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WIREs Nanomed Nanobiotechnol
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Recent advances of smart acid‐responsive gold nanoparticles in tumor therapy

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Abstract Due to the remarkable properties of gold nanoparticles (AuNPs), they have been extensively employed as a potential tool for the diagnosis and treatment of cancers. While the conventional drug delivery system fails to efficiently deliver the chemotherapeutics due to the complexity of tumor microenvironment, people have been seeking alternative nanoparticulate strategy to improve the tumor specificity, the therapeutic index as wells as the pharmacokinetic profile. The nontoxic and nonimmunogenic nature, the high permeability, and superior retention effect of AuNPs provide additional benefits by enabling easy penetration and accumulation of drugs at the tumor sites. Here in this review, we focused on discussing the recent advances regarding the design of acid‐responsive AuNPs as well as their applications in drug/gene delivery and imaging in cancer diagnosis and therapy. Particularly, we highlighted the size switch strategies used in the development of acid‐responsive AuNPs. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Schematic illustration of smart acid‐responsive AuNPs proposed for tumor theranostics. AuNP, gold nanoparticle
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(a) Diagram depicting the acid‐triggered aggregation and composition of AuNPs system and schematic illustrations of in vivo behavior of AuNPs system after intravenous injection for increased tumor retention and enhanced RT. (b) Dynamic light scattering of AuNPs system from pH 7.4 to pH 6.5 and (c) TEM images of AuNPs system at pH 7.4 (left) and pH 6.5 (right). (d) Colony formation curves of MCF‐7 cancer cells received various AuNPs formulations treated with 0, 2, 4, and 6 Gy of radiation. (e) Tumor retention of AuNPs system after intravenous injection. (f) in vivo tumor inhibition of AuNPs system in MCF‐7‐tumor bearing nude mice. (Reprinted with permission from Y. Zhang, Huang, et al. (). Copyright 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim). AuNP, gold nanoparticle; RT, radiotherapy; TEM, transmission electron microscopy
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(a) Schematic illustration of dual pH‐responsive AuNPs‐DNA release and subsequent DOX release. (b) The release profile of AuNPs from NLNti at pH = 7.4 or 6.5. (c) Regression of MDA‐MB‐231 tumor in mice model after the injection of various NLNs. Each sample was administrated systemically at a DOX dose of 5 mg/kg on Day 1 and Day 6, as indicated by the arrows. (d) Confocal images of spheroids treated with NLNti, NLNci, large‐pored mesoporous silica nanoparticles (LPMSNs) and DNA‐gold nanoparticles (AuNPs) only. NLN is abbreviation of nanoparticle‐loaded nanoparticle; NLNti and NLNci represents pH‐responsive NLN and pH‐nonresponsive NLN, respectively; NLNtc represents another control NLN with triplex DNA and duplex of control i‐motif. Green and red fluorescence stands for the released DNA‐AuNPs and LPMSNs, respectively. Yellow represents the colocalization of green and red fluorescence. Scale bar is 100 μm. (Reprinted with permission from J. Kim, Jo, et al. (2018). Copyright 2018 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim). AuNP, gold nanoparticle; DOX, doxorubicin; NLN, nanoparticle‐loaded nanoparticle
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(a) Schematic illustration of the preparation of pH‐responsive block copolymer‐decorated AuNPs with the aid of dodecanethiols (purple short lines) and reversible tuning of the self‐assembly at different pH values. pHt is referred to as transition pH value. (b) TEM images of the PEG‐b‐(PDiPA‐rCy5)‐decorated AuNPs at pH 7.4 and 6.0 solutions, respectively. (c) Representative fluorescent images of the three PEG‐b‐(PTA‐r‐dye)‐decorated AuNPs at different pH values. (Reprinted with permission from Dong et al. (). Copyright 2019 American Chemical Society). AuNP, gold nanoparticle; PEG, polyethylene glycol; TEM, transmission electron microscopy
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(a) Enhanced intracellular payload release at endosome by pH‐dependent charge‐reversal polyelectrolyte on AuNPs. (b) Zeta‐potential of different AuNPs. (c) Knockdown of lamin A/C expression was determined by Western blot over 48 hr in HeLa cells using lamin A/C‐siRNA delivered by PEI/PAH‐Cit/PEI/MUA‐AuNPs at various ratios. GADPH was used as the internal standard for Western blot. (d) HeLa cells were transfected with DNA/PEI/PAH‐Cit/PEI/MUA‐AuNPs complexes. The transfection was performed at various w/w ratios of Au/DNA (top panel). Lipofectamine, PEI/MUA‐AuNPs, PEI/PSS/PEI/MUA‐AuNPs, and PEI/DNA (N/p = 10) complexes were used as control (bottom panel). The scale bar is 30 μm. (Reprinted with permission from Guo et al. (). Copyright 2010 American Chemical Society). AuNP, gold nanoparticle; MUA, 11‐mercaptoundecanoic acid; PEI, polyetherimide
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(a) Schematic illustration of GA ligand's shield at blood pH (pH 7.4) and exposure at tumor extracellular environment pH (pH 6.8), and possible mechanism of sharp pH‐responsive assembly and disassembly of AuNPs. (b) Hydrodynamic diameter distribution of dispersed (blue) and assembled (red) AuNPs. (c) TEM image of the assemblies formed by 30 nm AuNPs (dry state diameter). The scale bar for partial enlargement is 20 nm. (Reprinted with permission from Z. Tian, Yang, Wang, & Yuan (). Copyright 2014 American Chemical Society). AuNP, gold nanoparticle; GA, glycyrrhetinic acid; TEM, transmission electron microscopy
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(a) Elucidation of the An‐PEG‐DOX‐AuNPs and its delivering procedure. (b) TEM of glioma slides from PEG‐DOX‐AuNPs and An‐PEG‐DOX‐AuNPs treated glioma bearing mice. (c) Survival curve of the brain glioma bearing mice treated with different formulations of the same dose, n = 10. (Reprinted with permission from Ruan, Yuan, et al. (). Copyright 2014 Elsevier Ltd.). AuNP, gold nanoparticle; DOX, doxorubicin; PEG, polyethylene glycol; TEM, transmission electron microscopy
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(a) Schematic illustration of the structure of DOX‐tethered responsive AuNPs and its enhanced DOX cellular entry and responsive intracellular release of DOX to overcome drug resistance. (b) Comparison of total DOX accumulation in different groups in MCF‐7/ADR cells. (c) Viability of MCF‐7/ADR cells after different treatments for 72 hr. (d) Confocal laser microscopic observation of MCF‐7/ADR cells incubated with different treatments for 24 hr. DOX‐[email protected] and DOX‐[email protected] represent acid‐responsive group and control group, respectively. The dose of DOX or its equivalent was 5 μg/ml. The cells were counterstained with DAPI (blue) for the cell nucleus and Alexa Fluor 488 phalloidin (green) for the cell membrane. (Reprinted with permission from F. Wang et al. (). Copyright 2011 American Chemical Society). AuNP, gold nanoparticle; DOX, doxorubicin
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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