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Rational Design of a New Self‐Codelivery System from Redox‐Sensitive Camptothecin–Cytarabine Conjugate Assembly for Effectively Synergistic Anticancer Therapy

Herein, two careful selected anticancer drugs camptothecin (CPT) and cytarabine (Ara‐C) with different biological action mechanisms and different water solubility are conjugated together through a glutathione (GSH) cleavable disulfide bond to construct a redox‐sensitive drug–drug conjugate, which can self‐assemble into nanoparticles, thus notably improving the water solubility of CPT and the cell membrane permeability of Ara‐C. Compared with free drugs, the self‐assembled CPT‐ss‐Ara nanoparticles can concentrate in tumor tissues through the enhanced permeability and retention (EPR) effect, then they can be rapidly internalized by tumor cells and degrade into free drugs for killing the tumor cells when exposed to the reductive environment (GSH) of tumor cells, thereby reducing the injury to normal cells. Meanwhile, the CPT‐ss‐Ara nanoparticles can effectively protect CPT and Ara‐C molecules from biological inactivation before their arrival in tumor microenvironment since free CPT and Ara‐C are easy to partly lose their therapy efficacy due to their structure degradation in blood circulation. The in vitro and in vivo anticancer experimental results indicate that simultaneous release of free CPT and Ara‐C can realize synergistic chemotherapy effects, thus markedly improve their anticancer activity. Therefore, our designed carrier‐free, redox‐sensitive CPT‐ss‐Ara nanoparticles might have promising clinical application to combat cancers.