这项研究的结果将是 该项目的第三年用于申请NIH RO1赠款。皇后学院的本科生和研究生， 其中许多来自生物医学研究社区中代表不足的人群，可以参与 研究。学生将接触到生物纳米技术新兴领域的方法和工具 纳米医学，从而增强了其生物医学科学技能。这项研究将克服公共卫生挑战 通过开发无毒的MRI对比剂，取代了与肾病全身纤维化有关的GBCA。