# PEGylation Effects on Amphiphilic Platinum(IV) Complexes: Influence on Uptake, Activation, and Cytotoxicity

## TL;DR

This study explores how adding different sizes of PEG chains to platinum-based cancer drugs affects their ability to enter cells, activate, and kill cancer cells.

## Contribution

The study reveals how PEG chain size impacts the efficacy of platinum-based prodrugs through cellular uptake and activation.

## Key findings

- Small PEG modifications preserve the cytotoxicity of Pt(IV) prodrugs.
- Large PEG chains reduce drug efficacy by limiting cellular uptake and activation.
- PEGylation significantly influences the biological behavior of platinum-based prodrugs.

## Abstract

Background/Objectives: The utilization of amphiphilic Pt(IV) complexes as prodrugs offers a promising strategy to revolutionize Pt-based cancer therapy by enhancing drug delivery and activation. While PEGylation is widely used to optimize drug properties, its impact on the biological behavior of amphiphilic Pt(IV) complexes remains unclear. This study systematically investigates how the PEGylation of varying molecular weights influences their cytotoxicity, cellular uptake, and activation. Methods: Pt(IV) complexes were synthesized with PEG chains of different molecular weights using HATU-catalyzed amide bond formation and copper-free click chemistry. Their biological properties were assessed through cell-based analyses, focusing on cytotoxicity, cellular uptake, and activation by biological reductants. Results: Small PEG modifications retained the potent cytotoxicity of amphiphilic Pt(IV) prodrugs, whereas large PEG chains significantly reduced efficacy. The decrease in potency was linked to impaired cellular uptake and mitochondrial accumulation. Additionally, large PEG modifications slowed the reduction and activation of Pt(IV) prodrugs by biological reductants, further limiting their anticancer activities. Conclusions: These findings underscore the critical role of PEGylation in metallodrug design and provide key insights into optimizing PEGylation strategies for enhancing platinum–based cancer therapies.