title: Bioinert Anodic Alumina Nanotubes for Targeting of Endoplasmic Reticulum Stress and Autophagic Signaling: A Combinatorial Nanotube-Based Drug Delivery System for Enhancing Cancer Therapy.
abstract: 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.
authors.affiliation: School of Chemical Engineering and ‡Discipline of Surgery, Basil Hetzel Institute, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Chemical Engineering and ‡Discipline of Surgery, Basil Hetzel Institute, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: Gagandeep
authors.initials: G
authors.lastname: Kaur
authors.affiliation: School of Chemical Engineering and ‡Discipline of Surgery, Basil Hetzel Institute, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Chemical Engineering and ‡Discipline of Surgery, Basil Hetzel Institute, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: Abel
authors.initials: A
authors.lastname: Santos
authors.affiliation: School of Chemical Engineering and ‡Discipline of Surgery, Basil Hetzel Institute, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: Dusan
authors.initials: D
authors.lastname: Losic
authors.affiliation: School of Chemical Engineering and ‡Discipline of Surgery, Basil Hetzel Institute, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000537:Aluminum Oxide / Q000737:chemistry*; D000818:Animals; D001343:Autophagy; D002384:Catalysis; D004298:Dopamine / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D006046:Gold / Q000737:chemistry*; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry*; D043942:Nanotubes / Q000737:chemistry*; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D012701:Serotonin; D006046:Gold; D000537:Aluminum Oxide; D004298:Dopamine
keywords: anodic alumina nanotubes; autophagy; cell signaling; drug delivery; endoplasmic reticulum stress; nanotoxicity