Biofunctionalised nanoparticles - new MRI contrast agents

Research within this project is based on the discovery of unique magnetic properties of nanosized materials. Gadolinium-containing nanoparticles can be used as tracers in molecular Magnetic Resonance Imaging (mMRI) for functional assessment of human tissue. These particles are designed for MRI applications, with high potential for microscopic imaging. The main advantages are the high contrast efficacy for each particle and the capacity to provide positive contrast, i.e. signal enhancement.

• Staff:

Maria Engström , PhD		Project manager		CMIV, IMV/Radiology
Anna Klasson , MSc		Medical biology		CMIV, IMV/Radiology
Kajsa Uvdal , Assoc. Prof.		Co-manager		IFM/Physics, Chemistry, and Biology
Per-Olof Käll , Assoc. Prof.		Synthesis		IFM/Physics, Chemistry, and Biology
Anders Rosén , Prof.		Cell biology		IKE/Cell Biology
Helene Zachrisson , MD/PhD		Clinical physiology		IMV/Clinical Physiology
Jan-Ingvar Jönsson , Prof.		Cell biology		IKE/Cell Biology
Marcel Warntjes , PhD		MR-physics		CMIV
Håkan Gustafsson , PhD		MR-physics		IMH/Radiology and Radiation Physics
Maria Ahrén , MSc		Material		IFM/Physics, Chemistry, and Biology
Fredrik Söderlind , PhD		Synthesis		IFM, Physics, Chemistry, and Biology

• Former Staff:

• Project Description:


Background
In recent time, MRI technology has developed from imaging anatomical structures to functional imaging. Novel possibilities for the life sciences are detection of molecular interaction and gene expression by means of nanotechnology and high-throughput MRI. Active research is also directed to in vivo mMRI using nanoparticles as tracers. Such tracers should have high contrast efficacy for each single particle and they should be functionalised for detection of molecular processes of interest. Preferentially, they should give positive contrast, which imply signal enhancement. The gadolinium-containing nanoparticles used in this project provide high positive contrast and they can also be functionalised for molecular targeting.

Molecular MRI
It has been shown that superparamagnetic iron oxide particles (SPIO) can be used as probes for molecular interactions. These are measured with high efficiency and sensitivity using magnetic resonance methods including MRI. The advantage with this approach compared to other screening methods is the possibility to use biological samples with minimal or no sample preparation. Morawski et al. show that it is possible to quantify molecular epitopes in picomolar concentration in single cells with clinical MRI equipment using perfluorocarbon nanoparticles loaded with gadolinium as contrast agent. Molecular imaging for early detection of atherosclerotic plaques is one example of important clinical applications. It has been shown that integrin targeted nanoparticles can be used for mMRI of angiogenesis in early stage of atherosclerosis. Vulnerable plaques can also be detected by fibrin specific contrast agents.
Several studies have shown that SPIOs can be used for cell tracking. Cells internalise nanoparticles either through phagocytosis or specific labelling with suitable ligands. Successful results from in vivo cell tracking with SPIOs are reported in several studies. For example, the distribution of transplanted pancreatic islets can be followed by magnetically labelled cells and atherosclerotic plaques can be detected through macrophage nanoparticle phagocytosis. It has also been shown that single cell imaging is possible with a clinical 1.5 T MRI scanner. In one of our studies, monocyte cells were incubated with Gd2O3 nanoparticles and imaged by MRI with high differentiation in signal intensity depending on Gd concentration in the cells.

Magnetic tracers
Molecular imaging is feasible by means of MRI contrast agents. The contrast in MRI images is altered by these agents due to their influence on the longitudinal, T1, and transverse, T2, relaxation times of hydrogen nuclei in tissue. Today, MRI contrast agents comprise paramagnetic complexes or SPIOs. Owing to the unique magnetic properties of gadolinium, chelates of Gd(III) are most commonly used as contrast agents in clinical MRI. However, the relative weak signal intensity enhancement for each single complex makes those chelates less suitable for molecular imaging. Preparation of biocompatible nanoparticles with high signal enhancement ability for each particle pave the way for a new generation of MRI contrast agents. We have shown that nanoparticles of Gd2O3 induce at least doubled proton relaxivity per mM Gd and resulting signal increase as compared to a Gd chelate in clinical use.
Nanoparticles are promising candidates for molecular imaging compared to chelates because they convey the possibility to high relaxivity per molecular binding site. Using nanoparticles with a ligand specific for a certain tissue, will enhance the local contrast owing to the high relaxivity of each particle. Today, SPIOs are the most widely applied contrast agents in the field of mMRI. These particles are mainly T2 relaxation agents, which implies that the main effect in MRI is to reduce the signal intensity. For many applications a positive contrast agent that increases the signal intensity would be advantageous. Gadolinium-containing nanoparticles are such T1 relaxation agents with excellent contrast enhancement properties.


References
ARTICLES
H. Gustafsson, M. Ahrén, F. Söderlind, J. Cordoba, P-O Käll, P. Nordblad, P-O Westlund, K. Uvdal, M. Engström. Magnetic and Electron Spin Relaxation Properties of (GdxY1-x)2O3 (0 ≤ x ≤1) Nanoparticles Synthesized by the Combustion Method. Increased Electron Spin Relaxation Times with Increasing Yttrium Content. J. Phys. Chem. C, 115: 5469-5477, 2011.

M. Ahrén, L Selegård, A Klasson, F Söderlind, N Abrikossova, C Skoglund, T Bengtsson, M Engström, P-O Käll, K Uvdal. Synthesis and characterization of PEGylated Gd2O3 nanoparticles for MRI contrast enhancement. Langmuir, 26:5753-5762, 2010

R. M. Petoral Jr., F. Söderlind, A. Klasson, A. Suska, M. A. Fortin, P-O Käll, M, Engström, K. Uvdal. Synthesis and characterization of Tb3+ doped Gd2O3 nanocrystals: A bifunctional material with combined fluorescent labeling and MRI contrast agent properties. J. Phys. Chem. C, 113:6913-6920, 2009.

A. Klasson, M. Ahrén, E. Hellqvist, F. Söderlind, A. Rosén, P-O Käll, K. Uvdal, and M. Engström. Positive MRI contrast enhancement in THP-1 cells with Gd2O3 nanoparticles. Contrast Media & Molecular Imaging, 3:106-111, 2008.

F. Söderlind, M-A Fortin, R. M. Petoral Jr, A. Klasson, T. Veres, M. Engström, K. Uvdal, and P-O Käll. Colloidal synthesis and characterization of ultrasmall perovskite GdFeO3 nanocrystals. Nanotechnology, 19 (2008) 085608.

M-A Fortin, R. M. Petoral Jr, F. Söderlind, A. Klasson, M. Engström, T. Veres, P-O Käll, and K. Uvdal. PEG-covered ultra-small Gd2O3 nanoparticles for positive contrast at 1.5 T MR clinical scanning. Nanotechnology 18:1-9, 2007.

High proton relaxivity for gadolinium oxide nanoparticles. M. Engström, A. Klasson, H. Pedersen, C. Vahlberg, P-O Käll and K. Uvdal. MAGMA,19:180-186, 2006.