title: pH-Sensitive Polymeric Nanoparticles with Gold(I) Compound Payloads Synergistically Induce Cancer Cell Death through Modulation of Autophagy.
abstract: Various nanomaterials have been demonstrated as autophagy inducers owing to their endocytosis cell uptake pathway and impairment of lysosomes. pH-dependent nanomaterials as drug delivery systems that are capable of dissociating in weakly acidic lysosomal environment (pH 4-5) and consequently releasing the payloads into the cytoplasm have been paid extensive attention, but their autophagy-modulating effects are less reported so far. In this study, we report pH-sensitive micelle-like nanoparticles (NPs) that self-assembled from poly(β-amino ester)s to induce cell autophagy. By encapsulation of gold(I) compounds (Au(I)) into hydrophobic domains of NPs, the resultant Au(I)-loaded NPs (Au(I)⊂NPs) shows synergistic cancer cell killing performance. The Au(I)⊂NPs enter cells through endocytosis pathway and accumulate into acidic lysosomes. Subsequently, the protonation of tertiary amines of poly(β-amino ester)s triggers the dissociation of micelles, damages the lysosomes, and blocks formation of autolysosomes from fusion of lysosomes with autophagosomes. In addition, Au(I) preferentially inhibits thioredoxin reductase (TrxR) in MCF-7 human breast cancer cells that directly links to up-regulate reactive oxygen species (ROS) and consequently induce autophagy and apoptosis. The blockade of autophagy leads to excessive depletion of cellular organelles and essential proteins and ultimately results in cell death. Therefore, pH-sensitive polymeric nanoparticles with gold(I) compound payloads can synergistically induce cancer cell death through regulation of autophagy. Identification of the pH-sensitive nanomaterials for synergistically inducing cell death through regulation autophagy may open a new avenue for cancer therapy.
authors.affiliation: †CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, China.|‡University of Chinese Academy of Science (UCAS), No. 19A Yuquan Road, Beijing, China.
authors.forename: Yao-Xin
authors.initials: YX
authors.lastname: Lin
authors.affiliation: †CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, China.
authors.forename: Yu-Juan
authors.initials: YJ
authors.lastname: Gao
authors.affiliation: †CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, China.|‡University of Chinese Academy of Science (UCAS), No. 19A Yuquan Road, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: †CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, China.
authors.forename: Zeng-Ying
authors.initials: ZY
authors.lastname: Qiao
authors.affiliation: †CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Fan
authors.affiliation: †CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, China.|‡University of Chinese Academy of Science (UCAS), No. 19A Yuquan Road, Beijing, China.
authors.forename: Sheng-Lin
authors.initials: SL
authors.lastname: Qiao
authors.affiliation: †CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, China.
authors.forename: Ruo-Xin
authors.initials: RX
authors.lastname: Zhang
authors.affiliation: †CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: †CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, Beijing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006046:Gold / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008247:Lysosomes / Q000378:metabolism; D061986:MCF-7 Cells; D053768:Metal Nanoparticles / Q000737:chemistry*; D008823:Micelles; D010588:Phagosomes / Q000378:metabolism; D011108:Polymers / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D017382:Reactive Oxygen Species; D006046:Gold
keywords: ROS; autophagy; cancer; nanoparticles; pH-sensitive; polymer