A novel versatile yolk-shell nanosystem based on NIR-elevated drug release and GSH depletion-enhanced Fenton-like reaction for synergistic cancer therapy
Graphical abstract
Introduction
In recent years, considerable efforts have been devoted to the treatment of cancer [[1], [2], [3], [4]]. Thus, various emerging therapy modalities have been developed to achieve an efficient ablation of the tumor and ensure the safety of normal tissue simultaneously, such as photothermal therapy (PTT), photodynamic therapy (PDT) and chemodynamic therapy (CDT) [[5], [6], [7], [8], [9], [10]]. For PTT, nanomaterials can ablate tumor cells by hyperthermia mediated by near-infrared (NIR) light [[11], [12], [13]], while PDT realizes the death of tumor cells via toxic reactive oxygen species (ROS) produced by photosensitizers [[14], [15], [16]]. CDT was defined as a production of toxic hydroxyl radicals (·OH) in tumor site through Fenton or Fenton-like reaction [17,18]. The combination of PTT and PDT can realize spatially and temporally controlled tumor-killing with minimal invasiveness to normal tissue [[19], [20], [21]]. Unfortunately, the reliance of PDT on O2 limits its efficiency in the hypoxic environment of major solid tumors [22,23]. On the contrary, PTT and CDT can kill tumor cells without the utilizing of O2, which brings a hope to the therapy of hypoxic tumors. Up to now, the combined therapy of PTT and PDT has been extensively studied. However, rare researches focused on the synergistic effects of CDT and PTT [24,25].
Fe-based inorganic nanomaterials, as traditional Fenton agents, have been extensively explored to produce toxic ROS through the decomposition of H2O2 [9,[26], [27], [28], [29], [30], [31]]. Nevertheless, Mn2+-based nanosystem exerts higher catalytic efficiency than Fe2+, which is also less strict with the tumor microenvironment (TME). Particularly, MnO2 exhibits a self-reinforcing CDT efficiency because of MnO2 scavenges GSH through Fenton-like reaction to produce more ·OH [32,33]. However, the reported MnO2-based nanomaterials mainly were bare nanoparticles, nanosheets or MnO2-coated mesoporous nanocomposites [34,35], which inevitably catalyzed the oxidation of the amino acid residues during systemic circulation and then induced undesired side effects. Therefore, we envisaged that MnO2 could be incorporated into a mesoporous nanomaterial to endow MnO2 with an “invisible cloak” and achieved specific tumor ablation simultaneously.
Herein, MnO2 was in-situ formed as the core of hollow mesoporous Cu2−xS (HMCu2−xS) with a transition metal sulfide with high photothermal conversion efficiency [36,37], which obtained the yolk-shell MnO2@HMCu2-xS nanocomposites (HMCM). In this system, HMCu2−xS behaved as an efficient light-harvesting agent to convert NIR light into heat [38]. The MnO2 core could occur a redox reaction with GSH to yield Mn2+ and the subsequent Fenton-like reaction happening between Mn2+ and overexpressed H2O2 in tumor cells [39]. The obtained HMCM achieved the advantages as follows: (1) The spatiotemporal controlled photoexcitation of PTT and the GSH-activation of CDT ensured the safety of normal tissues; (2) The hollow mesoporous characteristics could be regarded as the promising candidates as nanocarriers for tumor-specific drug delivery; (3) A chemotherapy drug (DOX) was loaded into PEG-modified HMCM (HMCMD-PEG) to promote the expression level of H2O2 for enhanced ROS production, which was of great value in tumor treatments.
Section snippets
Materials
Poly(-vinylpyrrolidone) (PVP-K30), cupric chloride (CuCl2), sodium sulfide (Na2S) and Hydrazine hydrate (80 %), potassium permanganate (KMnO4, 99 %), sodium bicarbonate (NaHCO3, 99.7 %), methylene blue (MB, 82 %), hydrogen peroxide (H2O2, 30 %), Manganese nitrate solution (Mn(NO3)2, 50 %), glutathione (GSH, 98 %), 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB), and amination polyethylene glycol (mPEG-NH2, MW = 2000 Da) were purchased from Sigma-Aldrich. Acridine orange (AO) and Ethidium bromide
Synthesis and characterization of HMCM
Highly uniform HMCuS nanoparticles with spherical shape and excellent dispersity were synthesized and characterized by transmission electron microscopy (TEM). As shown in Fig. 1A and 1B, the exhibition of MnO2 core (∼ 80 nm) in the HMCM (∼ 125 nm) were observed clearly, indicating that MnO2 was integrated with the HMCuS shell successfully. The scanning electron microscope (SEM) image of HMCM (Fig. 1C) validated its properties of good monodispersity and spherical morphology. According to the
Conclusion
In summary, an effective nanosystem (HMCMD-PEG) (∼ 125 nm) was designed and synthesized for NIR-responsive drug delivery with high loading capacity (49.4 %). The drug release could be elevated from 59.21 %–85.9 % under the NIR irradiation (808 nm, 1.54 W·cm−2) in tumor environment. Moreover, the temperature of HMCMD-PEG in aqueous solution could increase from 1.83 to 51.34 °C under NIR irradiation, which implied that the HMCMD-PEG possessed excellent photothermal conversion efficiency. The
CRediT authorship contribution statement
Dihai Gu: Conceptualization, Methodology, Validation, Writing - original draft. Peijing An: Writing - review & editing. Xiuli He: Resources. Hongshuai Wu: Data curation. Zhiguo Gao: Supervision. Yaojia Li: Investigation. Fanghui Chen: Visualization. Kaiwu Cheng: Project administration. Yuchen Zhang: Project administration. Chaoqun You: Funding acquisition. Baiwang Sun: Funding acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We are highly grateful to the International S&T Cooperation Program of China (No. 2015DFG42240), the financial support from the National Natural Science Foundation of China (Grant Nos. 21628101 and 21371031), the financial support from the project funded by China Postdoctoral Science Foundation (No. 2019M651841) and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.
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