Evaluation of Active and Passive Targeting Drug Delivery Systems as a Mechanism to Improve the Anticancer Potential of Titanium(IV).

Titanium(IV) compounds are promising anticancer agents, but their development is hindered by poor aqueous stability and/or inefficient cellular delivery. This study compares two Ti(IV) compounds with contrasting properties: titanocene-dichloride (TDC), which rapidly hydrolyzes at physiological pH, and the more stable chelated complex [Ti(deferasirox)2] (Ti(Def)2), which has limited cellular uptake. To overcome these limitations, passive and active cell targeting drug delivery systems were explored. TDC was intercalated into layered zirconium phosphate nanoparticles (TDC@ZrP), passive carriers enabling acid-triggered release under lysosomal environments. Bovine serum albumin (BSA) binding and conjugation to receptor-targeted deferasirox-peptide ligands were used as active carriers. TDC@ZrP increased intracellular Ti(IV) uptake by ∼ 26-fold relative to free TDC, yet without an increase in antiproliferative activity. Similarly, stabilization with BSA enhanced solution stability but not cytotoxicity. In contrast, Ti(Def)2 showed transporter-dependent activity. While albumin binding reduced its efficacy, conjugation to a transferrin receptor-1 targeting peptide significantly enhanced titanium uptake and cytotoxicity. Targeting the neurokinin-1 receptor had minimal effect, consistent with low receptor expression. Overall, these findings demonstrate that ligand identity is critical, as deferasirox not only controls Ti(IV) release but also contributes to cytotoxicity, highlighting the importance of metal-ligand design in improving anticancer performance.