# DOX-conjugated unimolecular micelles from benzaldehyde-functionalized star copolymer via metal-free ATRP for pH-responsive drug delivery

## TL;DR

A new method creates stable, pH-sensitive drug carriers using a metal-free process, improving drug delivery efficiency and sustainability.

## Contribution

A metal-free ATRP strategy for synthesizing DOX-conjugated star copolymers with pH-responsive drug release.

## Key findings

- The star copolymer forms stable unimolecular micelles with high colloidal stability.
- The system shows pH-triggered drug release under acidic conditions.
- In vitro tests show effective cellular uptake and cytotoxicity against H460 lung cancer cells.

## Abstract

The development of polymer prodrugs with well-defined architectures capable of forming stable nanomicelles is important for achieving precise and efficient drug delivery. Compared with conventional linear systems, star-shaped copolymer prodrugs offer enhanced micellar stability owing to their covalently tethered architecture. However, many existing synthetic approaches rely on transition-metal catalyzed polymerization and customized monomers, which limit their sustainability and practical applicability. Herein, we report a pH-responsive doxorubicin (DOX)-conjugated benzaldehyde-functionalized star-shaped copolymer synthesized via an environmentally benign metal-free atom transfer radical polymerization (ATRP) strategy. A hydroxyl-functionalized star-shaped copolymer scaffold was first prepared from readily available monomers and subsequently modified to introduce pendant benzaldehyde groups, enabling DOX conjugation through acid-labile imine linkages. This approach affords well-controlled polymer architectures while avoiding transition-metal residues and the need for pre-functionalized monomers. The resulting DOX-conjugated star-shaped copolymers form unimolecular micelles with high colloidal stability and exhibit pH-triggered drug release under acidic conditions. In vitro studies further demonstrate effective cellular internalization and a moderated cytotoxic profile toward human large-cell lung carcinoma (H460) cells, supporting the functional viability of this micellar system as a polymer prodrug delivery platform.

A metal-free ATRP approach enables the synthesis of a doxorubicin-conjugated star copolymer from readily available monomers, forming stable unimolecular micelles with pH-responsive drug release.