Stimuli-responsive degradable silica nanoparticles (NPs) are active topics of nanomaterial research, because they are expected to be low health-risk nanocarriers capable of controlled release of drugs. Among various stimuli-responsive silica NPs, disulfide bond-containing NPs show degradability by glutathione reduced form (GSH). Here, we synthesized and characterized three kinds of thiol-organosilica NPs made from 3-mercaptopropyltrimethoxysilane (MPMS) and 3-mercaptopropyl(dimethoxy)methylsilane (MPDMS). MPMS NPs, MPDMS NPs, and MPMS–MPDMS hybrid NPs revealed that the abundance ratio of disulfide bonds to thiols increased with the increase in content rate of MPDMS in thiol-organosilica NPs. We also revealed that thiol-organosilica NPs, which have disulfide bonds, are GSH-responsive degradable silica NPs using an electron microscopy and Ellman’s tests. Furthermore, we synthesized fluorescent MPMS–MPDMS NPs, including rhodamine B, and demonstrated the GSH-responsive release of dye from the NPs. These experiments indicate the potential of thiol-organosilica NPs, which have disulfide bonds as a GSH-responsive drug carrier.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
J.E. Gagner, S. Shrivastava, X. Qian, J.S. Dordick, and R.W. Siegel Engineering nanomaterials for biomedical applications requires understanding the nano-bio interface: A perspective. J. Phys. Chem. Lett. 3, 3149 (2012).
L-C. Cheng, X. Jiang, J. Wang, C. Chen, and R-S. Liu Nano-bio effects: Interaction of nanomaterials with cells. Nanoscale 5, 3547 (2013).
A. Bitar, N.M. Ahmad, H. Fessi, and A. Elaissari Silica-based nanoparticles for biomedical applications. Drug Discov. Today 17, 1147 (2012).
L. Tang and J. Cheng Nonporous silica nanoparticles for nanomedicine application. Nano Today 8, 290 (2013).
Y. Wang, Q. Zhao, N. Han, L. Bai, J. Li, J. Liu, E. Che, L. Hu, Q. Zhang, T. Jiang, and S. Wang Mesoporous silica nanoparticles in drug delivery and biomedical applications. Nanomedicine 11, 313 (2015).
P.M. Tiwari, K. Vig, V.A. Dennis, and S.R. Singh Functionalized gold nanoparticles and their biomedical applications. Nanomaterials 1, 31 (2011).
A. Ali, H. Zafar, M. Zia, I.U. Haq, A.R. Phull, J.S. Ali, and A. Hussain Synthesis, characterization, applications, and challenges of iron oxide nanoparticles. Nanotechnol. Sci. Appl. 9, 49 (2016).
Y. Zhang, T.R. Nayak, H. Hong, and W. Cai Biomedical applications of zinc oxide nanomaterials. Curr. Mol. Med. 13, 1633 (2013).
D. Chimene, D.L. Alge, and A.K. Gaharwar Two-dimensional nanomaterials for biomedical applications: Emerging trends and future prospects. Adv. Mater. 27, 7261 (2015).
N.J. Halas Nanoscience under glass: The versatile chemistry of silica nanostructures. ACS Nano 2, 179 (2008).
H. Nishimori, M. Kondoh, K. Isoda, S. Tsunoda, and Y. Tsutsumi Histological analysis of 70-nm silica particles-induced chronic toxicity in mice. Eur. J. Pharm. Biopharm. 72, 626 (2009).
G. Xie, J. Sun, G. Zhong, L. Shi, and D. Zhang Biodistribution and toxicity of intravenously administered silica nanoparticles in mice. Arch. Toxicol. 84, 183 (2010).
Y. Yu, J. Duan, Y. Li, Y. Li, L. Jing, M. Yang, J. Wang, and Z. Sun Silica nanoparticles induce liver fibrosis via TGF-β1/Smad3 pathway in ICR mice. Int. J. Nanomed. 12, 6045 (2017).
T. Liu, L. Li, X. Teng, X. Huang, H. Liu, D. Chen, J. Ren, J. He, and F. Tang Single and repeated dose toxicity of mesoporous hollow silica nanoparticles in intravenously exposed mice. Biomaterials 32, 1657 (2011).
T. Lin, L. Li, C. Fu, H. Liu, D. Chen, and F. Tang Pathological mechanisms of liver injury caused by continuous intraperitoneal injection of silica nanoparticles. Biomaterials 33, 2399 (2012).
H. Mekaru, J. Lu, and F. Tamanoi Development of mesoporous silica-based nanoparticles with controlled release capability for cancer therapy. Adv. Drug Deliv. Rev. 95, 40 (2015).
A.F. Moreira, D.R. Dias, and I.J. Correia Stimuli-responsive mesoporous silica nanoparticles for cancer therapy. Microporous Mesoporous Mater. 236, 141 (2016).
M. Karimi, P.S. Zangabad, S. Baghaee-Ravari, M. Ghazadeh, H. Mirshekari, and M.R. Hamblin Smart nanostructures for cargo delivery: Uncaging and activating by light. J. Am. Chem. Soc. 139, 4584 (2017).
A. Baeza, E. Guisasola, E. Ruiz-Hernández, and M. Vallet-Regí Magnetically triggered multidrug release by hybrid mesoporous silica nanoparticles. Chem. Mater. 24, 517 (2012).
P. Saint-Cricq, S. Deshayes, J.I. Zink, and A.M. Kasko Magnetic field activated drug delivery using thermodegradable azo-functionalised PEG-coated core–shell mesoporous silica nanoparticles. Nanoscale 7, 13168 (2015).
C-H. Lee, S-H. Cheng, I-P. Huang, J.S. Souris, C-S. Yang, C-Y. Mou, and L-W. Lo Intracellular pH-responsive mesoporous silica nanoparticles for the controlled release of anticancer chemotherapeutics. Angew. Chem., Int. Ed. 49, 8214 (2010).
H. Meng, M. Xue, T. Xia, Y-L. Zhao, F. Tamanoi, J.F. Stoddart, J.I. Zink, and A.E. Nel Autonomous in vitro anticancer drug release from mesoporous silica nanoparticles by pH-sensitive nanovalves. J. Am. Chem. Soc. 132, 12690 (2010).
Y-L. Zhao, Z. Li, S. Kabehie, Y.Y. Botros, J.F. Stoddart, and J.I. Zink pH-operated nanopistons on the surfaces of mesoporous silica nanoparticle. J. Am. Chem. Soc. 132, 13016 (2010).
S. Zhou, D. Wu, X. Yin, X. Jin, X. Zhang, S. Zheng, C. Wang, and Y. Liu Intracellular pH-responsive and rituximab-conjugated mesoporous silica nanoparticles for targeted drug delivery to lymphoma B cells. J. Exp. Clin. Canc. Res. 36, 24 (2017).
S. Giri, B.G. Trewyn, M.P. Stellmaker, and V.S-Y. Li Stimuli-responsive controlled-release delivery system based on mesoporous silica nanorods capped with magnetic nanoparticles. Angew. Chem., Int. Ed. 44, 5038 (2005).
Y. Cui, H. Dong, X. Cai, D. Wang, and Y. Li Mesoporous silica nanoparticles capped with disulfide-linked PEG gatekeepers for glutathione-mediated controlled release. ACS Appl. Mater. Interfaces 4, 3177 (2012).
Q. Zhang, F. Liu, K.T. Nguyen, X. Ma, X. Wang, B. Xing, and Y. Zhao Multifunctional mesoporous silica nanoparticles for cancer-targeted and controlled drug delivery. Adv. Funct. Mater. 22, 5144 (2012).
Y. Yang, J. Wan, Y. Niu, Z. Gu, J. Zhang, M. Yu, and C. Yu Structure-dependent and glutathione-responsive biodegradable dendritic mesoporous organosilica nanoparticles for safe protein delivery. Chem. Mater. 28, 9008 (2016).
E.A. Prasetyanto, A. Bertucci, D. Septiadi, R. Corradini, P. Castro-Hartmann, and L. De Cola Breakable hybrid organosilica nanoparticles for protein delivery. Angew. Chem., Int. Ed. 55, 3323 (2016).
K. Hayashi, T. Maruhashi, M. Nakamura, W. Sakamoto, and T. Yogo One-pot synthesis of dual stimuli-responsive degradable hollow hybrid nanoparticles for image-guided trimodal therapy. Adv. Funct. Mater. 26, 8613 (2016).
M. Zhou, X. Du, W. Li, X. Li, H. Huang, Q. Liao, B. Shi, X. Zhang, and M. Zhang One-pot synthesis of redox-triggered biodegradable hybrid nanocapsules with a disulfide-bridged silsesquioxane framework for promising drug delivery. J. Mater. Chem. B 5, 4455 (2017).
L. Mondragón, N. Mas, V. Ferragud, C. de la Torre, A. Agostini, R. Martínez-Máñez, F. Sancenón, P. Amorós, E. Pérez-Payá, and M. Orzáez Enzyme-responsive intracellular-controlled release using silica mesoporous nanoparticles capped with ε-poly-L-lysine. Chem.–Eur. J. 20, 5271 (2014).
J. Liu, B. Zhang, Z. Luo, X. Ding, J. Li, L. Dai, J. Zhou, X. Zhao, J. Ye, and K. Cai Enzyme responsive mesoporous silica nanoparticles for targeted tumor therapy in vitro and in vivo. Nanoscale 7, 3614 (2015).
S.H. van Rijt, D.A. Bölükbas, C. Argyo, S. Datz, M. Lindner, O. Eickelberg, M. Königshoff, T. Bein, and S. Meiners Protease-mediated release of chemotherapeutics from mesoporous silica nanoparticles to ex vivo human and mouse lung tumors. ACS Nano 9, 2377 (2015).
M.L. Circu and T.Y. Aw Glutathione and apoptosis. Free Radic. Res. 42, 689 (2008).
H.J. Forman, H. Zhang, and A. Rinna Glutathione: Overview of its protective roles, measurement, and biosynthesis. Mol. Aspect. Med. 30, 1 (2009).
M. Nakamura and K. Ishimura One-pot synthesis and characterization of three kinds of thiol-organosilica nanoparticles. Langmuir 24, 5099 (2008).
M. Nakamura, S. Ozaki, M. Abe, H. Doi, T. Matsumoto, and K. Ishimura Size-controlled synthesis, surface functionalization, and biological applications of thiol-organosilica particles. Colloids Surf., B 79, 19 (2010).
T. Doura, F. Tamanoi, and M. Nakamura Miniaturization of thiol-organosilica nanoparticles induced by an anionic surfactant. J. Colloid Interface Sci. 526, 51 (2018).
M. Nakamura, A. Awaad, K. Hayashi, K. Ochiai, and K. Ishimura Thiol-organosilica particles internally functionalized with propidium iodide as a multicolor fluorescence and X-ray computed tomography probe and application for non-invasive functional gastrointestinal tract imaging. Chem. Mater. 24, 3772 (2012).
M. Nakamura, K. Hayashi, M. Nakano, T. Kanadani, K. Miyamoto, T. Kori, and K. Horikawa Identification of polyethylene glycol-resistant macrophages on stealth imaging in vitro using fluorescent organosilica nanoparticles. ACS Nano 9, 1058 (2015).
M. Nakamura, K. Hayashi, H. Kubo, T. Kanadani, M. Harada, and T. Yogo Relaxometric property of organosilica nanoparticles internally functionalized with iron oxide and fluorescent dye for multimodal imaging. J. Colloid Interface Sci. 492, 127 (2017).
M. Nakamura, K. Hayashi, H. Kubo, M. Harada, K. Izumi, Y. Tsuruo, and T. Yogo Mesoscopic multimodal imaging provides new insight to tumor tissue evaluation: An example of macrophage imaging of hepatic tumor using organosilica nanoparticles. Sci. Rep. 7, 3953 (2017).
E. Blanco, H. Shen, and M. Ferrari Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941 (2015).
S. Svenson Theranostics: Are we there yet? Mol. Pharm. 10, 848 (2013).
G.S. Irmukhametova, G.A. Mun, and V.V. Khutoryanskiy Thiolated mucoadhesive and PEGylated nonmucoadhesive organosilica nanoparticles from 3-mercaptopropyltrimethoxysilane. Langmuir 27, 9551 (2011).
G.S. Irmukhametova, B.J. Fraser, J.L. Keddie, G.A. Mun, and V.V. Khutoryanskiy Hydrogen-bonding-driven self-assembly of PEGylated organosilica nanoparticles with poly(acrylic acid) in aqueous solutions and in layer-by-layer deposition at solid surface. Langmuir 28, 299 (2012).
J.H.A. Mahrooqi, E.A. Mun, A.C. Williams, and V.V. Khutoryanskiy Controlling the size of thiolated organosilica nanoparticles. Langmuir 34, 8347 (2018).
E.D.H. Mansfield, K. Sillence, P. Hole, A.C. Williams, and V.V. Khutoryanskiy POZylation: A new approach to enhance nanoparticle diffusion through mucosal barriers. Nanoscale 7, 13671 (2015).
E.D.H. Mansfield, V.R. de la Rosa, R.M. Kowalczyk, I. Grillo, R. Hoogenboom, K. Sillence, P. Hole, A.C. Williams, and V.V. Khutoryanskiy Side chain variations radically alter the diffusion of poly(2-alkyl-2-oxazoline) functionalized nanoparticles through a mucosal barrier. Biomater. Sci. 4, 1318 (2016).
S. Quignard, S. Masse, G. Laurent, and T. Coradin Introduction of disulfide bridges within silica nanoparticles to control their intra-cellular degradation. Chem. Commun. 49, 3410 (2013).
P. Bazylewski, R. Divigalpitiya, and G. Fanchini In situ Raman spectroscopy distinguishes between reversible and irreversible thiol modifications in L-cysteine. RSC Adv. 7, 2964 (2017).
H.E. Van Wart and H.A. Scherag Agreement with the disulfide stretching frequency-conformation correlation of Sugeta, Go, and Miyazawa. Proc. Natl. Acad. Sci. U. S. A 83, 3064 (1986).
A. Pawlukojć, J. Leciejewicz, A.J. Ramirez-Cuesta, and J. Nowicka-Scheibe L-Cysteine: Neutron spectroscopy, Raman, IR and ab initio study. Spectrochim. Acta, Part A 61, 2474 (2005).
This research was supported in part by JSPS KAKENHI Grant Number JP16K18909 (T.D.), YU Project for Formation of the Core Research Center (T.D.), JSPS KAKENHI Grant Number JP16K01358 (M.N.), and the JSPS Bilateral Programs (M.N.). Assistance with electron microscopic analyses was provided by Dr. Koichi Udo and the Institute for Biomedical Research and Education, Yamaguchi University Science Research Center, Japan. Assistance with solid-state 13C NMR measurements was provided by Dr. Hirotaka Fujimori, Dr. Yoshiko Murakami, Mr. Ryota Hori, Mr. Yudai Arisuda, and Mr. Yosuke Fukuzawa of Yamaguchi University. Raman spectroscopic measurements were supported by Dr. Kenta Fujii and Dr. Yanko Todorov of Yamaguchi University.
About this article
Cite this article
Doura, T., Nishio, T., Tamanoi, F. et al. Relationship between the glutathione-responsive degradability of thiol-organosilica nanoparticles and the chemical structures. Journal of Materials Research 34, 1266–1278 (2019). https://doi.org/10.1557/jmr.2018.501