Platinum-Triggered Bond-Cleavage of Pentynoyl Amide and N-Propargyl Handles for Drug-Activation.

The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions, the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.

Bioorthogonal Decaging Reactions for Targeted Drug Activation.

Bioorthogonal decaging reactions are highly selective transformations which involve the cleavage of a protecting group from a molecule of interest. Decaging reactions can be classified into subgroups depending on the nature of the trigger; they can be photo-, metal- or small molecule-triggered. Due to their highly selective and biocompatible nature, they can be carried out in living systems as they do not interfere with any endogenous processes. This gain-of-function allows controlled activation of proteins and release of fluorophores and drugs in vivo. Although there are many examples of fluorophore/protein release, this review focuses on the application of bioorthogonal decaging reactions for targeted drug activation. One strategy for targeted drug delivery is tissue-selective activation of prodrugs and antibody-drug conjugates (ADCs). Bioorthogonal decaging provides a highly selective, controllable method for activating prodrugs and ADCs, reducing toxicity due to the off-target drug release that occurs in endogenous activation strategies. Here we focus on the development of bifunctional linkers that enable studies of bioorthogonal chemistry for activation of ADCs.

A thioether-directed palladium-cleavable linker for targeted bioorthogonal drug decaging.

We describe the development of a bifunctional linker that simultaneously allows site-specific protein modification and palladium-mediated bioorthogonal decaging. This was enabled by a thioether binding motif in the propargyl carbamate linker and a readily available palladium complex. We demonstrate the efficiency of this reaction by controlled drug release from a PEGylated doxorubicin prodrug in cancer cells. The linker can be easily installed into cysteine bearing proteins which we demonstrated for the construction of an anti-HER2 nanobody-drug conjugate. Targeted delivery of the nanobody drug conjugate showed effective cell killing in HER2+ cells upon palladium-mediated decaging.