# Transmetalation in Cancer Pharmacology

## TL;DR

Transmetalation, the swapping of metal ions in cancer drugs, can be used to activate therapies inside tumor cells, reducing side effects and improving treatment.

## Contribution

The paper introduces transmetalation as a generalizable therapeutic strategy in cancer pharmacology, using metal ion exchange to activate drugs selectively in tumor cells.

## Key findings

- Redox-inert metal complexes can convert to redox-active forms in acidic lysosomes, generating ROS and depleting iron in tumor cells.
- Steric and electronic factors influence transmetalation kinetics and metal exchange hierarchies in thiosemicarbazones.
- Transmetalation strategies like chemical transferrin mimetics demonstrate a 'Trojan horse' approach for targeted cancer therapy.

## Abstract

Transmetalation, the exchange of metal ions between coordination complexes and biomolecules, has emerged as a powerful design lever in cancer metallopharmacology. Using thiosemicarbazones (TSCs) as a unifying case study, we show how redox-inert carrier states such as zinc(II) or gallium(III) can convert in situ into redox-active copper(II) or iron(III/II) complexes within acidic, metal-rich lysosomes. This conditional activation localizes reactive oxygen species (ROS) generation and iron deprivation to tumor cells. We critically compare redox-active and redox-inert states, delineating how steric and electronic tuning, backbone rigidity, and sulfur-to-selenium substitution govern exchange hierarchies and kinetics. We further map downstream consequences for metal trafficking, lysosomal membrane permeabilization, apoptosis, and ferroptosis. Beyond TSCs, iron(III)-targeted transmetalation from titanium(IV)-chelator “chemical transferrin mimetics” illustrates a generalizable Trojan horse paradigm. We conclude with translational lessons, including mitigation of hemoprotein oxidation via steric shielding, stealth zinc(II) prodrugs, and dual-chelator architectures and outline biomarker, formulation, and imaging strategies that de-risk clinical development. Collectively, these insights establish transmetalation as a central therapeutic principle. We also highlight open challenges such as quantifying in-cell exchange kinetics, predicting speciation under non-equilibrium conditions, and rationally combining these agents with existing therapies.