A Concise Review of Gold Nanoparticles-Based Photo-Responsive Liposomes for Controlled Drug Delivery
Corresponding Author: Chenjie Xu
Nano-Micro Letters,
Vol. 10 No. 1 (2018), Article Number: 10
Abstract
The focus of drug delivery is shifting toward smart drug carriers that release the cargo in response to a change in the microenvironment due to an internal or external trigger. As the most clinically successful nanosystem, liposomes naturally come under the spotlight of this trend. This review summarizes the latest development about the design and construction of photo-responsive liposomes with gold nanoparticles for the controlled drug release. Alongside, we overview the mechanism involved in this process and the representative applications.
Highlights:
1 Photo-responsive liposomes are powerful carriers for topical and transdermal drug delivery to superficial tissues like skin, eyes, and mucous membranes.
2 Photo-responsive liposomes can be built with gold nanoparticles, which allow the use of near-infrared lights as the light source for deep tissue penetration and low phototoxicity.
3 This review summarizes the latest development and scientific understanding of this complex in delivering drugs for tuning cell signaling pathway and treating cancer.
Keywords
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- T.M. Allen, P.R. Cullis, Liposomal drug delivery systems: from concept to clinical applications. Adv. Drug Deliv. Rev. 65(1), 36–48 (2013). doi:10.1016/j.addr.2012.09.037
- A.C. Anselmo, S. Mitragotri, Nanoparticles in the clinic. Bioeng. Transl. Med. 1(1), 10–29 (2016). doi:10.1002/btm2.10003
- U. Bulbake, S. Doppalapudi, N. Kommineni, W. Khan, Liposomal formulations in clinical use: an updated review. Pharmaceutics 9(2), 12 (2017). doi:10.3390/pharmaceutics9020012
- V.P. Torchilin, Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat. Rev. Drug Discov. 13(11), 813–827 (2014). doi:10.1038/nrd4333
- S. Mura, J. Nicolas, P. Couvreur, Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12(11), 991–1003 (2013). doi:10.1038/nmat3776
- Y. Lee, D.H. Thompson, Stimuli-responsive liposomes for drug delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 9(5), 1450 (2017). doi:10.1002/wnan.1450
- F. Movahedi, R.G. Hu, D.L. Becker, C. Xu, Stimuli-responsive liposomes for the delivery of nucleic acid therapeutics. Nanomedicine 11(6), 1575–1584 (2015). doi:10.1016/j.nano.2015.03.006
- A. Yavlovich, B. Smith, K. Gupta, R. Blumenthal, A. Puri, Light-sensitive lipid-based nanoparticles for drug delivery: design principles and future considerations for biological applications. Mol. Membr. Biol. 27(7), 364–381 (2010). doi:10.3109/09687688.2010.507788
- C. Kojima, Y. Hirano, E. Yuba, A. Harada, K. Kono, Preparation and characterization of complexes of liposomes with gold nanoparticles. Colloids Surf. B 66(2), 246–252 (2008). doi:10.1016/j.colsurfb.2008.06.022
- S.-H. Park, S.-G. Oh, J.-Y. Mun, S.-S. Han, Loading of gold nanoparticles inside the dppc bilayers of liposome and their effects on membrane fluidities. Colloids Surf. B 48(2), 112–118 (2006). doi:10.1016/j.colsurfb.2006.01.006
- L. Paasonen, T. Laaksonen, C. Johans, M. Yliperttula, K. Kontturi, A. Urtti, Gold nanoparticles enable selective light-induced contents release from liposomes. J. Control. Release 122(1), 86–93 (2007). doi:10.1016/j.jconrel.2007.06.009
- X. An, F. Zhang, Y. Zhu, W. Shen, Photoinduced drug release from thermosensitive aunps-liposome using a aunps-switch. Chem. Commun. 46(38), 7202–7204 (2010). doi:10.1039/c0cc03142a
- N. Zhang, H. Chen, A.-Y. Liu, J.-J. Shen, V. Shah, C. Zhang, J. Hong, Y. Ding, Gold conjugate-based liposomes with hybrid cluster bomb structure for liver cancer therapy. Biomaterials 74, 280–291 (2016). doi:10.1016/j.biomaterials
- E. Amstad, J. Kohlbrecher, E. Müller, T. Schweizer, M. Textor, E. Reimhult, Triggered release from liposomes through magnetic actuation of iron oxide nanoparticle containing membranes. Nano Lett. 11(4), 1664–1670 (2011). doi:10.1021/nl2001499
- M. Mathiyazhakan, Y. Yang, Y. Liu, C. Zhu, Q. Liu, C.-D. Ohl, K.C. Tam, Y. Gao, C. Xu, Non-invasive controlled release from gold nanoparticle integrated photo-responsive liposomes through pulse laser induced microbubble cavitation. Colloids Surf. B 126(6), 569–574 (2015). doi:10.1016/j.colsurfb.2014.11.019
- L. Viitala, S. Pajari, T. Lajunen, L.-S. Kontturi, T. Laaksonen, P. Kuosmanen, T. Viitala, A. Urtti, L. Murtomäki, Photothermally triggered lipid bilayer phase transition and drug release from gold nanorod and indocyanine green encapsulated liposomes. Langmuir 32(18), 4554–4563 (2016). doi:10.1021/acs.langmuir.6b00716
- T. Lajunen, L. Viitala, L.-S. Kontturi, T. Laaksonen, H. Liang et al., Light induced cytosolic drug delivery from liposomes with gold nanoparticles. J. Control. Release 203, 85–98 (2015). doi:10.1016/j.jconrel.2015.02.028
- A. Akbarzadeh, R. Rezaei-Sadabady, S. Davaran, S.W. Joo, N. Zarghami, Y. Hanifehpour, M. Samiei, M. Kouhi, K. Nejati-Koshki, Liposome: classification, preparation, and applications. Nanoscale Res. Lett. 8(1), 102 (2013). doi:10.1186/1556-276X-8-102
- M. Mathiyazhakan, P.K. Upputuri, K. Sivasubramanian, A. Dhayani, P.K. Vemula et al., In situ synthesis of gold nanostars within liposomes for controlled drug release and photoacoustic imaging. Sci. China Mater. 59(11), 892–900 (2016). doi:10.1007/s40843-016-5101-3
- J.-H. Lee, Y. Shin, W. Lee, K. Whang, D. Kim, L.P. Lee, J.-W. Choi, T. Kang, General and programmable synthesis of hybrid liposome/metal nanoparticles. Sci. Adv. 2(12), 1601838 (2016). doi:10.1126/sciadv.1601838
- N. Dave, J. Liu, Protection and promotion of uv radiation-induced liposome leakage via DNA-directed assembly with gold nanoparticles. Adv. Mater. 23(28), 3182–3186 (2011). doi:10.1002/adma.201101086
- T.K. Sau, A.S. Urban, S.K. Dondapati, M. Fedoruk, M.R. Horton, A.L. Rogach, F.D. Stefani, J.O. Rädler, J. Feldmann, Controlling loading and optical properties of gold nanoparticles on liposome membranes. Colloids Surf. A 342(1), 92–96 (2009). doi:10.1016/j.colsurfa.2009.04.014
- K. Sivasubramanian, M. Mathiyazhakan, C. Wiraja, P.K. Upputuri, C. Xu, M. Pramanik, Near-infrared light-responsive liposomal contrast agent for photoacoustic imaging and drug release applications. J. Biomed. Opt. 22(4), 41007 (2016). doi:10.1117/1.JBO.22.4.041007
- J. Xie, J.Y. Lee, D.I. Wang, Seedless, surfactantless, high-yield synthesis of branched gold nanocrystals in hepes buffer solution. Chem. Mater. 19(11), 2823–2830 (2007). doi:10.1021/cm0700100
- R. Chen, J. Wu, H. Li, G. Cheng, Z. Lu, C.-M. Che, Fabrication of gold nanoparticles with different morphologies in hepes buffer. Rare Met. 29(2), 180–186 (2010). doi:10.1007/s12598-010-0031-5
- L. Luo, Y. Bian, Y. Liu, X. Zhang, M. Wang, S. Xing, L. Li, D. Gao, Gold nanoshells: combined near infrared photothermal therapy and chemotherapy using gold nanoshells coated liposomes to enhance antitumor effect. Small 12(30), 4103–4112 (2016). doi:10.1002/smll.201670150
- D.V. Volodkin, A.G. Skirtach, H. Mohwald, Near-ir remote release from assemblies of liposomes and nanoparticles. Angew. Chem. Int. Ed. 48(10), 1807–1809 (2009). doi:10.1002/anie.200805572
- A. Agarwal, M.A. Mackey, M.A. El-Sayed, R.V. Bellamkonda, Remote triggered release of doxorubicin in tumors by synergistic application of thermosensitive liposomes and gold nanorods. ACS Nano 5(6), 4919–4926 (2011). doi:10.1021/nn201010q
- Y.-C. Ou, J.A. Webb, S. Faley, D. Shae, E.M. Talbert et al., Gold nanoantenna-mediated photothermal drug delivery from thermosensitive liposomes in breast cancer. ACS Omega 1(2), 234–243 (2016). doi:10.1021/acsomega.6b00079
- N. Fomina, J. Sankaranarayanan, A. Almutairi, Photochemical mechanisms of light-triggered release from nanocarriers. Adv. Drug Deliv. Rev. 64(11), 1005–1020 (2012). doi:10.1016/j.addr.2012.02.006
- D. Miranda, J.F. Lovell, Mechanisms of light-induced liposome permeabilization. Bioeng. Transl. Med. 1(3), 267–276 (2016). doi:10.1002/btm2.10032
- A.K. Rengan, A.B. Bukhari, A. Pradhan, R. Malhotra, R. Banerjee, R. Srivastava, A. De, In vivo analysis of biodegradable liposome gold nanoparticles as efficient agents for photothermal therapy of cancer. Nano Lett. 15(2), 842–848 (2015). doi:10.1021/nl5045378
- S.J. Leung, X.M. Kachur, M.C. Bobnick, M. Romanowski, Wavelength-selective light-induced release from plasmon resonant liposomes. Adv. Funct. Mater. 21(6), 1113–1121 (2011). doi:10.1002/adfm.201002373
- G. Wu, A. Mikhailovsky, H.A. Khant, C. Fu, W. Chiu, J.A. Zasadzinski, Remotely triggered liposome release by near-infrared light absorption via hollow gold nanoshells. J. Am. Chem. Soc. 130(26), 8175–8177 (2008). doi:10.1021/ja802656d
- C. Wiraja, M. Mathiyazhakan, F. Movahedi, P.K. Upputuri, Y. Cheng, M. Pramanik, L. Yang, D.L. Becker, C. Xu, Near-infrared light-sensitive liposomes for enhanced plasmid DNA transfection. Bioeng. Transl. Med. 1(3), 357–364 (2016). doi:10.1002/btm2.10020
- X. Li, Z. Che, K. Mazhar, T.J. Price, Z. Qin, Ultrafast near-infrared light-triggered intracellular uncaging to probe cell signaling. Adv. Funct. Mater. 27(11), 1605778 (2017). doi:10.1002/adfm.201605778
- M.J. Berridge, M.D. Bootman, P. Lipp, Calcium-a life and death signal. Nature 395(6703), 645–648 (1998). doi:10.1038/27094
- R. Gui, A. Wan, X. Liu, H. Jin, Intracellular fluorescent thermometry and photothermal-triggered drug release developed from gold nanoclusters and doxorubicin dual-loaded liposomes. Chem. Commun. 50(13), 1546–1548 (2014). doi:10.1039/c3cc47981a
- K. Kim, K.S. Oh, D.Y. Park, J.Y. Lee, B.S. Lee et al., Doxorubicin/gold-loaded core/shell nanoparticles for combination therapy to treat cancer through the enhanced tumor targeting. J. Control. Release 228, 141–149 (2016). doi:10.1016/j.jconrel.2016.03.009
- D. Luo, K.A. Carter, D. Miranda, J.F. Lovell, Chemophototherapy: an emerging treatment option for solid tumors. Adv. Sci. 4(1), 1600106 (2017). doi:10.1002/advs.201600106
- T.S. Troutman, J.K. Barton, M. Romanowski, Biodegradable plasmon resonant nanoshells. Adv. Mater. 20(13), 2604–2608 (2008). doi:10.1002/adma.200703026
- A.K. Rengan, M. Jagtap, A. De, R. Banerjee, R. Srivastava, Multifunctional gold coated thermo-sensitive liposomes for multimodal imaging and photo-thermal therapy of breast cancer cells. Nanoscale 6(2), 916–923 (2014). doi:10.1039/C3NR04448C
- L. Viitala, A.M. Maley, H.W.M. Fung, R.M. Corn, T. Viitala, L. Murtomäki, Surface plasmon resonance imaging microscopy of liposomes and liposome-encapsulated gold nanoparticles. J. Phys. Chem. C 120(45), 25958–25966 (2016). doi:10.1021/acs.jpcc.6b09503
References
T.M. Allen, P.R. Cullis, Liposomal drug delivery systems: from concept to clinical applications. Adv. Drug Deliv. Rev. 65(1), 36–48 (2013). doi:10.1016/j.addr.2012.09.037
A.C. Anselmo, S. Mitragotri, Nanoparticles in the clinic. Bioeng. Transl. Med. 1(1), 10–29 (2016). doi:10.1002/btm2.10003
U. Bulbake, S. Doppalapudi, N. Kommineni, W. Khan, Liposomal formulations in clinical use: an updated review. Pharmaceutics 9(2), 12 (2017). doi:10.3390/pharmaceutics9020012
V.P. Torchilin, Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat. Rev. Drug Discov. 13(11), 813–827 (2014). doi:10.1038/nrd4333
S. Mura, J. Nicolas, P. Couvreur, Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12(11), 991–1003 (2013). doi:10.1038/nmat3776
Y. Lee, D.H. Thompson, Stimuli-responsive liposomes for drug delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 9(5), 1450 (2017). doi:10.1002/wnan.1450
F. Movahedi, R.G. Hu, D.L. Becker, C. Xu, Stimuli-responsive liposomes for the delivery of nucleic acid therapeutics. Nanomedicine 11(6), 1575–1584 (2015). doi:10.1016/j.nano.2015.03.006
A. Yavlovich, B. Smith, K. Gupta, R. Blumenthal, A. Puri, Light-sensitive lipid-based nanoparticles for drug delivery: design principles and future considerations for biological applications. Mol. Membr. Biol. 27(7), 364–381 (2010). doi:10.3109/09687688.2010.507788
C. Kojima, Y. Hirano, E. Yuba, A. Harada, K. Kono, Preparation and characterization of complexes of liposomes with gold nanoparticles. Colloids Surf. B 66(2), 246–252 (2008). doi:10.1016/j.colsurfb.2008.06.022
S.-H. Park, S.-G. Oh, J.-Y. Mun, S.-S. Han, Loading of gold nanoparticles inside the dppc bilayers of liposome and their effects on membrane fluidities. Colloids Surf. B 48(2), 112–118 (2006). doi:10.1016/j.colsurfb.2006.01.006
L. Paasonen, T. Laaksonen, C. Johans, M. Yliperttula, K. Kontturi, A. Urtti, Gold nanoparticles enable selective light-induced contents release from liposomes. J. Control. Release 122(1), 86–93 (2007). doi:10.1016/j.jconrel.2007.06.009
X. An, F. Zhang, Y. Zhu, W. Shen, Photoinduced drug release from thermosensitive aunps-liposome using a aunps-switch. Chem. Commun. 46(38), 7202–7204 (2010). doi:10.1039/c0cc03142a
N. Zhang, H. Chen, A.-Y. Liu, J.-J. Shen, V. Shah, C. Zhang, J. Hong, Y. Ding, Gold conjugate-based liposomes with hybrid cluster bomb structure for liver cancer therapy. Biomaterials 74, 280–291 (2016). doi:10.1016/j.biomaterials
E. Amstad, J. Kohlbrecher, E. Müller, T. Schweizer, M. Textor, E. Reimhult, Triggered release from liposomes through magnetic actuation of iron oxide nanoparticle containing membranes. Nano Lett. 11(4), 1664–1670 (2011). doi:10.1021/nl2001499
M. Mathiyazhakan, Y. Yang, Y. Liu, C. Zhu, Q. Liu, C.-D. Ohl, K.C. Tam, Y. Gao, C. Xu, Non-invasive controlled release from gold nanoparticle integrated photo-responsive liposomes through pulse laser induced microbubble cavitation. Colloids Surf. B 126(6), 569–574 (2015). doi:10.1016/j.colsurfb.2014.11.019
L. Viitala, S. Pajari, T. Lajunen, L.-S. Kontturi, T. Laaksonen, P. Kuosmanen, T. Viitala, A. Urtti, L. Murtomäki, Photothermally triggered lipid bilayer phase transition and drug release from gold nanorod and indocyanine green encapsulated liposomes. Langmuir 32(18), 4554–4563 (2016). doi:10.1021/acs.langmuir.6b00716
T. Lajunen, L. Viitala, L.-S. Kontturi, T. Laaksonen, H. Liang et al., Light induced cytosolic drug delivery from liposomes with gold nanoparticles. J. Control. Release 203, 85–98 (2015). doi:10.1016/j.jconrel.2015.02.028
A. Akbarzadeh, R. Rezaei-Sadabady, S. Davaran, S.W. Joo, N. Zarghami, Y. Hanifehpour, M. Samiei, M. Kouhi, K. Nejati-Koshki, Liposome: classification, preparation, and applications. Nanoscale Res. Lett. 8(1), 102 (2013). doi:10.1186/1556-276X-8-102
M. Mathiyazhakan, P.K. Upputuri, K. Sivasubramanian, A. Dhayani, P.K. Vemula et al., In situ synthesis of gold nanostars within liposomes for controlled drug release and photoacoustic imaging. Sci. China Mater. 59(11), 892–900 (2016). doi:10.1007/s40843-016-5101-3
J.-H. Lee, Y. Shin, W. Lee, K. Whang, D. Kim, L.P. Lee, J.-W. Choi, T. Kang, General and programmable synthesis of hybrid liposome/metal nanoparticles. Sci. Adv. 2(12), 1601838 (2016). doi:10.1126/sciadv.1601838
N. Dave, J. Liu, Protection and promotion of uv radiation-induced liposome leakage via DNA-directed assembly with gold nanoparticles. Adv. Mater. 23(28), 3182–3186 (2011). doi:10.1002/adma.201101086
T.K. Sau, A.S. Urban, S.K. Dondapati, M. Fedoruk, M.R. Horton, A.L. Rogach, F.D. Stefani, J.O. Rädler, J. Feldmann, Controlling loading and optical properties of gold nanoparticles on liposome membranes. Colloids Surf. A 342(1), 92–96 (2009). doi:10.1016/j.colsurfa.2009.04.014
K. Sivasubramanian, M. Mathiyazhakan, C. Wiraja, P.K. Upputuri, C. Xu, M. Pramanik, Near-infrared light-responsive liposomal contrast agent for photoacoustic imaging and drug release applications. J. Biomed. Opt. 22(4), 41007 (2016). doi:10.1117/1.JBO.22.4.041007
J. Xie, J.Y. Lee, D.I. Wang, Seedless, surfactantless, high-yield synthesis of branched gold nanocrystals in hepes buffer solution. Chem. Mater. 19(11), 2823–2830 (2007). doi:10.1021/cm0700100
R. Chen, J. Wu, H. Li, G. Cheng, Z. Lu, C.-M. Che, Fabrication of gold nanoparticles with different morphologies in hepes buffer. Rare Met. 29(2), 180–186 (2010). doi:10.1007/s12598-010-0031-5
L. Luo, Y. Bian, Y. Liu, X. Zhang, M. Wang, S. Xing, L. Li, D. Gao, Gold nanoshells: combined near infrared photothermal therapy and chemotherapy using gold nanoshells coated liposomes to enhance antitumor effect. Small 12(30), 4103–4112 (2016). doi:10.1002/smll.201670150
D.V. Volodkin, A.G. Skirtach, H. Mohwald, Near-ir remote release from assemblies of liposomes and nanoparticles. Angew. Chem. Int. Ed. 48(10), 1807–1809 (2009). doi:10.1002/anie.200805572
A. Agarwal, M.A. Mackey, M.A. El-Sayed, R.V. Bellamkonda, Remote triggered release of doxorubicin in tumors by synergistic application of thermosensitive liposomes and gold nanorods. ACS Nano 5(6), 4919–4926 (2011). doi:10.1021/nn201010q
Y.-C. Ou, J.A. Webb, S. Faley, D. Shae, E.M. Talbert et al., Gold nanoantenna-mediated photothermal drug delivery from thermosensitive liposomes in breast cancer. ACS Omega 1(2), 234–243 (2016). doi:10.1021/acsomega.6b00079
N. Fomina, J. Sankaranarayanan, A. Almutairi, Photochemical mechanisms of light-triggered release from nanocarriers. Adv. Drug Deliv. Rev. 64(11), 1005–1020 (2012). doi:10.1016/j.addr.2012.02.006
D. Miranda, J.F. Lovell, Mechanisms of light-induced liposome permeabilization. Bioeng. Transl. Med. 1(3), 267–276 (2016). doi:10.1002/btm2.10032
A.K. Rengan, A.B. Bukhari, A. Pradhan, R. Malhotra, R. Banerjee, R. Srivastava, A. De, In vivo analysis of biodegradable liposome gold nanoparticles as efficient agents for photothermal therapy of cancer. Nano Lett. 15(2), 842–848 (2015). doi:10.1021/nl5045378
S.J. Leung, X.M. Kachur, M.C. Bobnick, M. Romanowski, Wavelength-selective light-induced release from plasmon resonant liposomes. Adv. Funct. Mater. 21(6), 1113–1121 (2011). doi:10.1002/adfm.201002373
G. Wu, A. Mikhailovsky, H.A. Khant, C. Fu, W. Chiu, J.A. Zasadzinski, Remotely triggered liposome release by near-infrared light absorption via hollow gold nanoshells. J. Am. Chem. Soc. 130(26), 8175–8177 (2008). doi:10.1021/ja802656d
C. Wiraja, M. Mathiyazhakan, F. Movahedi, P.K. Upputuri, Y. Cheng, M. Pramanik, L. Yang, D.L. Becker, C. Xu, Near-infrared light-sensitive liposomes for enhanced plasmid DNA transfection. Bioeng. Transl. Med. 1(3), 357–364 (2016). doi:10.1002/btm2.10020
X. Li, Z. Che, K. Mazhar, T.J. Price, Z. Qin, Ultrafast near-infrared light-triggered intracellular uncaging to probe cell signaling. Adv. Funct. Mater. 27(11), 1605778 (2017). doi:10.1002/adfm.201605778
M.J. Berridge, M.D. Bootman, P. Lipp, Calcium-a life and death signal. Nature 395(6703), 645–648 (1998). doi:10.1038/27094
R. Gui, A. Wan, X. Liu, H. Jin, Intracellular fluorescent thermometry and photothermal-triggered drug release developed from gold nanoclusters and doxorubicin dual-loaded liposomes. Chem. Commun. 50(13), 1546–1548 (2014). doi:10.1039/c3cc47981a
K. Kim, K.S. Oh, D.Y. Park, J.Y. Lee, B.S. Lee et al., Doxorubicin/gold-loaded core/shell nanoparticles for combination therapy to treat cancer through the enhanced tumor targeting. J. Control. Release 228, 141–149 (2016). doi:10.1016/j.jconrel.2016.03.009
D. Luo, K.A. Carter, D. Miranda, J.F. Lovell, Chemophototherapy: an emerging treatment option for solid tumors. Adv. Sci. 4(1), 1600106 (2017). doi:10.1002/advs.201600106
T.S. Troutman, J.K. Barton, M. Romanowski, Biodegradable plasmon resonant nanoshells. Adv. Mater. 20(13), 2604–2608 (2008). doi:10.1002/adma.200703026
A.K. Rengan, M. Jagtap, A. De, R. Banerjee, R. Srivastava, Multifunctional gold coated thermo-sensitive liposomes for multimodal imaging and photo-thermal therapy of breast cancer cells. Nanoscale 6(2), 916–923 (2014). doi:10.1039/C3NR04448C
L. Viitala, A.M. Maley, H.W.M. Fung, R.M. Corn, T. Viitala, L. Murtomäki, Surface plasmon resonance imaging microscopy of liposomes and liposome-encapsulated gold nanoparticles. J. Phys. Chem. C 120(45), 25958–25966 (2016). doi:10.1021/acs.jpcc.6b09503