title: Tf-PEG-PLL-PLGA nanoparticles enhanced chemosensitivity for hypoxia-responsive tumor cells.
abstract: Hypoxia is an inseparable component of the solid tumor as well as the bone marrow microenvironment. In this study, we investigated the effect of the novel polyethylene glycol (PEG)-poly L-lysine (PLL)-poly lactic-co-glycolic acid (PLGA) based nanoparticles (NPs) modified by transferrin (Tf) loaded with daunorubicin (DNR) (DNR-Tf-PEG-PLL-PLGA-NPs, abbreviated as DNR-Tf-NPs) on leukemia cells (K562) under hypoxia. In vitro and in vivo tests to determine the effect of the enhanced chemosensitivity were evaluated using the immunofluorescence, flow cytometry, 3,-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-tetrazoliumbromide assay, Western blot analysis, histopathological examination, and immunohistochemistry analysis. Under hypoxia, K562 cells were hypoxia-responsive with the inhibitory concentration 50% (IC50) of DNR increased, resulting in chemotherapy insensitivity. By targeting the transferrin receptor (TfR) on the surface of K562 cells, DNR-Tf-NPs led to an increased intracellular DNR level, enhancing drug sensitivity of K562 cells to DNR with a decreased IC50, even under hypoxia. We further detected the protein levels of hypoxia-inducible factor-1α (HIF-1α), Bcl-2, Bax, and caspase-3 in K562 cells. The results indicated that DNR-Tf-NPs downregulated HIF-1α and induced apoptosis to overcome hypoxia. In the xenograft model, injection of DNR-Tf-NPs significantly suppressed tumor growth, and the immunosignals of Ki67 in DNR-Tf-NPs group was significantly lower than the other groups. It was therefore concluded that DNR-Tf-NPs could be a promising candidate for enhancing drug sensitivity under hypoxia in tumor treatment.
authors: Department of Hematology and Oncology, Key Department of Jiangsu Province, Zhongda Hospital.
authors: Ping
authors: P
authors: Liu
authors: Department of Hematology and Oncology, Key Department of Jiangsu Province, Zhongda Hospital.
authors: Haijun
authors: H
authors: Zhang
authors: Department of Hematology and Oncology, Key Department of Jiangsu Province, Zhongda Hospital.
authors: Xue
authors: X
authors: Wu
authors: Department of Hematology and Oncology, Key Department of Jiangsu Province, Zhongda Hospital.
authors: Liting
authors: L
authors: Guo
authors: Department of Hematology and Oncology, Key Department of Jiangsu Province, Zhongda Hospital.
authors: Fei
authors: F
authors: Wang
authors: Department of Hematology and Oncology, Medical School of Southeast University.
authors: Guohua
authors: G
authors: Xia
authors: Department of Hematology and Oncology, Key Department of Jiangsu Province, Zhongda Hospital.
authors: Baoan
authors: B
authors: Chen
authors: School of Pharmacy, Nanjing University of Technology, Nanjing, People's Republic of China.
authors: HaiXiang
authors: H
authors: Yin
authors: School of Pharmacy, Nanjing University of Technology, Nanjing, People's Republic of China.
authors: Yonglu
authors: Y
authors: Wang
authors: School of Pharmacy, Nanjing University of Technology, Nanjing, People's Republic of China.
authors: Xueming
authors: X
authors: Li
keywords: PEG-PLL-PLGA nanoparticles; chemosensitivity; hypoxia; transferrin receptor