ACS Appl Mater Interfaces. 2016 Nov 16;8(45):30833-30844.

Redox-Sensitive Hydroxyethyl Starch-Doxorubicin Conjugate for Tumor Targeted Drug Delivery.

Hu H1, Li Y1, Zhou Q1, Ao Y1, Yu C1, Wan Y1, Xu H1, Li Z1,2, Yang X1.

1 National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan 430074, People’s Republic of China.

2 Wuhan Institute of Biotechnology , High Tech Road 666, East Lake High Tech Zone, Wuhan 430040, People’s Republic of China.


Doxorubicin (DOX) is one of the most potent anticancer agents in cancer chemotherapy, but the clinical use of DOX is restricted by its severe side effects caused by nonspecific delivery. To alleviate the side effects and improve the antitumor efficacy of DOX, a novel redox-sensitive hydroxyethyl starch-doxorubicin conjugate, HES-SS-DOX, with diameter of 19.9 ± 0.4 nm was successfully prepared for tumor targeted drug delivery and GSH-mediated intracellular drug release. HES-SS-DOX was relatively stable under extracellular GSH level (~2 µM) but released DOX quickly under intracellular GSH level (2-10 mM). In vitro cell study confirmed the GSH-mediated cytotoxicity of HES-SS-DOX. HES-SS-DOX exhibited prolonged plasma half-life time and enhanced tumor accumulation in comparison to free DOX. As a consequence, HES-SS-DOX exhibited better antitumor efficacy and reduced toxicity compared with free DOX in in vivo antitumor activity study. The redox-sensitive HES-SS-DOX was proved to be a promising prodrug of DOX, with clinical potentials, to achieve tumor targeted drug delivery and timely intracellular drug release for effective and safe cancer chemotherapy. 


chemotherapy; conjugate; doxorubicin; hydroxyethyl starch; redox-sensitive; tumor targeted drug delivery

PMID: 27791359



Doxorubicin (DOX) is one of the most potent anticancer agents in cancer chemotherapy, and it can be used to treat a broad spectrum of cancers, including cancer of liver, breast, bladder, esophagus, stomach, and endometrial [1]. But the use of DOX is limited by its side effects, such as severe cardiotoxicity and nephrotoxicity [2, 3].

In this study, we, for the first time, designed and synthesized a DOX prodrug HES-SS-DOX, by employing HES as a biodegradable and hydrophilic carrier and disulfide bond as a redox-sensitive linkage between HES and DOX. Redox insensitive HES-DOX was also synthesized as a control. The disulfide bonds of HES-SS-DOX can remain stable in blood circulation, so the massive premature drug release can be prevented. HES-SS-DOX can prolong the half-life time of DOX and preferentially accumulate in tumors by EPR effect. After uptake by tumor cells, the disulfide bonds between HES and DOX can be rapidly cleaved by intracellular high concentration of GSH (2-10 mM), triggering timely drug release and causing selective tumor cytotoxicity.

The reported results herein are significant because: first, conjugation with HES can alter the in vivo activity of DOX, for example, prolong its blood circulation time, enhance its tumor accumulation, and reduce its heart and kidney cytotoxicity, emphasizing the significance of HES conjugation; second, the disulfide bond linkage between HES and DOX is critical for superior in vivo antitumor activity, underlining the advantage of tumor microenvironment stimuli responsive polymer-drug conjugates.



Fig 1. Schematic illustration of the redox-sensitive HES-SS-DOX for tumor targeted drug delivery and GSH-triggered intracellular drug release. The small size (19.9 ± 0.4 nm) and hydrophilic nature endows HES-SS-DOX with long-circulating capability in the blood, which results in enhanced tumor accumulation by EPR effect, as reported in ACS Appl. Mater. Interfaces 8, 30833-30844 (2016). After endocytosed by tumor cells, DOX-SH is released from HES-SS-DOX under reductive intracellular microenvironment and transported into nucleus. The redox-sensitive HES-SS-DOX was proved to be a promising prodrug of DOX to achieve tumor targeted drug delivery and timely intracellular drug release for safe and effective cancer chemotherapy.



Fig 2. Cellular uptake and intracellular distribution of free DOX, HES-SS-DOX and HES-DOX. CLSM images of HepG-2 cells after incubation with free DOX, HES-SS-DOX, and HES-DOX (4µg/mL as DOX) for 12 h (A) and 24 h (B). DOX fluorescence intensity quantification of the CLSM images (C).



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