Surface-functionalized SPIONs for pH-sensitive MRI contrast in physiologically-re

用于生理学研究中 pH 敏感 MRI 对比的表面功能化 SPION

• 批准号: 8036908
• 负责人: YONG GAO
• 金额: $ 43.05万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036908
• 关键词: Attention; Behavior; Biological; Breathing; Cell Culture Techniques; Characteristics; Charge; Clinical; Complex; Contrast Media; Correlation Studies; Dendrimers; Development; Diagnosis; Dimensions; Disease; Dose; Drug Formulations; Environment; Feedback; Generations; Goals; Grant; Imagery; Inflammation; Injury; Ionic Strengths; Ischemia; Lead; Ligands; Light; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measurement; Measures; Metabolism; Methods; Microelectrodes; Modeling; Nature; Organic Synthesis; Performance; Physiological; Polymers; Positioning Attribute; Property; Relaxation; Research; Research Design; Sampling; Shapes; Solutions; Surface; Theoretical model; Therapeutic; Time; Tissues; Transmission Electron Microscopy; Variant; Work; aqueous; base; cancer therapy; density; design; improved; in vivo; insight; interest; iron oxide; light scattering; magnetic field; meetings; nanoparticle; next generation; novel; pH gradient; research study; response; surface coating; trait; tumor

DESCRIPTION (provided by applicant): Local variations in tissue pH are often associated with many pathological conditions-including injury, inflammation, and ischemia, as well as a variety of cancers. While progress has been made, the creation of magnetic resonance imaging (MRI) agents capable of sensing pH but that also meet all of the desired traits- including high sensitivity, low minimum dose, high biological compatibility, and concentration-independent pH response-remains a persistent challenge. Based upon the work performed as part of the original AREA R15 support, the overall goal of the work proposed in this renewal application is to develop a novel class of MRI contrast agents based on dendron-functionalized super paramagnetic iron oxide nanoparticles ('dendron- SPIONs') that will provide highly sensitive pH responses in physiologically-relevant regimes, and to characterize the nature of those pH-sensitive responses. It is believed that most of the pH response results from transient, reversible clustering of the dendron-SPIONs modulated by an interplay between the SPION surface charge density and the solution ionic strength. Correspondingly, the Proposal has two Specific Aims: (1) to synthesize and characterize novel dendron-functionalized SPIONs designed to give strong pH-sensitive MR responses in physiologically relevant regimes (with varying values between pH~6-8); and (2) to perform fundamental studies of these novel dendron-SPIONs-in both chemically homogeneous and realistic cellular environments-to obtain a greater understanding of the origins of such pH-sensitive responses. In support of (1), a variety of new dendron-SPIONs will be synthesized (via multi-step organic synthesis and covalent dendron linkage to the nanocrystallite SPION cores via ligand-exchange methods) whose dendron functionalities with be designed to provide peak pH sensitivity at a given location between ~6-8; variation of the dendron generation should allow fine tuning of the magnitude and position of the pH inflection for a given dendron-SPION. MR measurements of aqueous 1H spin relaxation rates (R1, R2, R2*) as functions of SPION loading will allow systematic relaxivity measurement and characterization for a given dendron-SPION under various conditions (including pH, ionic strength, and magnetic field). In support of (2), the correlation between a given MR response and the physical SPION behavior will be studied. Echo-time dependent CPMG MR measurements of effective R2 values will provide an indication of the degree of SPION clustering present under a given set of conditions; these results will be interpreted in the context of a theoretical model (under development) and complimentary results obtained by transmission electron microscopy (TEM) and dynamic light scattering (DLS). Furthermore, greater understanding of the pH-sensitive responses obtained in support of (2) will naturally be used as feedback for design and synthesis of next-generation pH-sensing SPIONs created in support of (1). Finally, experiments involving cell cultures will allow direct comparison of results obtained in multi-compartment, tissue-like environments with those obtained in chemically homogeneous environments. PUBLIC HEALTH RELEVANCE: Local variations in tissue pH are often associated with a range of diseases, including many cancers. Once successful, the proposed work should provide new insight into the design and mechanism-of-action of a novel class of pH-sensing agents, and furthermore, should lead directly to the development of novel MRI contrast agents that would allow the detailed mapping of pH gradients in the body for the improved visualization, diagnosis, and treatment of various malignancies (impact for other clinical situations where pH variance may be present is also envisioned). For example, it is anticipated that positive therapeutic measures in the treatment of cancers will manifest themselves first as changes in local metabolism, since the pH variance associated with such diseases is caused by problems with local metabolism. Thus, the ability to probe tissue pH in response to therapy promises to provide more rapid feedback than simple 'caliper-based' measurements of tumor dimensions (which can take much longer to manifest).

描述（由申请人提供）：组织pH的局部变化通常与许多病理状况相关，包括损伤、炎症和缺血以及各种癌症。虽然已经取得了进展，磁共振成像（MRI）的创造能够传感pH值，但也满足所有所需的特性-包括高灵敏度，低最小剂量，高生物相容性，和浓度无关的pH值响应-仍然是一个持续的挑战。基于作为原始AREA R15支持的一部分而进行的工作，在该更新申请中提出的工作的总体目标是开发基于树枝状官能化超顺磁性氧化铁纳米颗粒（“树枝状-SPION”）的新型MRI造影剂，其将在生理学相关方案中提供高度敏感的pH响应，并表征那些pH敏感响应的性质。据信，大多数的pH响应的结果从瞬态，可逆的簇的树枝状SPION调制的SPION表面电荷密度和溶液离子强度之间的相互作用。相应地，该建议有两个具体目标：（1）合成和表征新型树枝状官能化SPION，其设计用于在生理相关的机制中产生强pH敏感的MR响应（pH值在6-8之间变化）;和（2）在化学均质和真实的细胞环境中对这些新型树枝状自旋离子进行基础研究，以更好地了解这种pH的起源，敏感的反应。为了支持（1），将合成各种新的树枝状SPION（通过多步有机合成和经由配体交换方法共价树枝化基元连接到纳米硅灰石SPION核），其树枝化基元官能度被设计为在约6-8之间的给定位置提供峰值pH敏感性;树枝化基元产生的变化应允许对给定树枝化基元-SPION的pH拐点的大小和位置进行微调。MR测量水1H自旋弛豫速率（R1，R2，R2*）作为SPION负载的函数将允许系统弛豫率测量和表征给定的树枝状SPION在各种条件下（包括pH值，离子强度和磁场）。为了支持（2），将研究给定MR响应与物理SPION行为之间的相关性。有效R2值的回波时间依赖性CPMG MR测量将提供给定条件下SPION聚集程度的指示;这些结果将在理论模型（正在开发中）和透射电子显微镜（TEM）和动态光散射（DLS）获得的互补结果的背景下进行解释。此外，对支持（2）所获得的pH敏感响应的更深入理解将自然地用作支持（1）所创建的下一代pH传感SPION的设计和合成的反馈。最后，涉及细胞培养的实验将允许直接比较在多室、组织样环境中获得的结果与在化学均质环境中获得的结果。 公共卫生相关性：组织pH值的局部变化通常与一系列疾病有关，包括许多癌症。一旦成功，所提出的工作将为一类新型pH敏感剂的设计和作用机制提供新的见解，此外，还将直接导致新型MRI造影剂的开发，该造影剂将允许体内pH梯度的详细绘图，以改善可视化，诊断，和各种恶性肿瘤的治疗（也设想了对可能存在pH变化的其他临床情况的影响）。例如，预期癌症治疗中的积极治疗措施将首先表现为局部代谢的变化，因为与此类疾病相关的pH变化是由局部代谢的问题引起的。因此，响应于治疗而探测组织pH的能力有望提供比简单的肿瘤尺寸的“基于卡尺的”测量（其可能需要长得多的时间来显现）更快速的反馈。

项目成果

Esterification Catalysis by Pyridinium p-Toluenesulfonate Revisited-Modification with a Lipid Chain for Improved Activities and Selectivities.

对甲苯磺酸吡啶鎓的酯化催化用脂质链重新修饰以提高活性和选择性。

• DOI: 10.1080/00397911.2012.749990
• 发表时间: 2013
• 期刊: Synthetic communications
• 影响因子: 2.1
• 作者: Wang,Wei;Liu,Huimin;Xu,Shaoyi;Gao,Yong
• 通讯作者: Gao,Yong

pH-Sensitive MR Responses Induced by Dendron-Functionalized SPIONs.

• DOI: 10.1021/jp306128v
• 发表时间: 2013-01-31
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY C
• 影响因子: 3.7
• 作者: Saha, Indrajit;Chaffee, Kathleen E.;Duanmu, Chuansong;Woods, Brooke M.;Stokes, Ashley M.;Buck, Laura E.;Walkup, Laura L.;Sattenapally, Narsimha;Huggenvik, Jodi;Gao, Yong;Goodson, Boyd M.
• 通讯作者: Goodson, Boyd M.

N-Butyl-2,4-dinitro-anilinium p-toluenesulfonate as a highly active and selective esterification catalyst.

N-丁基-2,4-二硝基苯铵对甲苯磺酸盐作为高活性和选择性酯化催化剂。

• DOI: 10.1016/j.tetlet.2013.09.132
• 发表时间: 2013
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Sattenapally,Narsimha;Wang,Wei;Liu,Huimin;Gao,Yong
• 通讯作者: Gao,Yong