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.

Public Health Relevance

Prussian Blue Nanoparticles as Cellular T1 MRI Contrast Agents We aim to develop novel Prussian blue nanoparticulate T1-weighted MRI contrast agents suitable for cellular imaging of cancer cells. Such agents will penetrate the cell membrane, exhibit no cytotoxicity, and can integrate imaging and delivering capabilities into a single platform for image- guided drug delivery. The design paradigm developed from this research will prove to be transformative and have potential to significantly impact the diagnostic MR imaging.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA143408-01A1
Application #
8155168
Study Section
Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Ossandon, Miguel
Project Start
2011-09-16
Project End
2014-08-31
Budget Start
2011-09-16
Budget End
2012-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$210,343
Indirect Cost
Name
Kent State University at Kent
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041071101
City
Kent
State
OH
Country
United States
Zip Code
44242
Perera, Vindya S; Chen, Guojun; Cai, Qing et al. (2016) Nanoparticles of gadolinium-incorporated Prussian blue with PEG coating as an effective oral MRI contrast agent for gastrointestinal tract imaging. Analyst 141:2016-22
Kandanapitiye, Murthi S; Gott, Matthew D; Sharits, Andrew et al. (2016) Incorporation of gallium-68 into the crystal structure of Prussian blue to form K(68)GaxFe1-x[Fe(CN)6] nanoparticles: toward a novel bimodal PET/MRI imaging agent. Dalton Trans 45:9174-81
Kandanapitiye, Murthi S; Gunathilake, Chamila; Jaroniec, Mietek et al. (2015) Biocompatible D-Penicillamine Conjugated Au Nanoparticles: Targeting Intracellular Free Copper Ions for Detoxification. J Mater Chem B 3:5553-5559
Kandanapitiye, Murthi S; Wang, Fan Jennifer; Valley, Benjamin et al. (2015) Selective ion exchange governed by the Irving-Williams series in K2Zn3[Fe(CN)6]2 nanoparticles: toward a designer prodrug for Wilson's disease. Inorg Chem 54:1212-4
Kandanapitiye, Murthi S; Gao, Min; Molter, Joseph et al. (2014) Synthesis, characterization, and X-ray attenuation properties of ultrasmall BiOI nanoparticles: toward renal clearable particulate CT contrast agents. Inorg Chem 53:10189-94
Perera, Vindya S; Wickramaratne, Nilantha P; Jaroniec, Mietek et al. (2014) A Highly Efficient and Extremely Selective Intracellular Copper Detoxifying Agent Based on Nanoparticles of ZnMoS4. J Mater Chem B 2:257-261
Perera, Vindya S; Yang, Liu D; Hao, Jihua et al. (2014) Biocompatible nanoparticles of KGd(H?O)?[Fe(CN)?]·H?O with extremely high T?-weighted relaxivity owing to two water molecules directly bound to the Gd(III) center. Langmuir 30:12018-26
Kandanapitiye, Murthi S; Valley, Benjamin; Yang, Liu D et al. (2013) Gallium analogue of soluble Prussian blue KGa[Fe(CN)6]ýýnH2O: synthesis, characterization, and potential biomedical applications. Inorg Chem 52:2790-2
Wang, Hongxin; Yoda, Yoshitaka; Dong, Weibing et al. (2013) Energy calibration issues in nuclear resonant vibrational spectroscopy: observing small spectral shifts and making fast calibrations. J Synchrotron Radiat 20:683-90
Perera, Vindya S; Liu, Haijian; Wang, Zhi-Qiang et al. (2013) Cell Permeable Au@ZnMoS4 Core-Shell Nanoparticles: Towards a Novel Cellular Copper Detoxifying Drug for Wilson's Disease. Chem Mater 25:4703-4709