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

Bruno L Oliveira,V B Unnikrishnan,Felipe S S Schneider,Cátia Rebelo De Almeida,Rita Fior,Magda Negrão,Miguel Godinho Ferreira,João Conde,Josiel B Domingos,Benjamin J Stenton,Carlos Cordeiro,Gonçalo J L Bernardes,Giovanni F Caramori

doi:10.1021/jacs.0c01622

Abstract

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.

Highlights

The targeting of potent drugs with tumor-specific ligands is an essential feature of drug delivery and cancer therapy.[1]
The cleavage of antibody−drug conjugates (ADCs) linkers with endogenous triggers is the simplest method for drug release, external small-molecule triggers for extracellular drug release may be more advantageous because they avoid any disparity in cleavage rates caused by variable biology across subjects, and drug release is not dependent on the concentrations of cellular triggers.[4−7] ADCs built with protease cleavable linkers for drug release have been shown recently to not depend on the cathepsin B protease function for efficient and targeted cancer-cell killing.[4]
By using a noninternalizing ADC consisting of a diabody conjugated to trans-cyclooctene-linked drug monomethyl auristatin E (MMAE),[10] the allylic carbamate-containing linker can rapidly react with a tetrazine through an inverse-electron-demand Diels−Alder reaction.[10,11]

Summary

■ INTRODUCTION

The targeting of potent drugs with tumor-specific ligands is an essential feature of drug delivery and cancer therapy.[1]. In a similar fashion, decaging of pFU proceeds with yields of 46% ± 2 and 72% ± 2 for K2PtCl4 and CisPt, after 14 h reaction with 2 equiv, at room temperature and 37 °C, respectively (Figures S35−S37) These prodrugs (MMAE-am 11 and pFU 12, see the SI for synthetic details) were reacted with platinum salts in cell culture in the hope of observing a “turn-on” of toxicity. This deactivation of the metals in the presence of nucleophiles is in line with the modest decaging yields observed in the cell studies This is an issue that could be further improved, for example, by using platinum-based nanoparticles known to have reduced toxicity and higher payload concentrations or by using platinum complexes stabilized with different organic ligands in a way to optimize the metal reactivity.[62] Our data, demonstrate that decaging reactions with platinum complexes are possible in cell culture and could achieve release of sufficient amounts of the active drug in cells to induce cell death. Presence of nontherapeutic amounts of the anticancer drug CisPt in an in vivo setting

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES