Aim: N-acetyl-L-cysteine (NAC) is a free radical scavenger. We developed NAC-coated Ag₂S (NAC-Ag₂S) quantum dot (QD) as an optical imaging and therapeutic agent. Materials & methods: QDs were synthesized in water. Their optical imaging potential and toxicity were studied in vitro. Results: NAC-Ag₂S QDs have strong emission, that is tunable between 748 and 840 nm, and are stable in biologically relevant media. QDs showed significant differences both in cell internalization and toxicity in vitro. QDs were quite toxic to breast and cervical cancer cells but not to lung derived cells despite the higher uptake. NAC-Ag₂S reduces reactive oxygen species (ROS) but causes cell death via DNA damage and apoptosis. Conclusion: NAC-Ag₂S QDs are stable and strong signal-generating theranostic agents offering selective therapeutic effects.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1 Resch-Genger U, Grabolle M, Cavaliere-Jaricot S, Nitschke R, Nann T. Quantum dots versus organic dyes as fluorescent labels. Nat. Methods 5(9), 763 (2008).
Medline CASGoogle Scholar
2 Bruchez M, Moronne M, Gin P, Weiss S, Alivisatos AP. Semiconductor nanocrystals as fluorescent biological labels. Science 281(5385), 2013–2016 (1998).
Medline CASGoogle Scholar
3 Medintz IL, Uyeda HT, Goldman ER, Mattoussi H. Quantum dot bioconjugates for imaging, labelling and sensing. Nat. Mater. 4(6), 435 (2005).
Medline CASGoogle Scholar
4 Klohs J, Wunder A, Licha K. Near-infrared fluorescent probes for imaging vascular pathophysiology. Basic Res. Cardiol. 103(2), 144–151 (2008).
Medline CASGoogle Scholar
5 Altınoğlu Eİ, Adair JH. Near infrared imaging with nanoparticles. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2(5), 461–477 (2010).
Medline CASGoogle Scholar
6 Hilderbrand SA, Weissleder R. Near-infrared fluorescence: application to in vivo molecular imaging. Curr. Opin. Chem. Biol. 14(1), 71–79 (2010). • Review of in vivo applications of near-infrared fluorescence imaging with improved photon penetration through tissue and minimal tissue autofluorescence.
Medline CASGoogle Scholar
7 Chen H, Wang Y, Xu J et al. Non-invasive near infrared fluorescence imaging of CdHgTe quantum dots in mouse model. J. Fluoresc. 18(5), 801–811 (2008).
Medline CASGoogle Scholar
8 Qian H, Dong C, Peng J, Qiu X, Xu Y, Ren J. High-quality and water-soluble near-infrared photoluminescent CdHgTe/CdS quantum dots prepared by adjusting size and composition. J. Phys. Chem. C 111(45), 16852–16857 (2007).
CASGoogle Scholar
9 Liang G-X, Gu M-M, Zhang J-R, Zhu J-J. Preparation and bioapplication of high-quality, water-soluble, biocompatible, and near-infrared-emitting CdSeTe alloyed quantum dots. Nanotechnology 20(41), 415103 (2009).
MedlineGoogle Scholar
10 Deng D, Xia J, Cao J et al. Forming highly fluorescent near-infrared emitting PbS quantum dots in water using glutathione as surface-modifying molecule. J. Colloid Interface Sci. 367(1), 234–240 (2012).
Medline CASGoogle Scholar
11 Chen N, He Y, Su Y et al. The cytotoxicity of cadmium-based quantum dots. Biomaterials 33(5), 1238–1244 (2012).
Medline CASGoogle Scholar
12 Su Y, Hu M, Fan C et al. The cytotoxicity of CdTe quantum dots and the relative contributions from released cadmium ions and nanoparticle properties. Biomaterials 31(18), 4829–4834 (2010).
Medline CASGoogle Scholar
13 Du Y, Xu B, Fu T et al. Near-infrared photoluminescent Ag₂S quantum dots from a single source precursor. J. Am. Chem. Soc. 132(5), 1470–1471 (2010).
Medline CASGoogle Scholar
14 Hong G, Robinson JT, Zhang Y et al. In vivo fluorescence imaging with Ag₂S quantum dots in the second near-infrared region. Angew. Chem. 124(39), 9956–9959 (2012).
Google Scholar
15 Duman FD, Hocaoglu I, Ozturk DG, Gozuacik D, Kiraz A, Acar HY. Highly luminescent and cytocompatible cationic Ag₂S NIR-emitting quantum dots for optical imaging and gene transfection. Nanoscale 7(26), 11352–11362 (2015).
Medline CASGoogle Scholar
16 Hocaoglu I, Cizmeciyan MN, Erdem R et al. Development of highly luminescent and cytocompatible near-IR-emitting aqueous Ag₂S quantum dots. J. Mater. Chem. 22(29), 14674–14681 (2012). • Demonstrates high cytocompatability of 2-mercaptopropionic acid-coated Ag2S.
CASGoogle Scholar
17 Chen J, Feng L, Zhang M, Zhang X, Su H, Cui D. Synthesis of ribonuclease-a conjugated Ag2S quantum dots clusters via biomimetic route. Mater. Lett. 96 224–227 (2013).
CASGoogle Scholar
18 Smith AM, Duan H, Mohs AM, Nie S. Bioconjugated quantum dots for in vivo molecular and cellular imaging. Adv. Drug Deliv. Rev. 60(11), 1226–1240 (2008).
Medline CASGoogle Scholar
19 Qi L, Gao X. Emerging application of quantum dots for drug delivery and therapy. Expert Opin. Drug Deliv. 5(3), 263–267 (2008).
Medline CASGoogle Scholar
20 Derfus AM, Chen AA, Min D-H, Ruoslahti E, Bhatia SN. Targeted quantum dot conjugates for siRNA delivery. Bioconjugate Chem. 18(5), 1391–1396 (2007).
Medline CASGoogle Scholar
21 Hocaoglu I, Demir F, Birer O et al. Emission tunable, cyto/hemocompatible, near-IR-emitting Ag2S quantum dots by aqueous decomposition of DMSA. Nanoscale 6(20), 11921–11931 (2014).
Medline CASGoogle Scholar
22 Yang H-Y, Zhao Y-W, Zhang Z-Y, Xiong H-M, Yu S-N. One-pot synthesis of water-dispersible Ag₂S quantum dots with bright fluorescent emission in the second near-infrared window. Nanotechnology 24(5), 055706 (2013).
MedlineGoogle Scholar
23 Duman FD, Khodadust R, Durmusoglu EG, Yagci MB, Acar HY. Impact of reaction variables and PEI/l-cysteine ratio on the optical properties and cytocompatibility of cationic Ag 2 S quantum dots as NIR bio-imaging probes. RSC Adv. 6(81), 77644–77654 (2016).
CASGoogle Scholar
24 Zhao D, He Z, Chan W, Choi MM. Synthesis and characterization of high-quality water-soluble near-infrared-emitting CdTe/CdS quantum dots capped by N-acetyl-L-cysteine via hydrothermal method. J. Phys. Chem. C 113(4), 1293–1300 (2008).
Google Scholar
25 Xue B, Deng D-W, Cao J et al. Synthesis of NAC capped near infrared-emitting CdTeS alloyed quantum dots and application for in vivo early tumor imaging. Dalton Trans. 41(16), 4935–4947 (2012).
Medline CASGoogle Scholar
26 Xiao L, Zhao D, Chan W-H, Choi MM, Li H-W. Inhibition of beta 1–40 amyloid fibrillation with N-acetyl-L-cysteine capped quantum dots. Biomaterials 31(1), 91–98 (2010).
Medline CASGoogle Scholar
27 Wang Q, Zhan G, Li C. Facile synthesis of N-acetyl-L-cysteine capped CdHgSe quantum dots and selective determination of hemoglobin. Spectrochim. Acta A 117 198–203 (2014).
CASGoogle Scholar
28 Wang Q, Yu X, Zhan G, Li C. Fluorescent sensor for selective determination of copper ion based on N-acetyl-L-cysteine capped CdHgSe quantum dots. Biosens. Bioelectron. 54 311–316 (2014).
MedlineGoogle Scholar
29 Yang T, He Q, Liu Y, Zhu C, Zhao D. Water-soluble N-Acetyl-L-cysteine-capped CdTe quantum dots application for Hg (II) detection. J. Anal. Methods Chem. 2013 (2013).
Google Scholar
30 Heli H, Majdi S, Sattarahmady N. Ultrasensitive sensing of N-acetyl-L-cysteine using an electrocatalytic transducer of nanoparticles of iron (III) oxide core–cobalt hexacyanoferrate shell. Sens. Actuators B Chem. 145(1), 185–193 (2010).
CASGoogle Scholar
31 Kelly GS. Clinical applications of N-acetylcysteine. Altern. Med. Rev. 3(2), 114–127 (1998).
Medline CASGoogle Scholar
32 Agarwal A, Said TM. Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach. BJU Int. 95(4), 503–507 (2005).
Medline CASGoogle Scholar
33 Kopke RD, Jackson RL, Coleman JK, Liu J, Bielefeld EC, Balough BJ. NAC for noise: from the bench top to the clinic. Hear. Res. 226(1-2), 114–125 (2007).
MedlineGoogle Scholar
34 Feghali JG, Liu W, Van De Water TR. L-N-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity. Laryngoscope 111(7), 1147–1155 (2001). •• Demonstrates the protective effect of N-acetyl-L-cysteine (NAC) against the side effects of chemotherepeutic drug cisplatin.
Medline CASGoogle Scholar
35 Doroshow J, Locker GY, Ifrim I, Myers CE. Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine. J. Clin. Investig. 68(4), 1053–1064 (1981).
Medline CASGoogle Scholar
36 Choi AO, Cho SJ, Desbarats J, Lovrić J, Maysinger D. Quantum dot-induced cell death involves Fas upregulation and lipid peroxidation in human neuroblastoma cells. J. Nanobiotechnol. 5(1), 1 (2007). •• Discusses the mechanisms of quantum dot (QD)-induced toxicity in human neuroblastoma cell line exposed to NAC-conjugated, NAC-capped and cysteamine-capped CdTe QDs.
MedlineGoogle Scholar
37 James LP, Mccullough SS, Lamps LW, Hinson JA. Effect of N-acetylcysteine on acetaminophen toxicity in mice: relationship to reactive nitrogen and cytokine formation. J. Toxicol. Sci. 75(2), 458–467 (2003).
CASGoogle Scholar
38 Soenen SJ, Montenegro JM, Abdelmonem AM et al. The effect of nanoparticle degradation on poly(methacrylic acid)-coated quantum dot toxicity: the importance of particle functionality assessment in toxicology. Acta Biomater. 10(2), 732–741 (2014).
Medline CASGoogle Scholar
39 Morrell CN. Reactive oxygen species: finding the right balance. Circ Res. 103(6), 571–572 (2008).
Medline CASGoogle Scholar
40 Bazhin AV, Philippov PP, Karakhanova S. Reactive oxygen species in cancer biology and anticancer therapy. Oxid. Med. Cell Longev. doi: 10.1155/2016/4197815 4197815 (2016).
MedlineGoogle Scholar
41 Jeong C-H, Joo SH. Downregulation of reactive oxygen species in apoptosis. J. Cancer Prev. 21(1), 13 (2016). •• Reports the decline of reactive oxygen species (ROS) during apoptotic cell death.
MedlineGoogle Scholar
42 Cho S-G, Woo S-M, Ko S-G. Butein suppresses breast cancer growth by reducing a production of intracellular reactive oxygen species. J. Exp. Clin. Cancer Res. 33(1), 51 (2014). •• Indicates that NAC, a free radical scavenger, reduces ROS production and AKT phosphorylation, resulting in apoptotic cell death in breast cancer.
MedlineGoogle Scholar
43 Markoutsa E, Xu P. Redox potential-sensitive N-acetyl cysteine-prodrug nanoparticles inhibit the activation of microglia and improve neuronal survival. Mol. Pharm. 14(5), 1591–1600 (2017).
Medline CASGoogle Scholar
44 Xue C, Liu W, Wu J, Yang X, Xu H. Chemoprotective effect of N-acetylcysteine (NAC) on cellular oxidative damages and apoptosis induced by nano titanium dioxide under UVA irradiation. Toxicol. In Vitro 25(1), 110–116 (2011).
Medline CASGoogle Scholar
45 He Y-Y, Häder D-P. UV-B-induced formation of reactive oxygen species and oxidative damage of the cyanobacterium Anabaena sp.: protective effects of ascorbic acid and N-acetyl-L-cysteine. J. Photochem. Photobiol. B 66(2), 115–124 (2002).
Medline CASGoogle Scholar
46 Harada D, Anraku M, Fukuda H et al. Kinetic studies of covalent binding between N-acetyl-L-cysteine and human serum albumin through a mixed-disulfide using an N-methylpyridinium polymer-based column. Drug Metab. Pharmacokinet. 19(4), 297–302 (2004).
Medline CASGoogle Scholar
47 Giustarini D, Milzani A, Dalle-Donne I, Tsikas D, Rossi R. N-Acetylcysteine ethyl ester (NACET): a novel lipophilic cell-permeable cysteine derivative with an unusual pharmacokinetic feature and remarkable antioxidant potential. Biochem. Pharmacol. 84(11), 1522–1533 (2012).
Medline CASGoogle Scholar
48 Grinberg L, Fibach E, Amer J, Atlas D. N-acetylcysteine amide, a novel cell-permeating thiol, restores cellular glutathione and protects human red blood cells from oxidative stress. Free Radic. Biol. Med. 38(1), 136–145 (2005).
Medline CASGoogle Scholar
49 Wang B, Navath RS, Romero R, Kannan S, Kannan R. Anti-inflammatory and anti-oxidant activity of anionic dendrimer–N-acetyl cysteine conjugates in activated microglial cells. Int. J. Pharm. 377(1-2), 159–168 (2009).
Medline CASGoogle Scholar
50 Jiang P, Tian Z-Q, Zhu C-N, Zhang Z-L, Pang D-W. Emission-tunable near-infrared Ag2S quantum dots. Chem. Mater. 24(1), 3–5 (2011).
Google Scholar
51 Madelung O. Semiconductors: Data Handbook. 3rd Edition Springer, Berlin, Germany (2004).
Google Scholar
52 HFM Marlene C, Morris EHE, Paretzkin B, Parker HS, Panagiotopoulos NC. Standard x-ray diffraction powder patterns. UNT Digital Library, Washington DC, USA (1960).
Google Scholar
53 Pavlin M, Bregar VB. Stability of nanoparticle suspensions in different biologically relevant media. Dig. J. Nanomater. Bios. 7(4), 1389–1400 (2012).
Google Scholar
54 Eruslanov E, Kusmartsev S. Identification of ROS using oxidized DCFDA and flow-cytometry. In: Advanced Protocols in Oxidative Stress II. Amstrong, Donald (Eds). Springer 57–72 (2010).
Google Scholar
55 Nargi JL, Ratan RR, Griffin DE. p53-independent inhibition of proliferation and p21Waf1/Cip1-modulated induction of cell death by the antioxidants N-acetylcysteine and vitamin E. Neoplasia 1(6), 544–556 (1999).
Medline CASGoogle Scholar
56 Kawakami S, Kageyama Y, Fujii Y, Kihara K, Oshima H. Inhibitory effect of N-acetylcysteine on invasion and MMP-9 production of T24 human bladder cancer cells. Anticancer Res. 21(1A), 213–219 (2001).
Medline CASGoogle Scholar
57 Supabphol A, Muangman V, Chavasiri W, Supabphol R, Gritsanapan W. N-acetylcysteine inhibits proliferation, adhesion, migration and invasion of human bladder cancer cells. J. Med. Assoc. Thai. 92(9), 1171 (2009).
MedlineGoogle Scholar
58 Lee Y-J, Lee DM, Lee C-H et al. Suppression of human prostate cancer PC-3 cell growth by N-acetylcysteine involves over-expression of Cyr61. Toxicol. In Vitro 25(1), 199–205 (2011).
Medline CASGoogle Scholar
59 Lee M-F, Chan C-Y, Hung H-C, Chou I-T, Yee AS, Huang C-Y. N-acetylcysteine (NAC) inhibits cell growth by mediating the EGFR/Akt/HMG box-containing protein 1 (HBP1) signaling pathway in invasive oral cancer. Oral Oncol. 49(2), 129–135 (2013).
Medline CASGoogle Scholar
60 Hann SS, Zheng F, Zhao S. Targeting 3-phosphoinositide-dependent protein kinase 1 by N-acetyl-cysteine through activation of peroxisome proliferators activated receptor alpha in human lung cancer cells, the role of p53 and p65. J. Exp. Clin. Cancer Res. 32(1), 43 (2013).
Medline CASGoogle Scholar
61 Ulukaya E, Ozdikicioglu F, Oral AY, Demirci M. The MTT assay yields a relatively lower result of growth inhibition than the ATP assay depending on the chemotherapeutic drugs tested. Toxicol. In Vitro 22(1), 232–239 (2008). • Detailed report illustrating the effect of N-acetyl cysteine and penicillamine on apoptosis.
Medline CASGoogle Scholar
62 Amini A, Masoumi-Moghaddam S, Ehteda A, Morris DL. Bromelain and N-acetylcysteine inhibit proliferation and survival of gastrointestinal cancer cells in vitro: significance of combination therapy. J. Exp. Clin. Cancer Res. 33(1), 92 (2014).
MedlineGoogle Scholar
63 Guan D, Xu Y, Yang M, Wang H, Wang X, Shen Z. N-acetyl cysteine and penicillamine induce apoptosis via the ER stress response-signaling pathway. Mol. Carcinog. 49(1), 68–74 (2010).
Medline CASGoogle Scholar
64 Tsai J-C, Jain M, Hsieh C-M et al. Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells. J. Biol. Chem. 271(7), 3667–3670 (1996).
Medline CASGoogle Scholar
65 Liu M, Pelling JC, Ju J, Chu E, Brash DE. Antioxidant action via p53-mediated apoptosis. Cancer Res. 58(8), 1723–1729 (1998).
Medline CASGoogle Scholar
66 Havre PA, O’reilly S, Mccormick JJ, Brash DE. Transformed and tumor-derived human cells exhibit preferential sensitivity to the thiol antioxidants, N-acetyl cysteine and penicillamine. Cancer Res. 62(5), 1443–1449 (2002).
Medline CASGoogle Scholar
67 Navath RS, Kurtoglu YE, Wang B, Kannan S, Romero R, Kannan RM. Dendrimer−drug conjugates for tailored intracellular drug release based on glutathione levels. Bioconjugate Chem. 19(12), 2446–2455 (2008).
Medline CASGoogle Scholar
68 Lepri E, Gambelunghe C, Fioravanti A, Pedini M, Micheletti A, Rufini S. N-acetylcysteine increases apoptosis induced by H2O2 and mo-antiFas triggering in a 3DO hybridoma cell line. Cell Biochem. Funct. 18(3), 201–208 (2000).
Medline CASGoogle Scholar
69 Rieber M, Rieber MS. N-Acetylcysteine enhances UV-mediated caspase-3 activation, fragmentation of E2F-4, and apoptosis in human C8161 melanoma: inhibition by ectopic Bcl-2 expression. Biochem. Pharmacol. 65(10), 1593–1601 (2003).
Medline CASGoogle Scholar
70 Deshpande V, Kehrer JP. Mechanisms of N-acetylcysteine-driven enhancement of MK886-induced apoptosis. Cell Biol. Toxicol. 22(4), 303–311 (2006).
Medline CASGoogle Scholar
71 Zhang L, Cheng X, Gao Y et al. Induction of ROS-independent DNA damage by curcumin leads to G2/M cell cycle arrest and apoptosis in human papillary thyroid carcinoma BCPAP cells. Food Funct. 7(1), 315–325 (2016).
Medline CASGoogle Scholar
72 Yamashita N, Kawanishi S. Distinct mechanisms of DNA damage in apoptosis induced by quercetin and luteolin. Free Radic. Res. 33(5), 623–633 (2000). • In this study it was shown that ROS is not required for DNA damage.
Medline CASGoogle Scholar
73 Santus P, Corsico A, Solidoro P, Braido F, Di Marco F, Scichilone N. Oxidative stress and respiratory system: pharmacological and clinical reappraisal of N-Acetylcysteine. COPD 11(6), 705–717 (2014).
MedlineGoogle Scholar
74 Dekhuijzen PNR. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur. Respir. J. 23(4), 629–636 (2004).
Medline CASGoogle Scholar
75 Vanzandwijk N. N-acetylcysteine for lung-cancer prevention. Chest 107(5), 1437–1441 (1995).
Medline CASGoogle Scholar

Vol. 14, No. 8

Supplemental Materials

Metrics

Downloaded 296 times

History

Received 22 June 2018

Accepted 3 January 2019

Published online 27 March 2019

Published in print April 2019

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nnm-2018-0214

Acknowledgments

Authors are thankful to Dr Gulsu Simsek (KUYTAM, Koc University, Istanbul, Turkey) for her assistance in ICP-MS measurements, Dr Baris Yagci for his assistance in organic elemental analysis and Dr Emek Goksu Durmusoglu for his assistance in fluorescence lifetime analysis.

Financial & competing interests disclosure

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download

Development of near-infrared region luminescent N-acetyl-L-cysteine-coated Ag2S quantum dots with differential therapeutic effect

Abstract

References

Development of near-infrared region luminescent N-acetyl-L-cysteine-coated Ag₂S quantum dots with differential therapeutic effect