Exploring the Relationships between Targeted Structures and Antitumor Activities of Nuclear-Targeted Polypeptide-Functionalized Platinum(IV) Prodrugs

Polypeptides as drug delivery vehicles can achieve the targeted therapeutic effects of first-line platinum drugs in clinical practice, providing an important method to solve problems such as the high systemic toxicity of first-line platinum drugs. In this work, we employ a rational molecular conjugation strategy to design and synthesize two platinum(IV) prodrugs. The first, s-CisPt(IV)-TAT, is linked to a single nuclear-targeting polypeptide, while the second, d-CisPt(IV)-TAT, is conjugated with two of these polypeptides. Interestingly, despite the higher degree of functionalization, disubstituted d-CisPt(IV)-TAT exhibits lower reactivity and cytotoxicity than its monosubstituted counterpart. This counterintuitive result suggests that overloading with multiple ligands may reduce cellular uptake, thereby compromising therapeutic efficacy. Furthermore, both constructs are shown to induce apoptosis via DNA damage pathways, confirming their mechanism of action. These results underscore the importance of precisely tuning the ligand density in drug carriers. Our work provides valuable insights into the structure–activity relationships governing platinum prodrugs and highlights the need for a balance between functional density and biological performance in the design of next-generation polypeptide-conjugated chemotherapeutics.