A promising approach to target treatment resistant cancers is hyperthermia-induced release of drugs from thermally sensitive liposomes. This approach would be enabled by methods that track liposome deposition into tumor and subsequent drug release as a function of temperature. A new class of compounds containing iron (Fe(II)) coordination complexes will be developed to track liposome uptake into tumors and to monitor the liposome temperature. Our Fe(II) complexes produce contrast through chemical exchange saturation transfer (CEST) of exchangeable NH protons on amide or amino-pyridine groups that have proton resonances which are highly shifted from that of bulk water by the paramagnetic Fe(II) center (ferroCEST agents). Application of a radiofrequency pulse at the exchangeable proton resonance frequency saturates the magnetization of these protons and, through exchange, decreases the magnetization of the bulk water proton pool. Initial studies indicate that the CEST peak position of our ferroCEST agents is directly proportional to temperature over the range of 30-50 oC. This concentration independent shift leads to MRI thermometry agents that can be calibrated directly to temperature. Our specific goals are to develop Fe(II) PARACEST agents for incorporation into the lipid bilayer. These ferroCEST agents will contain long hydrocarbon tails and will be overall anionic, neutral or cationic in charge. The ferroCEST agents will be combined with commercially available lipids to form a series of liposomes, some of which are anticipated to be thermally sensitive over the desired range of 40-41 oC. The temperature dependence of the CEST peak will be determined in vitro by studies on a NMR spectrometer and in imaging phantoms on a 4.7 T MRI scanner. Initial in vivo studies of PARACEST thermometry of the Fe(II) complexes will be carried out by performing localized hyperthermia in murine colon carcinoma tumor in mice and performing CEST-imaging during treatment. Water proton frequency resonance (PFR) thermometry will be used to verify changes in tumor temperature. A long-term goal is to develop ferroCEST containing liposomes that are non-toxic, biodegradable and useful for measuring liposomal drug delivery and MR thermometry during hyperthermia or ablation therapies.
A promising approach to target treatment resistant cancers is hyperthermia-induced release of drugs from thermally sensitive liposomes. This approach would be enabled by methods that track the liposome uptake into tumor and subsequent drug release as a function of temperature. We propose to develop iron based MRI contrast agents (CAs) incorporated into liposomes for the registration of temperature by MRI. These systems utilize iron, a biologically relevant metal ion, towards the development of non-toxic CAs.
|Tsitovich, Pavel B; Cox, Jordan M; Benedict, Jason B et al. (2016) Six-coordinate Iron(II) and Cobalt(II) paraSHIFT Agents for Measuring Temperature by Magnetic Resonance Spectroscopy. Inorg Chem 55:700-16|
|Olatunde, Abiola O; Bond, Christopher J; Dorazio, Sarina J et al. (2015) Six, Seven or Eight Coordinate Fe(II) , Co(II) or Ni(II) Complexes of Amide-Appended Tetraazamacrocycles for ParaCEST Thermometry. Chemistry 21:18290-300|