The therapeutic efficacy of antitumor nanomedicines is influenced by numerous factors, with the most critical being the selection of an appropriate biomaterial and the use of suitable stimulus-responsive linkers. The chosen biomaterial must be biocompatible and capable of binding the drug via a linker that facilitates selective release and activation of the therapeutic effect, specifically within tumor tissue. In this study, we designed, synthesized, and compared the physicochemical and biological properties of various polymer nanomedicines, each bearing pirarubicin conjugated to water-soluble and biocompatible methacrylamide-based copolymers through pH-sensitive hydrazone bonds. Our findings indicate that the hydrophobicity and length of the linker near the hydrazone bond are crucial factors influencing the treatment efficacy of the nanomedicines. Conjugates with aminohexanoyl linkers exhibited superior drug release and enhanced antitumor activity compared with those with shorter linkers. Overall, our study highlights that the rate of drug release, governed by the linker structure, plays a pivotal role in therapeutic efficacy, while the hydrophilicity of the polymer backbone has a lesser impact.

Department of Gastrointestinal Surgery Shengjing Hospital of China Medical University No 36 Sanhao Street Shenyang 110004 Liaoning China

Department of General Surgery Shengjing Hospital of China Medical University No 36 Sanhao Street Shenyang 110004 Liaoning China

Faculty of Pharmaceutical Sciences Sojo University Kumamoto 860 0082 Japan

Institute of Macromolecular Chemistry Czech Academy of Sciences Heyrovského nám 2 Prague 6 162 00 Czech Republic

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