Injectable Thermoresponsive Hydrogel Formed by Alginate‑ g ‑Poly( N ‑isopropylacrylamide) That Releases Doxorubicin-Encapsulated Micelles as a Smart Drug Delivery System

作者：Min Liu, Xia Song, Yuting Wen, Jingling Zhu, Jun Li · 发表于：ACS Applied Materials & Interfaces · 年份：2017 · DOI：10.1021/acsami.7b12849 · 被引用次数：245 · 研究领域：Hydrogels: synthesis, properties, applications、Nanoparticle-Based Drug Delivery、Advanced Drug Delivery Systems

In this work, we have synthesized a thermoresponsive copolymer, alginate-g-poly(N-isopropylacrylamide) (alginate-g-PNIPAAm) by conjugating PNIPAAm to alginate, where PNIPAAm with different molecular weights and narrow molecular weight distribution was synthesized by atomic transfer radical polymerization. The copolymer dissolved in water or phosphate-buffered saline buffer solution at room temperature and formed self-assembled micelles with low critical micellization concentrations when the temperature increased to above their critical micellization temperatures. At higher concentration, that is, 7.4 wt % in water, the copolymer formed solutions at 25 °C and turned into thermosensitive hydrogels when temperature increased to the body temperature (37 °C). Herein, we hypothesized that the thermoresponsive hydrogels could produce self-assembled micelles with the dissolution of the alginate-g-PNIPAAm hydrogels in a biological fluid or drug release medium. If the drug was hydrophobic, the hydrogel eventually could release and produce drug-encapsulated micelles. In our experiments, we loaded the anticancer drug doxorubicin (DOX) into the alginate-g-PNIPAAm hydrogels and demonstrated that the hydrogels released DOX-encapsulated micelles in a sustained manner. The slowly released DOX-loaded micelles enhanced the cellular uptake of DOX in multidrug resistant AT3B-1 cells, showing the effect of overcoming the drug resistance and achieving better efficiency for killing the cancer cells....