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DOI: 10.1039/D4CP02554G (Paper) Phys. Chem. Chem. Phys., 2024, 26, 23386-23392

An endogenous oxygen self-supplied nanoplatform with GSH-depleted and NIR-II triggered electron–hole separation for enhanced photocatalytic anti-tumor therapy†

Yao Huang‡ ab, Hanlin Wei‡ b, Hui Feng d, Fengyu Tian *b, Qi Zheng *c and Zhiming Deng *b
aSchool of Physics and Electronic-Electrical Engineering, Xiangnan University, Chenzhou 423000, China
bState Key Laboratory for Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. E-mail: zhimingdeng@hnu.edu.cn; fengyutian@hnu.edu.cn
cKey Laboratory for Micro-Nano Optoelectronic Devices of Ministry of Education, School of Physics and Electronics, Hunan University, Changsha, China. E-mail: zhengqi@hnu.edu.cn
dChangsha Environmental Protection College, Hunan Province, Changsha 410082, China

Received 26th June 2024 , Accepted 18th August 2024

First published on 30th August 2024

Abstract

The use of artificial enzymes and light energy in photocatalytic therapy, a developing drug-free therapeutic approach, can treat malignant tumors in vivo. However, the relatively deficient oxygen concentration in the tumor microenvironment (TME) restrains their further tumor treatment capability. Herein, a novel nanoplatform with Cu7S4@Au nanocatalyst coated by MnO2 was successfully designed. After 1064 nm light irradiation, the designed nanocatalyst can promote the separation of light generated electron–hole pairs, resulting in ROS generation and tumor cell apoptosis. The MnO2 shelled nanoplatform can function as a TME-responsive oxygen self-supplied producer to improve photocatalyst treatment and GSH depletion. In summary, the designed novel nanoplatform shows efficient inhibition of tumor growth via GSH depletion and synergistic photocatalytic therapy, which is of great significance for improving the clinical tumor treatment effect.

Introduction

One potential therapeutic avenue for anti-tumor therapy is photocatalysis, which can transform photonic energy into potent active substances.1–3 Additionally, under complex physiological conditions, well-developed photocatalytic therapy could produce ROS and retain stable catalytic capability. Until now, traditional UV-vis light and NIR-I responsive nanocatalysts were developed for anti-tumor therapy.4–10 However, the developed traditional nanocatalysts were triggered by UV-vis light and NIR-I, resulting in a very shallow penetration depth and remarkably restricting deep tissue photocatalytic therapy. Compared with UV-vis and NIR regions, the 1000–1700 nm regions (defined as NIR-II), as a more preferable light source with reduced photon scattering and deeper tissue penetration show great promise for anti-tumor therapy.11–15 Due to the hypoxicity of the tumor microenvironment,16 mostly developed NIR-II light activated photocatalysts for anti-tumor therapy still face the challenge of limited ROS production. Therefore, developing a new type of NIR-II light triggered nanocatalyst with effective ROS production is urgently demanded for deep tissue malignant tumor therapy.

The tumor microenvironment (TME) has critical functions in tumor therapy; it is primarily characterized by hypoxia,16 low pH,17 and high H2O2 levels18,19 in tumor tissue. Due to the rapid proliferation of cancer cells that speed up the consumption of O2, a hypoxic TME is typically present in the interior of the malignant tumors and exerts an adverse effect on the O2-dependent therapy mode. Numerous nano-diagnostic agents with the capacity to produce ROS have been developed based on this biochemical feature.20–22 The generation of ROS is highly dependent on O2 and H2O2 concentrations in the tumor regions; however, there is a significant obstacle to producing enough ROS to achieve excellent anticancer effects since the commonly present hypoxia and H2O2 in tumors makes it inadequate for tumor treatment. It is more advantageous to develop TME-responsive O2 self-generated nanoplatforms employing MnO2-based catalyst-like reactions in order to overcome anoxic conditions and enhance photocatalytic therapy efficacy. Thus, in order to achieve synergistically increased photocatalytic treatment and hypoxia amelioration, the design of a TME-specifically activated nanoplatform is extremely desirable.

Meanwhile, one of the most difficult barriers to anti-tumor therapy may be over-expressed glutathione (GSH) in tumor cells.23,24 Although GSH is essential for defending cells against a range of harmful substances, studies have also demonstrated that cancer cells with higher GSH levels are more resistant to photodynamic, radioactive, and chemotherapy treatments.25–30 Furthermore, GSH dramatically increases the resistance of cancer cells to oxidative stress and decreases the efficacy of anti-tumor therapy by scavenging the highly reactive ROS generated by chemodynamic medications. Therefore, in order to overcome tumor resistance and enhance the effectiveness of therapy, it is highly desired that tumor therapy nanoagents should reduce the intracellular GSH levels.

The Cu7S4@Au@MnO2 nanocatalyst designed by us presents enhanced production and separation of electron–hole pairs, enabling on-demand photocatalytic therapy under a 1064 nm laser irradiation (Scheme 1). Interestingly, under NIR irradiation, the Cu7S4@Au@MnO2 component of the nanoplatform can catalyze the decomposition of endogenous hydrogen peroxide within the tumor microenvironment, leading to the generation of oxygen and highly ROS. The ROS can induce oxidative stress within the tumor cells, leading to DNA damage, lipid peroxidation, and disruption of cellular functions, ultimately contributing to tumor cell death. And the MnO2 shell can modulate the TME via the depletion of the endogenous GSH in TME. More importantly, the designed nanodrug shows efficient growth inhibition of tumors via GSH depletion and synergistic photocatalytic therapy.


image file: d4cp02554g-s1.tif
Scheme 1 Schematic illustration of the Cu7S4@Au@MnO2 oxygen self-supplying system for GSH depletion and synergistically enhanced photocatalytic tumor therapy.

Results and discussion

The synthesis scheme of Cu7S4@Au@MnO2 nanoparticles is illustrated in Fig. 1A. The transmission electron microscopy (TEM) images (Fig. 1B) clearly display the porous structure of the uniform Cu2O nanospheres. Upon vulcanization, the Cu7S4 nanoparticles exhibit a hollow shape (Fig. 2C) with an average diameter of around 100 nm. In order to form a heterojunction structure, the satellite shape was formed by the homogeneous deposition of gold nanoparticles on the Cu7S4 surface (Fig. 2D). In order to construct a TME responsive O2 releasing system, the MnO2 nanosheet nanoparticles were coated on the surface of Cu7S4@Au nanocrystals. As shown in Fig. 2E, a thin layer of MnO2 nanosheets is perfectly coated on the surface of Cu7S4@Au. The lattice distances of Cu7S4 and Au were measured to be 1.618 Å and 2.378 Å, corresponding to the (126) plane of Cu7S4 and the (111) plane of Au (Fig. S1, ESI†), respectively. The Cu2O, Cu7S4, and Cu7S4@Au formation are confirmed by X-ray diffraction (XRD) research. As for cubic phase Cu2O (JCPDS: 34-1354), hexagonal phase Cu7S4 (JCPDS: 06-0464), and cubic phase Au (JCPDS: 04-0784), respectively, the XRD patterns of Cu2O, Cu7S4, and Cu7S4@Au (Fig. 2F) matches well the standard data. The potential analysis of the product at each stage in PBS revealed a considerable potential shift, predicting the effective synthesis of Cu7S4@Au@MnO2 nanoparticles (Fig. 2G). Furthermore, X-ray photoelectron spectroscopy (XPS) explicitly verified the successful coating of Cu7S4@Au with MnO2. The XPS results of Cu7S4@Au@MnO2 are shown in Fig. 2H and I, and the wide scan spectrum indicates the presence of O and Mn. In the Mn 2p spectra (Fig. 2G–K), there are two strong peaks at 642.8 and 654.5 eV that match the Mn4+ cation, suggesting the presence of MnO2.
image file: d4cp02554g-f1.tif
Fig. 1 (A) Schematic representation of the fabrication of the Cu7S4@Au@MnO2. (B)–(E) The TEM images of Cu2O, Cu7S4, Cu7S4@Au and Cu7S4@Au@MnO2, respectively. (F) XRD patterns of Cu2O, Cu7S4 and Cu7S4@Au nanomaterials, respectively. (G) The ξ potential analysis of Cu2O, Cu7S4, Cu7S4@Au and Cu7S4@Au@MnO2 nanomaterials. (H) and (I) The XPS pattern of Cu7S4@Au and Cu7S4@Au@MnO2 nanomaterials. (J) and (K) XPS high-resolution scans of Mn 2p peaks in Cu7S4@Au and Cu7S4@Au@MnO2 nanomaterials, respectively.

image file: d4cp02554g-f2.tif
Fig. 2 Enhanced ROS generation and GSH depletion. (A) UV-vis spectra of Cu7S4 and Cu7S4@Au nanocatalyst. (B) Plot of (αhν)2versus photon energy (hν) of Cu7S4 and Cu7S4@Au nanocatalyst. (C) VB-XPS spectra of Cu7S4 and Cu7S4@Au nanocatalyst. (D) The photocurrent curves of Cu7S4@Au nanocatalyst under 1064 nm laser radiation. (E) Time-dependent UV-vis absorbance spectra of DPBF after NIR-II laser irradiation for Cu7S4@Au. (F) Time-dependent UV-vis absorbance spectra of DPBF after NIR-II laser irradiation for Cu7S4. (G) The normalized absorption intensity at 410 nm of DPBF from F–I. (H) Time-dependent UV-vis absorbance spectra of DPBF without NIR-II laser irradiation at pH 7.4. (I) Time-dependent UV-vis absorbance spectra of DPBF after NIR-II laser irradiation at pH 7.4. (J) Time-dependent UV-vis absorbance spectra of DPBF after NIR-II laser irradiation at pH 5.4. (K) Time-dependent UV-vis absorbance spectra of DPBF after NIR-II laser irradiation at pH 5.4 with H2O2. (L) The normalized absorption intensity at 410 nm of DPBF from F–I. (M) Time-dependent GSH depletion by Cu7S4@Au nanocatalyst at different incubating times with DTNB. (N) ESR spectra of DMPO capturing ROS generated by Cu7S4@Au nanomaterials under 1064 nm laser irradiation. (O) The schematic illustration of the NIR-II light driven photocatalytic therapy based on the Cu7S4@Au@MnO2 nanomaterials.

As shown in Fig. 2A, the Cu7S4@Au nanocatalyst designed by us exhibits obvious absorption in the NIR-II regions, making it an ideal NIR-II photocatalytic nanomaterial for anti-tumor therapy. To investigate the mechanism of photocatalysis, the band gap of our designed samples was studied (Fig. 2B). The band gap of the Cu7S4@Au nanocatalyst was about 2 eV. And VB-XPS spectroscopy was used to determine the potentials of the VB in the Cu7S4@Au nanocatalyst. The VB values of Cu7S4@Au nanocatalyst vs. NHE were estimated as follows:

ENHE = φ (instrument work function: 4.2 eV) + EVB-XPS-4.44

The VB values vs. NHE were calculated to be 0.98 eV and 1.33 eV for Cu7S4@Au and Cu7S4 nanocatalysts, respectively. The CB position can be determined using ECB = EVB − Eg, and ECB was calculated to be −1.26 eV for the Cu7S4@Au nanocatalyst (Fig. 2C). At the same time, we systematically studied the effect of different ratios of Au and Cu7S4 on the energy band, and found that as the gold ratio increased, the CB became increasingly positive (Fig. S2, ESI†). This further proves that the ratio of gold to copper sulfide can be regulated to achieve precise photocatalytic regulation. Meanwhile, the VB potential of the Cu7S4@Au nanocatalyst is relatively higher than the oxidative potential of GSH to GSSG (≥0.32 eV),31 leading to efficient GSH depletion. It should be pointed out that after the growth of gold nanoparticles, the narrowing of the band gap is more favorable for the catalytic energy triggered by NIR-II laser. Next, we evaluated the photocurrent generated from Cu7S4@Au nanocatalyst under 1064 nm laser irradiation. As indicated in Fig. 2D, the obviously photocurrent was achieved in the Cu7S4@Au nanocatalyst upon irradiation by the 1064 nm laser, validating the efficient electron–hole separation.

To evaluate the properties of ROS generation under the NIR-II laser irradiation, 1,3-diphenylisobenzofuran (DPBF) was utilized to indicate the ability of ROS production. The absorbance intensity of the DPBF peak in Cu7S4 and Cu7S4@Au nanocatalyst was decreased with prolonging the irradiation time of the 1064 nm laser (Fig. 2E–G), indicating the efficient generation of ROS. Meanwhile, after the formation of heterojunctions, enhanced ROS production can be clearly observed. And, the absorbance intensity of DPBF peak in the Cu7S4@Au@MnO2 nanocatalyst was decreased with prolonging the irradiation time of the 1064 nm laser (Fig. 2H–L), indicating the efficient generation of ROS. Obviously, for pure laser irradiation, under acidic conditions, more active oxygen can be produced after adding hydrogen peroxide, which is mainly due to the fact that the nano-catalyst we designed can catalyze hydrogen peroxide to produce oxygen under acidic conditions and realize enhanced catalytic ability. It should be pointed out that the nanocatalyst cannot generate ˙OH, but the potential is enough for hole therapy by GSH depletion. Next, we studied the GSH depleting ability of the Cu7S4@Au@MnO2 nanocatalyst by 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB). With increasing NIR-II laser irradiation time, the GSH level decreased sharply (Fig. 2M) in the presence of the Cu7S4@Au nanocatalyst. The depletion of GSH by the Cu7S4@Au@MnO2 nanocatalyst can maintain a highly efficient ROS level in TME via breaking the redox balance in the tumor. Then, to further verify the ROS, the electron spin resonance (ESR) was employed. As shown in Fig. 2N, the ESR spectrum demonstrated the obvious 1[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]2[thin space (1/6-em)]:[thin space (1/6-em)]1 sextuplet signal, further elucidating the generation of ˙OH under 1064 nm laser irradiation. In summary, the nanocatalyst we designed can achieve enhanced ROS release and GSH degradation (Fig. 2O). Meanwhile, we observed significant oxygen production when the material was co-incubated with hydrogen peroxide under acidic conditions (Fig. S3, ESI†).

As shown in Fig. S2 (ESI†), the inductively coupled plasma mass spectrometry (ICP-MS) results show that the Cu7S4@Au@MnO2 nanomaterials can be engulfed by cells over time, providing the possibility for subsequent tumor treatment experiments. Owing to the enhanced release of ROS, we speculate that the designed nanocatalyst can also be used as a promising probe for tumor therapy (Fig. 3A). As shown in Fig. 3B, a slight cytotoxicity of Cu7S4@Au@MnO2 is concentration-dependent for the cancer cells. This is mainly due to the degradation of MnO2. Meanwhile, as shown in Fig. 3C, Cu7S4@Au + NIR-II and Cu7S4@Au@MnO2 inhibited the proliferation of tumor cells, while Cu7S4@Au@MnO2 inhibited the proliferation of 4T1 up to 62%. And, similar results are seen from the cell live/dead double staining assay and Fig. 3D. As shown in Fig. 3E, no green fluorescence was observed in the control and Cu7S4@Au@MnO2 groups, and the Cu7S4@Au@MnO2 + NIR-II group displayed a brighter green fluorescence than the Cu7S4@Au + NIR-II group. It should be pointed out that the green fluorescence is related to ROS. All these results show that the Cu7S4@Au@MnO2 + NIR-II group presents the strongest ability to enhanced photocatalytic therapy.


image file: d4cp02554g-f3.tif
Fig. 3 In vitro therapeutic effects of 4T1 cells. (A) Schematic illustration of enhanced photocatalytic therapy for the Cu7S4@Au@MnO2 nanocatalyst. (B) Cell viability of 4T1 cells incubated with various concentrations of the Cu7S4@Au@MnO2 nanocatalyst. (C) Cell viabilities after being treated by (1) PBS; (2) Cu7S4@Au@MnO2; (3) Cu7S4@Au + NIR-II; (4) Cu7S4@Au@MnO2 + NIR-II. (D) Live and dead staining of 4T1 with different treatments. (E) Fluorescence microscopy images of the ROS levels under various treatments.

The in vitro performance of the composite encouraged us to investigate its in vivo therapeutic effect. The in vivo anti-tumor performance was then evaluated with 4T1 tumor-bearing mice (Fig. 4A). The tumor-bearing mice were randomly divided into four groups for different treatments: (I) control, (II) Cu7S4@Au + NIR-II, (III) Cu7S4@Au@MnO2, (IV) Cu7S4@Au@MnO2 + NIR-II. The mice were intravenously injected with a dosage of 20 mg kg−1. The laser treatment groups were then exposed to a 1064 nm laser for 5 minutes every two days. Every two days, the mice's weights and tumor volumes were recorded. As demonstrated in Fig. 4B, the average body weight remained reasonably steady across all groups, indicating little side effect. As revealed by the profiles of the tumor volume in Fig. 4C, the tumors in control group grew rapidly. A certain inhibitory was observed on tumor growth for the Cu7S4@Au@MnO2 and Cu7S4@Au + NIR-II group owing to the limited therapy effect. In contrast, the multifunctional integration of Cu7S4@Au@MnO2 + NIR-II group demonstrated a significantly greater tumor inhibition efficacy. As shown in Fig. 3D, the tumor weights are consistent with the corresponding tumor growth trend. In order to assess the therapeutic impact even more, tumor slides were lastly gathered and stained with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and hematoxylin and eosin (H&E) (Fig. 4E and F). The Cu7S4@Au@MnO2 + NIR-II group had the greatest nucleus shrinkage, as seen by the H&E staining. Similarly, TUNEL testing for maximum tumor cell death revealed that group Cu7S4@Au@MnO2 + NIR-II had the greatest green fluorescence. The Cu7S4@Au@MnO2 and Cu7S4@Au + NIR-II, the control group, however, exhibited very little green fluorescence. The H&E examination showed that no overt signs of organ damage or inflammation were seen in the main organs following the various treatments (Fig. S5, ESI†). Although less catalytic reaction occurs in neutral tissues with lower GSH levels, the nanozyme composite responds to intratumoral acid GSH specifically for tumor-specific cascade catalytic reaction and hence effective formation of ROS. As a result, the nanozyme composite shows promise for use as a self-supplied oxygen tumor therapeutic agent that is both safe and efficacious with negligible toxicity concerns.


image file: d4cp02554g-f4.tif
Fig. 4 (A) A schematic representation of the creation of a 4T1 tumor-bearing mouse model and its treatment using the composite. The body weight changes of mice (B) and their tumor development curves (C) following various treatments. (D) Mean tumor masses following various interventions. (E) and (F) Images of tumors stained with H&E and TUNEL following various treatments. Scale bar: 200 μm.

The designed Cu7S4@Au@MnO2 nanocatalyst addresses the challenge of tumor hypoxia by providing an endogenous oxygen supply within the tumor area. This innovative approach has the potential to significantly enhance the efficacy of anti-tumor therapy, as tumor hypoxia is a major obstacle in current cancer treatment strategies. And through NIR-II triggered electron–hole separation, the nanoplatform demonstrates enhanced photocatalytic activity, leading to improved production of ROS. This innovative feature is crucial for augmenting the cytotoxic effects on tumor cells, thereby enhancing the therapeutic outcome. The multifunctional nature of the nanoplatform, integrating oxygen supply, ROS enhancement, and GSH depletion, represents a significant advancement in the development of next-generation anti-tumor therapeutic strategies. This innovative approach has the potential to revolutionize current treatment paradigms for cancer. By emphasizing these innovative contributions, the work underscores its potential to significantly advance the field of anti-tumor therapy and pave the way for the development of novel, more effective cancer treatment modalities.

Conclusions

To summarize, a novel Cu7S4@Au@MnO2 nanocatalyst that is driven by NIR-II light was created for enhanced photocatalytic treatment. Our designed nanocatalyst is a suitable photocatalytic material for producing ROS, and it can be utilized for GSH depletion and endogenous oxygen supply. Next, we demonstrated that the self supplied oxygen photocatalytic treatment approach could successfully inhibit the tumors for the first time. These results open up a new avenue for the development of NIR-II light-triggered nanocatalysts with improved photocatalytic treatment via self supplied oxygen.

Ethical statement

All animal procedures were performed in accordance with the Guidelines for Care and Use of Laboratory Animals of “Hunan” University and approved by the Animal Ethics Committee of “Hunan Province”.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article [and/or its supplementary materials].

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

This work was supported by China Postdoctoral Science Foundation (2023M731063) and Natural Science Foundation of Hunan Province (2022JJ60094).

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4cp02554g
‡ These authors contributed equally.
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