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Cisplatin and related Pt(II) chemotherapeutics are indispensable tools for the treatment of various solid tumors. Despite their widespread clinical use in approximately 50 % of chemotherapy regimens, they are hindered by issues with off-target toxicity and chemoresistance, both innate and acquired. To date, there is no effective way to predict the outcome of Pt(II) chemotherapy because the genes associated with resistance are not completely known or understood. Instead, patients undergo weeks to months of potentially harmful therapy before knowing if it is effective. Here we report two Gd(III)-Pt(II) theranostic MR contrast agents that contain cisplatin and carboplatin-based moieties respectively. We used these agents to demonstrate that accumulation differences in Pt(II) sensitive and resistant cells, a dominant factor in chemoresistance, can be imaged by MR. Both theranostic agents bind to DNA, are cytotoxic, and enhance the intracellular T1 -weighted MR contrast of multiple cell lines. Most importantly, the cisplatin-based agent accumulates less in Pt(II) resistant cells in vitro and in vivo, resulting in decreased MR contrast enhancement compared to the parent Pt(II) sensitive cell line. This straightforward method to image a key factor of Pt(II) resistance using MRI is an important first step towards the ultimate goals of predicting response to Pt(II) chemotherapy and monitoring for the onset of chemoresistance - a critical unmet need in medicine that could significantly improve patient outcomes.

New bifunctional hexa- and octadentate analogues of the hydroxamate-containing siderophore desferrichrome (DFC) have been synthesized and evaluated as 89Zr-chelating agents for immunoPET applications. The in vitro and in vivo inertness of these new ligands, Orn3-hx (hexadentate) and Orn-4hx derivatives (octadentate), was compared to the gold standard hexadentate, hydroxamate-containing chelator for 89Zr desferrioxamine (DFO). Density functional theory was employed to model the geometries of the resulting Zr(IV) complexes and to predict their relative stabilities as follows: Zr(Orn4-hx) > Zr(DFC) > Zr(Orn3-hx). Transchelation challenge experiments of the corresponding radiochemical complexes with excess ethylenediaminetetraacetate (EDTA) indicated complex stability in accordance with DFT calculations. Radiolabeling of these ligands with 89Zr was quantitative (0.25 μmol of ligand, pH 7.4, room temperature, 20 min). For antibody conjugation, the isothiocyanate (NCS) functional group was introduced to the N terminus of Orn3-hx and Orn-4hx. An additional trifunctional derivative that bears a silicon-rhodamine fluorophore on the C-terminus and NCS on the N terminus was also furnished. As proof of concept, all NCS derivatives were conjugated to the HER2-targeting antibody, trastuzumab. Radiolabeling of immunoconjugates with 89Zr was accomplished with radiochemical yields of 16 ± 2% to 95 ± 2%. These constructs were administered to naive mice (male, C57BL/6J, n = 4) to assess in vivo inertness, which is inversely correlated with uptake of 89Zr in bone, after 96 h circulation time. We found bone uptake to range from 7.0 ± 2.2 to 10.7 ± 1.3% ID/g, values that compare well to the corresponding DFO conjugate (7.1 ± 0.8% ID/g). In conclusion, we have rationally designed linear, bifunctional and trifunctional desferrichrome analogues suitable for the mild and inert radiolabeling of antibodies with the radionuclide 89Zr.