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Novel targeting of PEGylated liposomes for codelivery of TGF-β1 siRNA and four antitubercular drugs to human macrophages for the treatment of mycobacterial infection: a quantitative proteomic study

Niu, Ning-Kui, Yin, Juan-Juan, Yang, Yin-Xue, Wang, Zi-Li, Zhou, Zhi-Wei, He, Zhi-Xu, Chen, Xiao-Wu, Zhang, Xueji, Duan, Wei, Yang, Tianxin and Zhou, Shu-Feng 2015, Novel targeting of PEGylated liposomes for codelivery of TGF-β1 siRNA and four antitubercular drugs to human macrophages for the treatment of mycobacterial infection: a quantitative proteomic study, Drug design, development and therapy, vol. 9, pp. 4441-4470, doi: 10.2147/DDDT.S79369.

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Title Novel targeting of PEGylated liposomes for codelivery of TGF-β1 siRNA and four antitubercular drugs to human macrophages for the treatment of mycobacterial infection: a quantitative proteomic study
Author(s) Niu, Ning-Kui
Yin, Juan-Juan
Yang, Yin-Xue
Wang, Zi-Li
Zhou, Zhi-Wei
He, Zhi-Xu
Chen, Xiao-Wu
Zhang, Xueji
Duan, WeiORCID iD for Duan, Wei orcid.org/0000-0001-5782-9184
Yang, Tianxin
Zhou, Shu-Feng
Journal name Drug design, development and therapy
Volume number 9
Start page 4441
End page 4470
Total pages 30
Publisher Dove Medical Press
Place of publication Macclesfield, Eng.
Publication date 2015-08-07
ISSN 1177-8881
Keyword(s) NF-κB
SILAC
apoptosis
autophagy
cell cycle
cytokine
interleukin
liposome
proteomics
tuberculosis
Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
NF-kappa B
MULTIDRUG-RESISTANT TUBERCULOSIS
CELL-CULTURE SILAC
SPINAL TUBERCULOSIS
DELIVERY SYSTEMS
MESENCHYMAL TRANSITION
INFLAMMATORY RESPONSE
COURSE CHEMOTHERAPY
AURORA KINASE
CANCER CELLS
AMINO-ACIDS
Summary Tuberculosis (TB) is still a major public health issue in developing countries, and its chemotherapy is compromised by poor drug compliance and severe side effects. This study aimed to synthesize and characterize new multimodal PEGylated liposomes encapsulated with clinically commonly used anti-TB drugs with linkage to small interfering RNA (siRNA) against transforming growth factor-β1 (TGF-β1). The novel NP-siRNA liposomes could target THP-1-derived human macrophages that were the host cells of mycobacterium infection. The biological effects of the NP-siRNA liposomes were evaluated on cell cycle distribution, apoptosis, autophagy, and the gene silencing efficiency of TGF-β1 siRNA in human macrophages. We also explored the proteomic responses to the newly synthesized NP-siRNA liposomes using the stable isotope labeling with amino acids in cell culture approach. The results showed that the multifunctional PEGylated liposomes were successfully synthesized and chemically characterized with a mean size of 265.1 nm. The novel NP-siRNA liposomes functionalized with the anti-TB drugs and TGF-β1 siRNA were endocytosed efficiently by human macrophages as visualized by transmission electron microscopy and scanning electron microscopy. Furthermore, the liposomes showed a low cytotoxicity toward human macrophages. There was no significant effect on cell cycle distribution and apoptosis in THP-1-derived macrophages after drug exposure at concentrations ranging from 2.5 to 62.5 μg/mL. Notably, there was a 6.4-fold increase in the autophagy of human macrophages when treated with the NP-siRNA liposomes at 62.5 μg/mL. In addition, the TGF-β1 and nuclear factor-κB expression levels were downregulated by the NP-siRNA liposomes in THP-1-derived macrophages. The Ingenuity Pathway Analysis data showed that there were over 40 signaling pathways involved in the proteomic responses to NP-siRNA liposome exposure in human macrophages, with 160 proteins mapped. The top five canonical signaling pathways were eukaryotic initiation factor 2 signaling, actin cytoskeleton signaling, remodeling of epithelial adherens junctions, epithelial adherens junction signaling, and Rho GDP-dissociation inhibitor signaling pathways. Collectively, the novel synthetic targeting liposomes represent a promising delivery system for anti-TB drugs to human macrophages with good selectivity and minimal cytotoxicity.
Language eng
DOI 10.2147/DDDT.S79369
Field of Research 1115 Pharmacology And Pharmaceutical Sciences
111502 Clinical Pharmacology and Therapeutics
Socio Economic Objective 920109 Infectious Diseases
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution non-commercial licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30080629

Document type: Journal Article
Collections: Open Access Collection
Molecular and Medical Research
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.