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ROS-Switchable Polymeric Nanoplatform with Stimuli-Responsive Release for Active Targeted Drug Delivery to Breast Cancer
- Zhang, Yu, Guo, Qin, An, Sai, Lu, Yifei, Li, Jianfeng, He, Xi, Liu, Lisha, Zhang, Yujie, Sun, Tao, Jiang, Chen
- ACS Applied Materials & Interfaces 2017 v.9 no.14 pp. 12227-12240
- biomarkers, breast neoplasms, doxorubicin, drug delivery systems, glucose transporters, metastasis, micelles, pH, pharmacokinetics, reactive oxygen species, toxicity
- Tumor microenvironment plays a vital role in the process of tumor development, proliferation, invasion, and metastasis. It is well acknowledged that reduction in pH, reactive oxygen species (ROS), and increased level of glucose transporter 1 (GLUT1) have become featured intracellular and extracellular biochemical markers of cancer owing to oncogenic transformation and abnormal metabolism. To establish a distinctive drug delivery system directed against the tumor microenvironment features, we develop a newly engineered polymeric nanoplatform for efficient doxorubicin (DOX) delivery with reduced systemic toxicity and high antitumor efficiency. A thioketal cross-linker is used to improve the formulation’s stability during circulation and to foster quick intracellular drug release in response to tumor’s ROS potential. Furthermore, the low drug loading efficiency of conventional micelles is ameliorated in this polymeric nanoplatform via a drug-conjugation strategy with an acid-labile chemical bond. The optimized formulation, MPLs-sB-DOX micelles, possesses a high drug-loading efficiency (31%) within nanosize diameter (37.8 nm). In addition, this formulation shows significant improvement in the pharmacokinetics and biodistribution profiles with a 2.69-fold increase of tumor accumulation, while with largely reduced systemic toxicity in comparison with free DOX. With advantages of efficient cellular uptake, preferential tumor accumulation, and controlled release behaviors, MPLs-sB-DOX micelles demonstrate good tumor-targeting ability with reduced systemic toxicity, proving to be a promising formulation for breast cancer therapy.