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Advanced Science Volume 5 ,Issue 12 ,2018-10-26
Enhancing Antitumor Efficacy by Simultaneous ATP‐Responsive Chemodrug Release and Cancer Cell Sensitization Based on a Smart Nanoagent
Full Papers
Xiao‐Rong Song 1 , 2 Shi‐Hua Li 2 Hanhan Guo 1 Wenwu You 1 Datao Tu 1 Juan Li 2 Chun‐Hua Lu 2 Huang‐Hao Yang 2 Xueyuan Chen 1
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DOI:10.1002/advs.201801201
Received 2018-07-26,
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摘要

Abstract The exploitation of smart nanoagents based drug delivery systems (DDSs) has proven to be a promising strategy for fighting cancers. Hitherto, such nanoagents still face challenges associated with their complicated synthesis, insufficient drug release in tumors, and low cancer cell chemosensitivity. Here, the engineering of an adenosine triphosphate (ATP)‐activatable nanoagent is demonstrated based on self‐assembled quantum dots‐phenolic nanoclusters to circumvent such challenges. The smart nanoagent constructed through a one‐step assembly not only has high drug loading and low cytotoxicity to normal cells, but also enables ATP‐activated disassembly and controlled drug delivery in cancer cells. Particularly, the nanoagent can induce cell ATP depletion and increase cell chemosensitivity for significantly enhanced cancer chemotherapy. Systematic in vitro and in vivo studies further reveal the capabilities of the nanoagent for intracellular ATP imaging, high tumor accumulation, and eventual body clearance. As a result, the presented multifunctional smart nanoagent shows enhanced antitumor efficacy by simultaneous ATP‐responsive chemodrug release and cancer cell sensitization. These findings offer new insights toward the design of smart nanoagents for improved cancer therapeutics.

关键词

quantum dots;nanoagents;chemodrugs;cell sensitization;antitumor

授权许可

© 2018 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

图表

Schematic illustration of QDs@TA‐PEG/DOX for enhanced chemotherapy by simultaneous ATP‐responsive chemodrug release and cancer cell sensitization. The nanoagent was constructed via one‐step assembly of tannic acid, QDs, and DOX mediated by metal–phenolic coordination, which displayed ATP‐activated disassembly due to the strong metal–triphosphate coordination. Upon entering cancer cells, the nanoagent enabled ATP‐responsive drug release and cellular ATP depletion, resulting in the increased cell chemosensitivity and enhanced therapeutic efficacy without causing side effects to normal cells.

a) TEM image of hydrophobic CdSe@ZnS QDs. b) Schematic illustration of the assembly of QDs@TA NCs and ATP‐activated disassembly. c) TEM image of QDs@TA NCs. d) Excitation spectrum (black lines, λem: 640 nm) and emission spectrum (red line, λex: 365 nm) of CdSe@ZnS QDs in cyclohexane. The “I” in Y‐axis was short for “intensity”. e) TEM image of the NCs after 20 × 10−3 m ATP treatment for 4 h. f) Emission spectra of QDs (black line) and QDs@TA NCs (red line) excited by 365 nm. g) DLS measurement of the related samples: QDs (bottom), QDs@TA NCs (middle), and QDs@TA NCs after 20 mM ATP treatment for 4 h (upper).

a) Emission spectra of QDs@TA NCs treated with different concentrations of ATP. Inset: images of various samples under 365 nm light irradiation. b) Time evolution of the fluorescence intensity of QDs@TA NCs in PBS (control) and 20 × 10−3 m ATP, respectively. c) Time evolution of cellular uptake after incubating the HepG2 cells with QDs@TA‐PEG (100 µg mL−1) for various time periods. d) Confocal images of HepG2 cells after treating with QDs@TA‐PEG for different time periods (0, 6, and 12 h). (+): with apyrase treatment. Images were acquired using an exication laser of 408 nm and emission range from 570–1000 nm.

a) UV–vis–NIR absorbance spectra of QDs@TA‐PEG, DOX and QDs@TA‐PEG/DOX. b) The DOX‐loading capability of QDs@TA‐PEG NCs under various DOX feeding amounts and different loading manner. c) Time evolution of DOX release profiles of QDs@TA‐PEG/DOX under different conditions. d) Relative HepG2 cell viability after treating with QDs@TA‐PEG/DOX or free DOX for 24 h. e) ATP contents in HepG2 cells cultured with different concentrations of the NCs for 24 h. f) HepG2 cell viability after the treatment of different dosages of DOX plus 100 µg mL−1 NCs for 24 h.

a) Hemolysis assay of RBCs treated with water, PBS, and different concentrations of QDs@TA‐PEG NCs for 3 h. Inset: Photographs of corresponding solutions after centrifugation. b) Blood circulation time study of QDs@TA‐PEG in tumo‐bearing mice. c) Biodistribution of the NCs in major organs and tumors after IV injection of QDs@TA‐PEG for 12, 24, 48, 96 h. d) Fluorescence images of major organs and tumors collected at 12, 24, 48, and 96 h post IV injection. The fluorescent bar was shown in false colour scale (1 unit = 1 × 106 photons per s per cm2 per sr). e) Fluorescence intensity of the corresponding samples presented in panel (d) quantitated by Image J software. f) Biodistribution of the NCs in major organs and tumors at 1, 7, 14, and 21 d post IV injection.

a) Time evolution of tumor volume in mice of different groups: PBS (control), QDs@TA‐PEG, DOX, QDs@TA‐PEG/DOX and 2 × QDs@TA‐PEG/DOX, respectively (DOX: 5 mg kg−1; NCs: 20 mg kg−1). b) H&E stained histological images of tumors collected at day 2. c) Body weights of mice during various treatments. d) Representative photos of mice after 16 days' treatment. e) H&E stained histological images of major organs collected at day 16 in mice of QDs@TA‐PEG/DOX group.

通讯作者

1. Huang‐Hao Yang.MOE Key Laboratory for Analytical Science of Food Safety and Biology, State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350116, China.hhyang@fzu.edu.cn
2. Xueyuan Chen.CAS Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, 350002, China.hhyang@fzu.edu.cn

推荐引用方式

Xiao‐Rong Song,Shi‐Hua Li,Hanhan Guo,Wenwu You,Datao Tu,Juan Li,Chun‐Hua Lu,Huang‐Hao Yang,Xueyuan Chen. Enhancing Antitumor Efficacy by Simultaneous ATP‐Responsive Chemodrug Release and Cancer Cell Sensitization Based on a Smart Nanoagent. Advanced Science ,Vol.5, Issue 12(2018)

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