Metal-mediated, Autolytic Amide Bond Cleavage for the Selective, Metal-Complexation Catalyzed, Controlled Release of Metallodrugs

Background

Clinically viable prodrugs release activated drug molecules at the site of interest, requiring close spatiotemporal control. Bond cleavage strategies for the release of the activated drug often incorporate triggers such as pH, UV irradiation, or enzyme proteolysis. The reliance on such triggers to modulate drug selectivity, function, and pharmacokinetics can drastically limit drug eﬃcacy and applicability. Stimulus-responsive prodrugs involving metal ions also depend on external stimuli or catalyst concentration, which can limit the threshold abundance of the biological target. Selective, metal ion-mediated amide bond cleavage is a well-characterized process in nature and has been used for prodrug activation. However, current strategies are limited in vivo by their reliance on labile metal ion binding and bimolecular reaction mechanisms.

Technology

The Boros lab has developed a new radiopharmaceutical agent as an imaging agent that will release a metallodrug containing Gallium-67/68, Scandium-3, or Copper-3 to the tumor sites. Unlike traditional imaging agents, the new compound will be able to release the metallodrug without the need to use other potentially harmful activation techniques such as changing the pH or UV light exposure, which are invasive procedures. Once the compound has been exposed for long enough to normal body heat, the metallodrug will be released by a N-O acyl shift, as to preemptively cleave the amide bonds holding the radiometals. Once the acyl shift has been performed, the local pH will lower to 5.5 with an immediate adjustment of the reaction temperature. This gives the biomarker guide enough time to deliver the radiometal to the desired tumor sites without having to use a large amount of imaging agents.

Advantages

Autolytic, independent release of metallodrug - Not dependent on exogenous catalyst concentrations - Improved in vivo performance of high-molar-activity radiopharmaceuticals - Less intrusive and damaging than current methods