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: 10393040
• 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/10393040
• 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; 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：计分资助将结合PI在硅基蛋白质封装方面的专业知识 溶胶-凝胶基质和纳米颗粒，以及他对稳定的环氮氧自由基的研究和他在光谱方面的专业知识 方法，并允许他开发和应用它来应对公共卫生领域的重大挑战。我们的目标是 制备新型氮氧化物杂化纳米凝胶，作为MRI诊断测试的无毒造影剂 与肾源性全身性疾病发展有关的常用格拉基造影剂(GBCA) 患者的纤维化。我们的方法是创新的，因为我们利用溶胶-凝胶纳米颗粒基质来增强 嵌入的氮氧自由基的驰豫能力，以及增加其体内稳定性和抑制其 生物还原。本研究将探索以溶胶-凝胶法为基础的包埋杂化纳米粒子的制备方法 氮氧化物或氮氧化物-蛋白质结合物，可改善生物稳定性、亲水性和1H水弛豫度(R1)。在……里面 与该领域的领先专家Krishna博士合作，精选氮氧化物杂化纳米凝胶(NHN)，展示了改进的 活性将使用体外核磁共振进行表征和优化。这些研究将确定有前景的NHN 进一步扩展到NCI的动物研究。具体目标1.基于Sol-Gel的纳米颗粒(纳米凝胶)的制备 将使用正硅酸四甲酯和/或正硅酸乙酯及其衍生物进行溶胶-凝胶合成，优化 纳米凝胶的大小和溶解度。我们将探索一种新的仿生方法来制备杂化纳米凝胶。 具体目标2.氮氧化物和氮氧化物-蛋白质结合物在纳米凝胶中的固定化。已选择 将测试氮氧化物，包括TEMPOL、3-CP、TEMPO-Lomustine、螺环己基氮氧化物1-OH和四乙基 氮氧化物2-OH立体保护的不易被生物还原的氮氧化物，以及氮氧化物-蛋白质 共轭关系。具体目标3.包埋的氮氧化物的结构和功能表征：我们将研究 改性纳米凝胶的尺寸分布、溶解度、聚集性和负载量以及它们的速率 释放/泄漏。将使用UV/Vis光谱、EPR光谱和生化分析来表征 嵌入的氮氧化物，包括其还原速率的测定。具体目标4.氮氧化物的测试 包埋杂化纳米凝胶作为磁共振成像的造影剂，在体外和小鼠模型中。优化NHN以获得最高 体外弛豫度(&gt；5 mm~(-1)s~(-1))，随后进行体内药代动力学和毒性表征。这笔赠款将用于 通过加快数据收集和提高出版生产率，加强私营部门的研究方案， 派将发展他的研究竞争力，并过渡到非分数支持。这项研究的结果将是 用于在项目第三年申请美国国立卫生研究院RO1拨款。皇后学院本科生和研究生， 他们中的许多人来自生物医学研究社区中代表性不足的人群，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仪器，以及 纳米医学，从而提高他们的生物医学科学技能。这项研究将克服公共卫生方面的挑战 通过开发无毒的MRI造影剂来取代与肾源性系统性纤维化有关的GBCA。