Prussian Blue Nanoparticles as Cellular T1 MRI Contrast Agents

普鲁士蓝纳米颗粒作为细胞 T1 MRI 造影剂

基本信息

批准号：
8532658
负责人：
SONGPING D HUANG
金额：
$ 9.21万
依托单位：
KENT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8532658
关键词：
Animals Area Biomedical Research Blood Circulation Time Cell Survival Cell membrane Cells Characteristics Clinical Contrast Media Detection Development Diagnostic Diagnostic Imaging Dose Drug Delivery Systems Dyes Engineering Exhibits Fibrosis Gadolinium Generations Goals Image Impaired Renal Function In Vitro Injection of therapeutic agent Ions Iron Ligands Link Magnetic Resonance Imaging Manganese Measures Methods Molecular Particulate Patients Penetration Pharmaceutical Preparations Polymers Positioning Attribute Positron-Emission Tomography Protons Prussian blue Radioisotopes Relaxation Research Solubility Solutions Structure Surface Testing Time TimeLine Toxic effect Water Weight base cancer cell cellular imaging cytotoxicity design gadolinium oxide improved in vivo iron cyanide nanoparticle nanoparticulate next generation novel quantum single photon emission computed tomography small molecule surface coating uptake

项目摘要

DESCRIPTION (provided by applicant): This proposal is aimed at developing Prussian blue nanoparticles (PBNPs) as a new generation of T1-weighted MRI contrast agents (CAs) with high relaxivity, long blood circulation times and ability to penetrate the cell membrane. Prussian blue (PB) is iron(III) hexacyanoferrate(II) with anidealized formula Fe4III[FeII(CN)6]3.nH2O (n=14-16) in which two different iron centers, Fe3+ (high-spin S=5/2) and Fe2+ (low-spin S=0) are bridged by the CN- groups. In the crystal structure of PB, a quarter (25%) of the FeII(CN)6 unit is absent from the crystal lattice, creating a large cavity inside the structure that is filled with water molecules. The missing FeII(CN)6 unit also causes the Fe3+ center to be coordinated by one water molecule and five CN- groups, thus giving rise to an active inner-sphere relaxation mechanism for enhancing the T1 relaxation. Due to the strong ligand-field effect and simultaneous coordination of the CN- group to both the Fe3+ and Fe2+ centers in the extended 3D network, the CN- ligand and the Fe3+/Fe2+ ions are completely locked in their lattice positions and cannot be released from the structure. As a result, PB has the lowest solubility product constant ever measured for any compound (Ksp=10-41). We have found that replacement of some of the Fe3+ ions with Mn2+ or/and Gd3+ ions in the crystal lattice can form the manganese- or gadolinium-incorporated nanoparticles, Mn@PBNPs and Gd@PBNPs with significantly increased r1 relaxivity. Besides, the structural rigidity and reduced tumbling rates of PBNPs in solution, as compared to the small molecular Gd3+-chelates, can contribute to additional T1-weighted MRI contrast enhancement in this new nanoplatform. Our goals are: (i) to explore methods for optimizing the r1 relaxivity by adjusting the nanoparticle size, level of Mn2+- or/and Gd3+-doping, and surface coating with small molecules or polymers; (ii) to systematically investigate the characteristics of cellular uptake and cellular imaging as well as potential for image-guided drug delivery applications; and (iii) to simultaneously incorporate Mn2+ or/and Gd3+ ions along with the radionuclide Ga-67 or Ga-68 for MRI-SPECT and MRI-PET bimodal imaging applications. We will endeavor to test the following four hypotheses: 1) Prussian blue nanoparticles, when properly tailored and engineered, will be effective in reducing the longitudinal relaxation time of protons from bulk water. Incorporation of Mn2+ or/and Gd3+ into this nanoplatform will significantly increase the r1 relaxivity; 2) Prussian blue nanoparticles will be internalized by cells, exhibit no toxicity and be effective in cellular imaging and in delivering small-molecular agents; 3) Prussian blue nanoparticles will be effective T1-weighted MRI contrast agents in vivo; and 4) Simultaneous incorporation of paramagnetic ions of manganese(II) or/and gadolinium(III) along with the radionuclide Ga-67 or Ga-68 into Prussian blue nanoparticles will produce effective bimodal contrast agents for in vitro and in vivo MRI-SPECT and MRI-PET imaging. Impact Our approach to exploring PBNPs as novel T1-weighted MRI is unprecedented and represents a paradigm shift in the design of new-generation CAs. The new paradigm that will emerge from this proposed research will prove to be revolutionary rather than evolutionary for increasing r1 relaxivity in a novel class of particulate T1-weighted MRI CAs, and thus will have high potential to produce a major breakthrough in MRI diagnostic imaging and may even completely change the landscape in this area of research.

描述（申请人提供）：本提案旨在开发普鲁士蓝纳米粒子（PBNP）作为新一代T1加权MRI造影剂（CA），具有高弛豫率、长血液循环时间和穿透细胞膜的能力。普鲁士蓝 (PB) 是铁(III)六氰基铁酸(II)，具有理想化式 Fe4III[FeII(CN)6]3.nH2O (n=14-16)，其中两个不同的铁中心，Fe3+（高自旋 S=5） /2) 和 Fe2+ (低自旋 S=0) 通过 CN- 基团桥接。在 PB 的晶体结构中，晶格中不存在四分之一 (25%) 的 FeII(CN)6 单元，从而在结构内部形成一个充满水分子的大空腔。缺失的 FeII(CN)6 单元还导致 Fe3+ 中心由一个水分子和五个 CN- 基团协调，从而产生一种活跃的内球弛豫机制，以增强 T1 弛豫。由于强配体场效应以及CN-基团同时与扩展3D网络中的Fe3+和Fe2+中心配位，CN-配体和Fe3+/Fe2+离子被完全锁定在其晶格位置并且无法释放从结构上看。因此，PB 具有有史以来测量的任何化合物中最低的溶度积常数 (Ksp=10-41)。我们发现，用Mn2+或/和Gd3+离子取代晶格中的一些Fe3+离子可以形成掺锰或钆的纳米颗粒Mn@PBNPs和Gd@PBNPs，其r1弛豫率显着增加。此外，与小分子 Gd3+ 螯合物相比，溶液中 PBNP 的结构刚性和降低的翻滚速率有助于在该新纳米平台中额外增强 T1 加权 MRI 对比度。我们的目标是：（i）探索通过调整纳米颗粒尺寸、Mn2+-或/和Gd3+-掺杂水平以及小分子或聚合物表面涂层来优化r1弛豫率的方法； (ii) 系统地研究细胞摄取和细胞成像的特征以及图像引导药物输送应用的潜力； (iii) 同时将 Mn2+ 或/和 Gd3+ 离子与放射性核素 Ga-67 或 Ga-68 结合，用于 MRI-SPECT 和 MRI-PET 双峰成像应用。我们将努力测试以下四个假设：1）普鲁士蓝纳米颗粒经过适当的定制和设计后，将有效减少散装水中质子的纵向弛豫时间。将 Mn2+ 或/和 Gd3+ 纳入该纳米平台将显着提高 r1 弛豫率； 2) 普鲁士蓝纳米粒子会被细胞内化，无毒性，可有效进行细胞成像和小分子药物输送； 3）普鲁士蓝纳米颗粒将成为体内有效的T1加权MRI造影剂； 4) 将锰 (II) 或/和钆 (III) 的顺磁离子与放射性核素 Ga-67 或 Ga-68 同时掺入普鲁士蓝纳米颗粒中，将产生用于体外和体内 MRI-SPECT 的有效双峰造影剂和 MRI-PET 成像。影响我们探索 PBNP 作为新型 T1 加权 MRI 的方法是前所未有的，代表了新一代 CA 设计的范式转变。这项拟议研究中出现的新范式将被证明是革命性的，而不是进化性的，对于增加一类新型颗粒 T1 加权 MRI CA 中的 r1 弛豫率来说，因此将有很大潜力在 MRI 诊断成像和甚至可能彻底改变这一研究领域的格局。