期刊
ACS APPLIED MATERIALS & INTERFACES
卷 7, 期 49, 页码 27140-27151出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.5b07557
关键词
anodic alumina nanotubes; endoplasmic reticulum stress; autophagy; cell signaling; nanotoxicity; drug delivery
资金
- Australian Research Council (ARC) [DP120101680, FT110100711, DE14010054]
- National Health and Medical Research Council (NHMRC) of Australia [APP627015]
- Australian Breast Cancer Research (ABCR)
- The Hospital Research Foundations (THRF)
- University of Adelaide Interdisciplinary Research Fund (DVC IRF)
Although nanoparticle-based targeted delivery systems have gained promising achievements for cancer therapy, the development of sophisticated strategies with effective combinatorial therapies remains an enduring challenge. Herein, we report the fabrication of a novel nanomaterial, so-called anodic alumina nanotubes (AANTs) for proof-of-concept cancer therapy by targeting cell signaling networks. This strategy is to target autophagic and endoplasmic reticulum (ER) stress signaling by using thapsigargin (TG)-loaded AANTs cotreated with an autophagy inhibitor 3-methyladenine (3-MA). We first show that AANTs are nontoxic and can activate autophagy in different cell types including human fibroblast cells (HFF), human monocyte cells (THP-1), and human breast cancer cells (MDA-MB 231-TXSA). Treatment with 3-MA at a nontoxic dose reduced the level of autophagy induced by AANTs, and consequently sensitized breast cancer cells to AANTs-induced cellular stresses. To target autophagic and ER stress signaling networking, breast cancer cells were treated with 3-MA together with AANTs loaded with the prototype ER stress inducer TG. We demonstrated that 3-MA enhanced the cancer cell killing effect of AANTs loaded with TG. This effect was associated with enhanced ER stress signaling due to the combination effect of TG and 3-MA. These findings not only demonstrate the excellent biocompatibility of AANTs as novel biomaterials but also provide new opportunities for developing ER- and autophagy-targeted delivery systems for future clinical cancer therapy.
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