Development of Theranostic and Bioresponsive Small Molecule Magnetic Resonance Imaging Contrast Agents

Adams, Casey

doi:https://doi.org/10.21985/n2-kbx9-v828

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Development of Theranostic and Bioresponsive Small Molecule Magnetic Resonance Imaging Contrast Agents

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Biomedical imaging is an essential part of medicine that enables the non-invasive observation of biological phenomena. This, in turn, allows for more accurate and earlier diagnoses, monitoring of therapies, and even fundamental research into biological processes. Molecular imaging, a fast-growing subdiscipline of biomedical imaging, seeks to image biochemical processes at the cellular level and beyond. There are a variety of imaging modalities used in molecular imaging, such as fluorescence, positron emission tomography (PET), single photon emission computed tomography (SPECT), computed tomography (CT), and magnetic resonance imaging (MRI), each of which have benefits and drawbacks. MRI is a uniquely powerful imaging modality, as it is safe, has unlimited depth penetration (can image any part of the body), and provides unparalleled soft tissue contrast and anatomical information. However, it suffers from poor sensitivity, and therefore contrast agents are commonly used to enhance the signal. Gd(III) based contrast agents (GBCAs) result in brighter contrast where present and have multiple parameters that affect their relaxivity (i.e. how well they behave as contrast agents). Targeting groups can be added to GBCAs to image biological targets of interest and bioresponsive groups can be added that change the relaxivity of Gd(III) in response to a stimulus, providing a way of imaging biochemical processes. As such, there is a wide variety of ways in which GBCAs can be used for molecular imaging. The first two uses of GBCAs described in this thesis (chapters 2 and 3) involve Gd-Pt theranostic agents. Theranostics enable simultaneous imaging and therapy through combining a therapeutic with a diagnostic. In the first case, Gd(III)-Pt(II) theranostics were developed to image chemoresistance to Pt(II) drugs (e.g. cisplatin), which are among the most important cancer therapeutics. By coupling a GBCA to a cisplatin-like moiety, we were able to image agent accumulation differences in chemosensitive and chemoresistant tumors using MRI. Decreased drug accumulation is a hallmark of chemoresistance, therefore this method is a promising first step towards the ability to image Pt(II) chemoresistance. Future work will involve optimizing these Gd(III)-Pt(II) agents and performing more in depth in vivo experiments to establish the ability of the agents to predict chemoresistance. Chapter 3 describes the development of Gd(III)-Pt(IV) theranostic agents. Pt(IV) complexes are commonly used in prodrug strategies because they are non-toxic in the IV oxidation state but can be reduced by biologically relevant reducing agents to an active cytotoxic Pt(II) complex. By coupling a GBCA to a Pt(IV) cisplatin prodrug, we were able to deliver Gd(III) intracellularly, whereas all clinically used GBCAs are limited to the extracellular space. Because the agent releases cisplatin, it was significantly more cytotoxic than the Gd(III)-Pt(II) agents previously described. Therefore, these Gd(III)-Pt(IV) agents are a promising platform for effective tandem chemotherapy and MR imaging. Future work will involve incorporating additional diagnostic and therapeutic moieties onto the Gd(III)-Pt(IV) agents for multimodal imaging and combination therapy. Chapter 4 describes the development of a Ca(II) responsive GBCA with high cellular uptake and NIR fluorescence capability. The agent increases its relaxivity >100% (at 7 T) in the presence of Ca(II), enabling detection of intracellular Ca(II) flux. A derivative of a NIR fluorescent dye, IR-783, was incorporated to target organic anion transporter polypeptides (OATPs) on cells. We found that the incorporation of IR-783 drastically increased the cellular accumulation of the agent (>10 fmol/cell), resulting in significant intracellular contrast enhancement, especially when Ca(II) flux was induced. In vivo experiments imaging neuronal activity in mouse brains are currently underway.

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