Bioinorganic chemistry: Magnetic resonance imaging contrast agents based on iron, cobalt or nickel, bimodal (fluorescent) probes, ligand synthesis, self-assembled multinuclear iron complexes for imaging and drug delivery, yeast cell labeling with inorganic complexes.
The central theme in our research is the synthesis of inorganic complexes for biomedical diagnostics, sensing, therapeutics or catalytic applications.
Current research in our laboratories focuses on the following topics:
Magnetic resonance imaging probes that are responsive to biological environment
Paramagnetic metal ion complexes are widely used in clinical medicine as contrast agents for MRI. We have developed the first examples of paramagnetic transition metal complexes that act as chemical exchange saturation transfer agents (paraCEST). ParaCEST agents produce contrast that can be turned on and off with a presaturation pulse, eliminating the need for pre- and post-contrast agent MRI scans.
Metal ions with excellent magnetic properties for paraCEST include the biologically relevant metal ions Fe(II), Co(II) and Ni(II). We have prepared macrocyclic complexes of these metal ions that are inert towards dissociation and are in high spin form. These complexes produce intense CEST contrast that is shifted far from the signal from bulk water in tissue. These complexes are being further developed and tested in vivo in collaboration with Roswell Park Comprehensive Cancer Center imaging scientists.
Our paraCEST contrast agents are sensitive to temperature and to pH and are under development for mapping temperature and pH in tissue. Complexes that have multiple CEST peaks are especially promising in this regard for ratiometric imaging (see figure below). Tuning the redox properties of the iron and cobalt complexes produces paraCEST agents that switch on and off according to redox potential. For example, cobalt complexes are magnetic switches that proceed from paramagnetic Co(II) to diamagnetic Co(III) complexes upon reaction with oxygen. Co(II) complexes have been incorporated into liposomes to increase the sensitivity of these probes through lipoCEST.
Iron(III) coordination complexes as alternatives to Gadolinium(II) MRI contrast agents.
High spin Fe(III) complexes show great promise as contrast agents that increase relaxation of water protons for T1 weighted MRI. Our group has produced a new class of macrocyclic Fe(III) complexes that produce water proton relaxivity in serum that rivals that of clinically used Gd(III) complexes. These iron complexes do not have an exchangeable water ligand, but function through second-sphere water interactions and also through proton exchange.
The synthetic chemistry of the Fe(III) macrocyclic complexes is quite versatile, allowing us to change ancillary groups to tune the biodistribution and pharmacokinetics of clearance from mice. The overall charge and lipophilicity of the complexes is varied in order to produce a strong signal in the vasculature and for rapid renal clearance. Complexes that bind tightly to serum albumin for use as blood pool agents are also being studied.
Yeast-derived Β-glucan particles (GPs) are hollow shells that act as carriers for drugs and imaging probes. The GPs are promising for targeting immune cells including macrophages and monocytes. Fe(III) complexes with open coordination sites bind strongly to GPs and are released upon treatment with mild acid or a chelator. The iron-loaded GPs are taken up by macrophages, opening up the possibility of targeting macrophages in tumors for imaging.
Cell labeling with metal complexes for tracking in vivo.
Studies are underway to label yeast cells for tracking yeast infections in animals. Fe(III) complexes bind to the cell wall of yeast enhance the T2 water proton relaxation in a shape dependent manner. Studies are underway to optimize conditions for uptake in various types of yeast including in Candida Albicans in yeast and hyphal form.