Spin Probes in Semipermeable Nanospheres: EPR spectroscopy & imaging of tumor pH

半透性纳米球中的自旋探针：EPR 光谱

• 批准号: 7363533
• 负责人: Valery V Khramtsov
• 金额: $ 16.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-09 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7363533
• 关键词: Acidosis; Acids; Amines; Animals; Ascorbic Acid; Biochemical; Biochemical Process; Biochemistry; Biological; Buffers; Characteristics; Chemicals; Chloride Ion; Chlorides; Condition; Data; Depth; Detection; Development; Electron Spin Resonance Spectroscopy; Ensure; Enzymes; Female; Fluorine; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Image; Intercellular Fluid; Ions; Lactic acid; Life; Lipids; Liposomes; Magnetic Resonance Imaging; Mammary Neoplasms; Measurement; Medicine; Membrane; Methods; Modeling; Monitor; Mus; Nanosphere; Neoplasm Metastasis; Normal tissue morphology; Numbers; Nylons; Organism; Oxygen; Penetration; Perfusion; Permeability; Phase; Phospholipids; Phosphorus; Play; Preparation; Procedures; Prognostic Factor; Reaction Time; Reducing Agents; Reporting; Role; Solid Neoplasm; Solutions; Specificity; Spectrum Analysis; System; Techniques; Therapeutic; Time; Tissues; UV induced; Variant; Vesicle; Water; angiogenesis; antitumor drug; aqueous; base; bioimaging; capsule; crosslink; design; extracellular; gramicidin A; in vivo; inorganic phosphate; insight; interest; interfacial; monomer; nanosensors; nanosized; nitroxyl; particle; polymerization; research study; sensor; size; success; tumor; tumor growth; tumor initiation; tumor progression; Acidosis; Acids; Amines; Animals; Ascorbic Acid; Biochemical; Biochemical Process; Biochemistry; Biological; Buffers; Characteristics; Chemicals; Chloride Ion; Chlorides; Condition; Data; Depth; Detection; Development; Electron Spin Resonance Spectroscopy; Ensure; Enzymes; Female; Fluorine; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Image; Intercellular Fluid; Ions; Lactic acid; Life; Lipids; Liposomes; Magnetic Resonance Imaging; Mammary Neoplasms; Measurement; Medicine; Membrane; Methods; Modeling; Monitor; Mus; Nanosphere; Neoplasm Metastasis; Normal tissue morphology; Numbers; Nylons; Organism; Oxygen; Penetration; Perfusion; Permeability; Phase; Phospholipids; Phosphorus; Play; Preparation; Procedures; Prognostic Factor; Reaction Time; Reducing Agents; Reporting; Role; Solid Neoplasm; Solutions; Specificity; Spectrum Analysis; System; Techniques; Therapeutic; Time; Tissues; UV induced; Variant; Vesicle; Water; angiogenesis; antitumor drug; aqueous; base; bioimaging; capsule; crosslink; design; extracellular; gramicidin A; in vivo; inorganic phosphate; insight; interest; interfacial; monomer; nanosensors; nanosized; nitroxyl; particle; polymerization; research study; sensor; size; success; tumor; tumor growth; tumor initiation; tumor progression

DESCRIPTION (provided by applicant): The overall goal of this project is to develop new functional EPR probes of enhanced stability for in vivo EPR spectroscopy and imaging of pH, one of the most important parameters in the biochemistry of living organisms. pH-sensitive nitroxyl radicals have been previously developed by the P.I. and colleagues but often suffer insufficient stability in living tissues. In this project two different strategies will be used to develop paramagnetic probes with stability in vivo based on the original idea of constructing nano-Sized Particles with the Incorporated Nitroxides, or nanoSPINs. The semipermeable membrane of the nanoSPINs will differentiate sensing nitroxides from biological reductants while allowing free penetration of the analyze, H+. This will fill a niche between fluorescent pH probes, which have provided advances in applications for cellular and subcellular detection, and NMR/MRI, which have provided applications in living animals and humans, but these current techniques often suffer from the lack of sensitivity (1000 fold or lower than EPR) and specificity. The specific aims are: (SA1) To develop effective approaches for the design of pH-sensitive nanoSPINs. Two alternative strategies for the incorporation of the nitroxides into semipermeable nanospheres will be used, namely incorporation into phospholipids liposomes and polyamide capsules. (SA2) To define spectroscopic and physicochemical characteristics of pH-sensitive nanoSPINs. Quantitative characterization of the obtained nanoSPIN is absolutely crucial both for the optimization of the preparation procedures and for efficiency of their further applications. (SA3) To apply in vivo EPR measurements of pHe in PyMT tumor-bearing mice using developed nanoSPINs. The measurement of the extracellular pHe in the PyMT mammary tumors in living mice using developed pH- sensitive nanoSPINs will provide new insights into related biochemical processes, including better understanding of the observed anti-tumor activity of Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), a therapeutic approach which is currently of much interest. The results may provide an opportunity for the design of other corresponding therapeutic approaches. In summary, the success of this project may have a significant impact on the future of functional in vivo EPR spectroscopy and bioimaging applications to medicine. This project will develop pH-sensitive paramagnetic probes of enhanced stability based on encapsulation of the nitroxides into semipermeable nanospheres. These probes, termed nanoSPINs, will allow in vivo EPR spectroscopy and imaging of pH. The experiments using pH-sensitive nanoSPINs in PyMT mammary tumors in living mice are planned to contribute to the understanding of the mechanisms of extracellular acidosis in solid tumors and to use extracellular pH to monitor tumor progression and thus evaluate the efficacy of anti-tumor drugs, and provide opportunities for designing corresponding therapeutic approaches.

描述（由申请人提供）：该项目的总体目标是开发新的功能EPR探针，以增强体内EPR光谱和pH成像的稳定性，pH是生物体生物化学中最重要的参数之一。 P.I.先前已经开发了pH敏感的硝氧基自由基。和同事，但在生物组织中通常不足。在该项目中，将使用两种不同的策略来开发具有体内稳定性的顺磁性探针，该探针是基于与掺杂的硝基氧化物或纳米替剂构造纳米尺寸颗粒的最初想法。纳米蛋白的半透明膜将使感觉氮氧化物与生物还原剂区分开，同时允许分析的自由渗透H+。这将填充荧光pH探针之间的细分市场，这些pH探针为细胞和亚细胞检测的应用提供了进步，而NMR/MRI则在活着的动物和人类中提供了应用，但是这些当前技术通常会遭受缺乏灵敏度（1000倍或低于EPR）和特异性的敏感性。具体目的是：（SA1）开发设计有效的pH敏感纳米替代方法。将使用将氮氧化物掺入半透明纳米球中的两种替代策略，即将其掺入磷脂脂质体和聚酰胺胶囊中。 （SA2）定义pH敏感纳米辛的光谱和物理化学特征。所获得的纳米素的定量表征对于优化制备程序和其进一步应用的效率至关重要。 （SA3）使用发达的纳米固定剂在PYMT肿瘤小鼠中对PHE进行体内EPR测量。使用开发的ph-敏感的纳米替代物在活小鼠中的细胞外PHE测量将提供有关相关生物化学过程的新见解，包括更好地了解观察到的粒细胞巨噬细胞巨噬细胞巨噬细胞刺激性刺激性因子（GM-CSF）的抗肿瘤活性，目前有很多感兴趣的方法。结果可能为设计其他相应的治疗方法设计提供了机会。总之，该项目的成功可能会对体内EPR光谱和医学生物成像应用的功能的未来产生重大影响。该项目将基于将氮氧化物封装到半透明的纳米球中的增强稳定性的pH敏感顺磁性探针。这些称为纳米辛的探针将允许体内EPR光谱和pH成像。计划在活小鼠中使用pH敏感的纳米替辛进行实验，从而有助于理解固体瘤中细胞外酸中毒机制，并使用细胞外pH来监测肿瘤进展，从而评估抗肿瘤药物的功效，并为设计相应的治疗方法提供机会。