Towards Imaging Pt Chemoresistance Using Gd(III)‐Pt(II) Theranostic MR Contrast Agents

Abstract

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.

Metallodrugs in cancer nanomedicine

“…It is not surprising that this versatile Pt(IV) prodrug chemistry has resulted in a considerable number of reported dual, [120][121][122] triple [123][124][125][126][127] and even quadruple 128 action Pt(IV) complexes that aim to interact with multiple cellular targets and processes via a single structure which, once reduced in cancer cells to the active Pt(II), releases the axially bound bioactive scaffolds as well. [129][130][131][132] This approach has even been expanded towards multi-metal compounds for (but not limited to) photo-chemotoxicity (e.g., Pt(IV)-Ru(II) 133 and Pt(IV)-Re(I) 134 ) and theranostic purposes (Gd(III)-Pt(IV) 135 for MRI), which offer higher speciation control over the equatorial modification of Pt(II) compounds (e.g., Pt(II)-Ru(II) 136,137 or Gd(III)-Pt(II) 138 ). This and other potential options for combined therapies by chemical functionalization will be further discussed in Section 2.2.…”

“…, Pt( iv )–Ru( ii ) 133 and Pt( iv )–Re( i ) 134 ) and theranostic purposes (Gd( iii )–Pt( iv ) 135 for MRI), which offer higher speciation control over the equatorial modification of Pt( ii ) compounds ( e.g. , Pt( ii )–Ru( ii ) 136,137 or Gd( iii )–Pt( ii ) 138 ). This and other potential options for combined therapies by chemical functionalization will be further discussed in Section 2.2.…”

Molecular Engineering of Self-Immolative Bioresponsive MR Probes

“…The increase in q and τ r leads to a higher r 1 under an optimal τ m state. Our research has focused on a q -enhancement strategy, and we have developed several platforms of bio-responsive Gd­(III) agents for in vivo tracking of enzyme activity, gene expression, Ca­(II) and Zn­(II), and imaging gene therapy. − …”