Research in the Morrow group is focused on the interface of inorganic chemistry, biomedical imaging, and medicinal chemistry. A central theme of our research is the preparation of new ligands and inorganic complexes for magnetic resonance imaging (MRI) of animals, including cell labeling by dual fluorescence/MRI probes. Our inorganic probes range from small molecules that contain macrocyclic ligands, amphiphilic complexes incorporated into nanoparticles such as liposomes, or metal organic polyhedral cages as hosts for metallodrugs. Recent projects feature the delivery of metal-based anticancer drugs to murine tumors encapsulated in metallocages and new imaging probes that are responsive to pH, temperature, or redox status for molecular imaging applications.
Our lab specializes in the synthesis and spectroscopic characterization of complexes for studies in laboratory flasks, in cells, and animals. Students and postdocs will be trained in organic synthesis of ligands, the preparation of metal ion complexes, and their characterization by NMR and EPR spectroscopy, cyclic voltammetry, pH potentiometric titrations, and X-ray crystallography. CEST NMR spectra and relaxivity measurements are recorded on departmental instruments. Magnetic resonance imaging experiments are done in collaboration with Roswell Park Comprehensive Cancer Center or at the Clinical and Translational Research Center at the University at Buffalo.
Mononuclear, multinuclear and nanoparticle-based iron MRI probes
Synthesis of iron(III) complexes as alternatives to gadolinium(III)-based agents
High-spin Fe(III) coordination complexes are under investigation as alternatives to Gd(III) contrast agents. Iron-based MRI probes are uniquely suited for development as contrast agents that are well tolerated, as the human body has mechanisms for transport, sequestration, and storage of this abundant transition metal. Our research in this area focuses on the preparation of high-spin Fe(III) complexes in macrocyclic or linear ligands in multinuclear or in nanoparticle (liposomal) form.1 The macrocyclic complexes stabilize the trivalent high-spin state and may provide a site with an exchangeable inner-sphere water. Our best iron MRI probes show promising solution proton relaxivity and strong T1-weighted signal in MRI studies of mice.2-4 Incorporation of the macrocyclic complexes as amphiphilic agents into liposomes give MRI probes that accumulate in murine tumors.
Representative publications
((1) Kras, E. A.; Snyder, E. M.; Sokolow, G. E.; Morrow, J. R. The Distinct Coordination Chemistry of Fe(III)-based MRI Probes. Acc. Chem. Res. 2022, 55, 1435-1444.
(2) Chowdhury, M. S. I.; Kras, E. A.; Turowski, S. G.; Spernyak, J. A.; Morrow, J. R. Liposomal MRI probes containing encapsulated or amphiphilic Fe(iii) coordination complexes. Biomater Sci 2023, 11 (17), 5942-5954.
(3) Asik, D.; Abozeid, S. M.; Turowski, S. G.; Spernyak, J. A.; Morrow, J. R. Dinuclear Fe(III) Hydroxypropyl-Appended Macrocyclic Complexes as MRI Probes. Inorg Chem 2021, 60 (12), 8651-8664.
(4) Cineus, R.; Abozeid, S. M.; Sokolow, G. E.; Spernyak, J. A.; Morrow, J. R. Fe(III) T(1) MRI Probes Containing Phenolate or Hydroxypyridine-Appended Triamine Chelates and a Coordination Site for Bound Water. Inorg Chem 2023, 62 (40), 16513-16522.
Molecular imaging agents
Iron, cobalt, or nickel probes that respond to changes in physiological environment
Molecular magnetic resonance imaging agents report on changes in physiological environment or in biochemical processes that are characteristic of disease states to give additional information not provided by standard MRI probes. We design coordination complexes that register changes in pH, temperature, or redox status through changes in relaxivity, proton chemical shift, or modulation of chemical exchange saturation transfer (CEST) effects. For example, we have prepared paramagnetic Co(II) CEST probes that produce signal through amide NH group exchange with water protons.5 The pH sensitivity of these peaks can be used to register pH in the range of 6.5 to 7.4 as ratiometric probes towards mapping extracellular tumor pH, as shown below.6 A few such Co(II) complexes have been studied as liposomal CEST agents.7 Co(II) complexes with fluorophore tags are used as cell-based CEST agents.8 Fe(II) complexes that produce a shift of the NH peak position upon changes with pH are also promising.9 A second type of responsive probe features oxidation and/or spin state changes as a function of redox environment.10 Fe(II)/Fe(III) and Co(II)/Co(III) complexes are under study as redox-responsive paramagnetic CEST agents or T1 agents.
Representative Publications.
(5) Raymond, J. J.; Abozeid, S. M.; Sokolow, G. E.; Bond, C. J.; Yap, C. E.; Nazarenko, A. Y.; Morrow, J. R. Co(II) complexes of tetraazamacrocycles appended with amide or hydroxypropyl groups as paraCEST agents. Dalton Trans 2023, 52 (28), 9831-9839.
(6) Bond, C. J.; Cineus, R.; Nazarenko, A. Y.; Spernyak, J. A.; Morrow, J. R. Isomeric Co(ii) paraCEST agents as pH responsive MRI probes. Dalton T 2020, 49 (2), 279-284.
(7) Abozeid, S. M.; Asik, D.; Sokolow, G. E.; Lovell, J. F.; Nazarenko, A. Y.; Morrow, J. R. CoII Complexes as Liposomal CEST Agents. Angew Chem Int. Ed. 2020, 132 (29), 12191-12195.
(8) Patel, A.; Abozeid, S. M.; Cullen, P. J.; Morrow, J. R. Co(II) Macrocyclic Complexes Appended with Fluorophores as paraCEST and cellCEST Agents. Inorg Chem 2020, 59 (22), 16531-16544.
(9) Tsitovich, P. B.; Cox, J. M.; Spernyak, J. A.; Morrow, J. R. Gear Up for a pH Shift: A Responsive Iron(II) 2-Amino-6-picolylAppended Macrocyclic paraCEST Agent That Protonates at a Pendent Group. Inorg Chem 2016, 55 (22), 12001-12010.
(10) Morrow, J. R.; Raymond, J. J.; Chowdhury, M. S. I.; Sahoo, P. R. Redox-Responsive MRI Probes Based on First-Row Transition-Metal Complexes. Inorg Chem 2022, 61 (37), 14487-14499.
Metallocages for magnetic resonance imaging and drug delivery
Design of MOPs as T1 MRI probes and study of their host-guest properties
An approach to further increase the signal from the paramagnetic probe involves the incorporation of multiple centers in a metal organic polyhedron or metallocage. Our initial studies used the tetrahedral iron(III) cages originally developed by the Raymond group.11 The four rigidly-connected iron centers in the anionic cage produce a high relaxivity MRI probe. The naphthyl groups enable binding to serum albumin to give a blood pool agent that accumulates in tumors. Recent studies show that gold metallodrugs act as guests within the cage under biological conditions. These Au(I) complexes are solubilized in aqueous solution and produce a unique biodistribution upon intravenous injection in animals, including increased tumor uptake. Studies are underway to examine the theragnostic potential of these agents.
(11) Sokolow, G. E.; Crawley, M. R.; Morphet, D. R.; Asik, D.; Spernyak, J. A.; McGray, A. J. R.; Cook, T. R.; Morrow, J. R. Metal-Organic Polyhedron with Four Fe(III) Centers Producing Enhanced T1 Magnetic Resonance Imaging Contrast in Tumors. Inorg Chem 2022, 61 (5), 2603-2611.