Metal-Mediated, Autolytic Amide Bond Cleavage: A Strategy for the Selective, Metal Complexation-Catalyzed, Controlled Release of Metallodrugs.

Activation of metalloprodrugs or prodrug activation using transition metal catalysts represents emerging strategies for drug development; however, they are frequently hampered by poor spatiotemporal control and limited catalytic turnover. Here, we demonstrate that metal complex-mediated, autolytic release of active metallodrugs can be successfully employed to prepare clinical grade (radio-)pharmaceuticals. Optimization of the Lewis-acidic metal ion, chelate, amino acid linker, and biological targeting vector provides means to release peptide-based (radio-)metallopharmaceuticals in solution and from the solid phase using metal-mediated, autolytic amide bond cleavage (MMAAC). Our findings indicate that coordinative polarization of an amide bond by strong, trivalent Lewis acids such as Ga ³⁺ and Sc ³⁺ adjacent to serine results in the N, O acyl shift and hydrolysis of the corresponding ester without dissociation of the corresponding metal complex. Compound [ ⁶⁸ Ga]Ga- 10 , incorporating a cleavable and noncleavable functionalization, was used to demonstrate that only the amide bond-adjacent serine effectively triggered hydrolysis in solution and from the solid phase. The corresponding solid-phase released compound [ ⁶⁸ Ga]Ga- 8 demonstrated superior in vivo performance in a mouse tumor model compared to [ ⁶⁸ Ga]Ga- 8 produced using conventional, solution-phase radiolabeling. A second proof-of-concept system, [ ⁶⁷ Ga]Ga- 17A (serine-linked) and [ ⁶⁷ Ga]Ga- 17B (glycine-linked) binding to serum albumin via the incorporated ibuprofen moiety, was also synthesized. These constructs demonstrated that complete hydrolysis of the corresponding [ ⁶⁸ Ga]Ga-NOTA complex from [ ⁶⁷ Ga]Ga- 17A can be achieved in naïve mice within 12 h, as traceable in urine and blood metabolites. The glycine-linked control [ ⁶⁸ Ga]Ga- 17B remained intact. Conclusively, MMAAC provides an attractive tool for selective, thermal, and metal ion-mediated control of metallodrug activation compatible with biological conditions.