High Cytotoxic Effect by Combining Copper-64 with a NOTA-Terpyridine Platinum Conjugate

Terpyridine platinum (TP)-based chemotherapeutic agents target three-dimensional structures on DNA known as G-quadruplexes. We report the rational design and synthesis of a TP conjugate combined with copper-64 (⁶⁴Cu), the decay characteristics of which include emission of β^- and Auger electrons for radiotherapy and β⁺ particles for positron emission tomography (PET) imaging. The present experimental studies show that the novel [⁶⁴Cu]Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-TP is stable, permitting selective killing of cancer cells. The antitumor activity of [⁶⁴Cu]Cu-NOTA-TP at high apparent molar activity is in the low nanomolar range and 27,800-fold greater than that of ^natCu-NOTA-TP at 24 h post treatment. These results suggest that this combination of a cytotoxic TP agent with ⁶⁴Cu has considerable potential for cancer treatment and PET imaging.