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Tf-PEG-PLL-PLGA nanoparticles enhanced chemosensitivity for hypoxia-responsive tumor cells

Authors Liu P, Zhang H, Wu X, Guo L, Wang F, Xia G, Chen B, Yin H, Wang Y, Li X

Received 10 March 2016

Accepted for publication 16 May 2016

Published 12 August 2016 Volume 2016:9 Pages 5049—5059


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ram Prasad

Peer reviewer comments 2

Editor who approved publication: Dr William Cho

Ping Liu,1 Haijun Zhang,1 Xue Wu,1 Liting Guo,1 Fei Wang,1 Guohua Xia,2 Baoan Chen,1 HaiXiang Yin,3 Yonglu Wang,3 Xueming Li3

1Department of Hematology and Oncology, Key Department of Jiangsu Province, Zhongda Hospital, 2Department of Hematology and Oncology, Medical School of Southeast University, 3School of Pharmacy, Nanjing University of Technology, Nanjing, People’s Republic of China

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.

Keywords: hypoxia, PEG-PLL-PLGA nanoparticles, transferrin receptor, chemosensitivity

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