# PEGylated Heterofunctional Dendrimers Enable Multivalent Diclofenac Delivery for ROS-Driven Anticancer Activity

## TL;DR

Scientists developed a new drug delivery system using dendrimers to improve the anticancer effects of diclofenac by increasing its solubility and targeting cancer cells more effectively.

## Contribution

A modular nanocarrier platform using PEGylated dendrimers for multivalent diclofenac delivery with improved therapeutic index and ROS-driven anticancer activity.

## Key findings

- PEGylated dendrimers reduced cancer cell viability by 50–70% at 1–10 μM while preserving noncancerous cell viability.
- Dendrimers induced reactive oxygen species (ROS) at 10–100× lower concentrations than free diclofenac.
- ROS-mediated cytotoxicity was confirmed as a key pathway across multiple cancer models.

## Abstract

Cancer drug development faces escalating costs and limited
success,
driving interest toward drug repurposing strategies. Diclofenac, a
widely used nonsteroidal anti-inflammatory drug (NSAID) with emerging
anticancer potential, exhibits poor aqueous solubility and rapid systemic
clearance, limiting its chemotherapeutic suitability. Here, we engineered
PEGylated heterofunctional polyester dendrimers (HFDs) as modular
nanocarriers that enable controlled multivalent presentation of diclofenac
through orthogonal chemistry. Diclofenac was conjugated within the
dendritic interior using copper­(I)-catalyzed azide–alkyne cycloaddition
(CuAAC) while peripheral PEGylation was introduced through anhydride
esterification. First- and second-generation constructs, G1-(Dicl)3-(mPEG)6 and G2-(Dicl)9-(mPEG)12, assembled into amphiphilic core–shell nanostructures with
hydrodynamic diameters of 170–330 nm and well-defined drug
loading. G1-(Dicl)3-(mPEG)6 demonstrated the
strongest therapeutic performance, reducing viability by 50–70%
in MCF-7, U-87 MG, and PANC-1 cancer cells at 1–10 μM
while maintaining >95% viability in noncancerous fibroblasts. This
represents a >20-fold improvement in therapeutic index compared
to
free diclofenac. G2-(Dicl)9-(mPEG)12 displayed
potent but cell-line-dependent activity, with highest efficacy in
MCF-7 cells. Both dendrimers required 10–100× lower concentrations
than free diclofenac to induce comparable reactive oxygen species
(ROS) levels, with G1 producing 3–4-fold ROS elevation at 10
μM and G2 achieving similar induction at 0.1 μM. Mechanistic
analysis confirmed ROS-mediated cytotoxicity as a key contributing
pathway and correlated directly with cytotoxicity across various cancer
models. These findings establish HFDs as an adaptable nanomedicine
platform for repurposing clinically approved drugs, with G1 dendrimer
providing the optimal balance of efficacy, selectivity, and translational
potential.