Redox-Sensitive Shell-Crosslinked Polypeptide- block-Polysaccharide Micelles for Efficient Intracellular Anticancer Drug Delivery a Aiping Zhang, Zhe Zhang, Fenghua Shi, Chunsheng Xiao, Jianxun Ding, Xiuli Zhuang,* Chaoliang He, Li Chen,* Xuesi Chen Redox-responsive SCMs based on amphiphilic PBLG-b-dextran with good biocompatibility are synthesized and used for efficient intracellular drug delivery. The molecular structures and SCMs characteristics are characterized by 1 H NMR, FT-IR, TEM, and DLS. The hydrodynamic radius of SCMs increases gradually in PBS due to the cleavage of disulfide bond in micellar shell caused by the presence of GSH. The encapsulation efficiency and release kinetics of DOX are investigated. The fastest DOX release is observed under intracellular-mimicking reductive environments. An MTT assay demonstrates that DOX-loaded SCMs show higher cellular prolifera- tion inhibition against GSH-OEt pretreated HeLa and HepG2 than that of the non-pretreated and BSO- pretreated ones. 1. Introduction The control and therapy of cancer represents an increas- ingly serious global public health problem now. Many anticancer drugs [e.g., doxorubicin (DOX) and paclitaxel] have been used for the treatment of this disease, but the potential of current drugs is often hampered by rapid blood clearance, low tumor selectivity, and severe side effects for healthy tissues. [1] Polymeric micelles prepared from self- assembly of amphiphilic copolymers are thus used as the carriers of the drugs to greatly enhance their water solubility and stability, prolong their circulation in blood compartments, target cancerous tissues by passive accu- mulation via the enhanced permeability and retention (EPR) effect. [2–7] Micelles generally exhibit a core/shell structure with hydrophobic inner core as a depot for hydrophobic drugs and hydrophilic outer shell as a protective interface between the hydrophobic core and external aqueous milieu. [8] For the polymeric micelles to be an ideal carrier, they should meet the following requisites: ideal preparation materials, high stability in blood, and controlled drug release. The ideal preparation materials of micelles should be well characterized, easily functionalized, and biocompati- ble and biodegradable. [9] Natural materials (such as polysaccharides or polypeptides) successfully fulfill all of these requirements and are therefore widely used for the preparation of nanoparticles as drug delivery vehicles. [10–14] A. Zhang, Z. Zhang, F. Shi, L. Chen Department of Chemistry, Northeast Normal University, Changchun 130024, China E-mail: chenl686@nenu.edu.cn C. Xiao, J. Ding, X. Zhuang, C. He, L. Chen, X. Chen Key Laboratory of Polymer Ecomaterials. Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China E-mail: zhuangxl@ciac.jl.cn a Supporting Information is available at Wiley Online Library or from the author. Full Paper ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/mabi.201300175 1249 Macromol. Biosci. 2013, 13, 1249–1258 wileyonlinelibrary.com