Monofunctional platinum-acridine antitumor agents have shown promising activity in non-small cell lung cancer (NSCLC), however were found to suffer from severe systemic toxicity, which potentially limits their clinical applications. Here, we present novel conjugation strategies based on chemically modified platinum-acridine �warheads� to improve the tumor-targeting ability and extend the anticancer spectrum of this agent.  To target estrogen receptor (ER)-positive breast cancer, (Z)-tamoxifen and endoxifen were chosen as the targeting moieties covalently attached to a hydroxyl-modified platinum-acridine analog using a (enzymatically) cleavable carbamate bond. The relative binding affinities (RBA) of the conjugates were determined using a competitive radiometric binding assay. The cell damage was measured using MTS assays in the ER-positive cell line MCF-7 and the triple-negative breast cancer cell line MDA-MB-231. In addition, clickable azide-modified platinum-acridine derivatives were developed as targetable warheads and as fluorescently detectable probes for further mechanistic study of platinum-acridine antitumor agents.

Development and evaluation of novel conjugation chemistries for the targeted delivery and cellular imaging of potent platinum-acridine anticancer agents

243rd National Meeting (2012)

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