Photoactive conjugated polymer/graphdiyne nanocatalyst for CO2 reduction to CO in living cells for hypoxia tumor treatment

Endong Zhang ab, Zicheng Zuo a, Wen Yu ab, Hao Zhao ab, Shengpeng Xia ab, Yiming Huang a, Fengting Lv a, Libing Liu a, Yuliang Li *a and Shu Wang *a
aBeijing National Laboratory for Molecular Science, Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China. E-mail: ylli@iccas.ac.cn; wangshu@iccas.ac.cn
bCollege of Chemistry, University of Chinese Academy of Sciences, Beijing 100049, China

Received 9th May 2021 , Accepted 13th June 2021

First published on 14th June 2021


Abstract

Carbon monoxide (CO) gas therapy has grown to be an emerging tumor therapy strategy to avoid the low treatment efficiency of photodynamic therapy (PDT) caused by the hypoxia tumor microenvironment. However, intracellular in situ generation of CO for hypoxia tumor treatment remains challenging. Herein, photoactive conjugated polymer/graphdiyne nanocatalyst (CP@GDY/DSPE-PEG) was constructed to in situ reduce endogenous carbon dioxide (CO2) into CO for hypoxia tumor therapy. Under light irradiation, the CO production rates of PFP@GDY/DSPE-PEG and PBF@GDY/DSPE-PEG reached 23 μmol h−1 gmat−1 and 31 μmol h−1 gmat−1 respectively, which can significantly affect mitochondrial respiration, leading to cancer cell apoptosis. Thus, the therapeutic effect of catalysis from metabolic CO2 into CO therapy under hypoxia conditions was achieved. This work provides a conjugated polymer/graphdiyne nanocatalyst to in situ generate CO for hypoxia tumor treatment.


Cancer, as one of the high fatality diseases, has threatened global public health.1–6 A major obstacle to cancer therapy is the extreme hypoxia tumor microenvironment, which is usually caused by the rapid proliferation of tumor cells and enormous oxygen (O2) consumption.2–14 Relatively low O2 concentration limits photodynamic strategy for long-term cancer therapy in hypoxia conditions.15–18 Development of new therapeutic methods or agents for hypoxia cancer therapy is still highly required.

Carbon monoxide (CO), as one of the therapeutic gas molecules, has been utilized for hypoxia tumor treatment in an O2-free manner.19 CO can interfere with the second stage of mitochondrial respiration and further affects the balance of ATP production, finally inducing cell apoptosis.20 Recently, CO releasing molecules (CORMs) have been prepared as nanoparticles by coordinating CO molecules with transition metals for intracellular CO delivery.21 The release of CO could be spatiotemporally triggered by a variety of external stimuli.22–26 The disadvantages of deficient delivery capacity, ineffective delivery efficiency, and uncontrollable release amount of CO still severely limit the development of CO therapy for tumor treatment.

Alternatively, we aim to develop biocompatible materials that can convert metabolic CO2 into CO in situ for antitumor treatment in hypoxia conditions, which would be highly desirable for hypoxia cancer therapy. Rapid metabolism of cancer cells increases the level of respiratory metabolism of CO2, causing higher HCO3 concentration in the hypoxia tumor microenvironment.27 Combined with low O2 level and high CO2 level of the hypoxia condition, in situ photo-catalytic CO2-to-CO conversion avoids the limitation of insufficient O2 and continually generates therapeutic CO. Organic semiconducting materials provide promising choices for such photocatalytic applications. Conjugated polymers (CPs) have attracted much attention in biosensors, imaging, and bioelectronics due to their π-extended conjugated structure and strong light-harvesting ability.23–25,28–30 By designing the π-conjugated backbone of the CPs, the bandgap could be variably tuned.31–33 In comparison with organic dyes and inorganic quantum dots, CPs with high brightness, excellent photostability, and low cytotoxicity are preferred as light-sensitive molecules in a photocatalyst system. Besides, graphdiyne (GDY) is a new type of two-dimensional carbon allotrope material, in which consecutive diacetylenic triangular structure between adjacent benzene rings constitutes the basic structural unit of GDY. Owing to the highly delocalized π bonds and large specific surface area, GDY shows good electron transfer efficiency and adsorptive property.34 GDY possesses a porous structure that provided a good three-dimensional substrate in catalytic gas reactions.35,36

In this work, water-soluble nanocatalysts (CP@GDY/DSPE-PEG) that can catalytically reduce CO2 into CO for cancer therapy in hypoxia conditions were developed through the assembly of conjugated polymers (CPs, PFP, and PBF) with GDY by electrostatic and hydrophobic interactions. The introduction of amphiphilic DSPE-PEG2000 imparted CP@GDY with good dispersibility in an aqueous solution. The CO production rates of PFP@GDY/DSPE-PEG and PBF@GDY/DSPE-PEG respectively reached 23 μmol h−1 gmat−1 and 31 μmol h−1 gmat−1 under hypoxia condition. CP@GDY/DSPE-PEG could be internalized by cancer cells located in the lysosome. They catalyzed the reduction of endogenous CO2 into CO, which affected mitochondrial respiration. Meanwhile, intracellular ATP level was changed, leading to cell apoptosis through the mitochondrial pathway (Scheme 1).


image file: d1qm00677k-s1.tif
Scheme 1 . Schematic illustration of CP@GDY/DSPE-PEG nanocatalysts converting endogenous CO2 into CO for hypoxia cancer therapy and chemical structure of graphdiyne and conjugated polymers (PFP and PBF).

The absorption and fluorescence spectra of conjugated polymers PFP and PBF were measured and are shown in Fig. S1 (ESI). GDY was synthesized by a Glaser coupling reaction with hexaethynylbenzene as the precursor. Quantitative interaction thermodynamic parameters of CP@GDY were calculated from the isothermal titration calorimetry (ITC) fitting curves (Fig. 1a and b). Upon dropwise addition of GDY suspension into CPs aqueous solution, the initial enthalpy change (ΔHobs) is negative, indicating that the interaction of GDY and CPs is an exothermic process. With the addition of GDY, ΔHobs decreased and approached zero, implying that the binding process gradually approached saturation. The ΔHobs and binding constant (K) indicate that the assembly between CPs and GDY is dominated by electrostatic interactions. The binding constants (K) of GDY with PFP and PBF are calculated to be 1.10 × 104 M−1 and 1.92 × 104 M−1, respectively. As shown in Fig. 1c, the zeta potential of GDY was measured to be −34.2 ± 0.33 mV, suggesting the negative charge characteristic of GDY. Upon addition of the same equivalent CPs to form the CP@GDY composite, the zeta potential of CP@GDY changed to 44.6 ± 0.72 mV (PFP@GDY) and 43.5 ± 0.60 mV (PBF@GDY), respectively, due to the quaternary amine group in the side chain of CPs. The thermodynamic and zeta potential results illustrated that the interactions of GDY with CPs were dominated by electrostatic interactions. As displayed in Fig. 1d and e, compared to CPs, the introduction of GDY promoted the photocurrent of CPs, which exhibited the photogenerated electron ability of CP@GDY. To obtain a stable nanocatalyst in aqueous solution, amphiphilic DSPE-PEG2000 was utilized to realize CP@GDY/DSPE-PEG by hydrophobic interactions, which was well dispersed in the aqueous solution. The sizes of PFP@GDY/DSPE-PEG and PBF@GDY/DSPE-PEG were measured to be 187.5 ± 4.2 nm and 202.0 ± 5.6 nm, respectively from dynamic light scattering (DLS), which is well consistent with transmission electron microscopy results (TEM) (Fig. 1f and g). To ensure the feasibility of CP@GDY to invert CO2, ultraviolet photoelectron spectroscopy (UPS) was utilized for theoretically calculating the highest occupied molecular orbital (HOMO) of CPs (Fig. S2a and b, ESI). As shown in Fig. 1h and i, under light irradiation, the CPs produced the holes and electrons, and the electron transited into the lowest unoccupied molecular orbital (LUMO) following the reduction of CO2 into CO. Due to the large specific surface area and good electron transfer efficiency, GDY provided a three-dimensional substrate that promoted the catalytic reaction.


image file: d1qm00677k-f1.tif
Fig. 1 Absorption and fluorescence spectra of PFP and PBF. Fitting curves of ΔHobs against the GDY/CPs molar ratio by titrating GDY into PFP solutions (a) and PBF solution (b). (c) Zeta potential of GDY and CP@GDY. (d) Photocurrents of PFP, GDY, and PFP/GDY. (e) Photocurrents of PFP, GDY, and PFP/GDY. (f) Size from DLS and TEM images of PFP@GDY/DSPE-PEG. (g) Size from DLS and TEM images of PBF@GDY/DSPE-PEG. The scale bar is 200 nm. Energy levels of PFP (h) and PBF (i) for electron transfer to reduce CO2 into CO.

To verify the catalytic CO generation ability of CP@GDY/DSPE-PEG, the amount of CO was measured using gas chromatography (GC) and compared with the CO standard curve (Fig. S3, ESI). As shown in Fig. 2a, the CO production rates of PFP@GDY/DSPE-PEG and PBF@GDY/DSPE-PEG were 23 μmol h−1 gmat−1 and 31 μmol h−1 gmat−1 in simulative hypoxia atmosphere (1% O2), respectively, which were much higher than that of GDY without modification by CPs. To test the CO production in the cells, the CO probe (Fl-CO) was synthesized according to a previous report.14 In the presence of CO, the dipropenyl carbonate group was removed by Tsu-ji-Trost reaction, followed by the release of fluorescent molecules. The probe had selectivity for CO and did not interfere with other ROS, reactive nitrogen species, and reactive sulfur. As shown in Fig. S4 (ESI), with the gradual addition of CO into the Fl-CO solution, the fluorescence intensity at 520 nm increased dramatically, implying the fluorescent response to CO. The cytotoxicity of CP@GDY/DSPE-PEG and triethanolamine (TEOA) were investigated via a standard MTT assay (Fig. S5, ESI). The CP@GDY/DSPE-PEG was incubated with 4T1 cells for 12 h to ensure complete entry into the cells. The cancer cells were incubated under hypoxia conditions for another 6 h, consuming the O2 at a hypoxia level. As shown in Fig. 2b, in the presence of TEOA, strong fluorescence was observed for the 4T1 cells treated with CP@GDY/DSPE-PEG under visible light irradiation. This result indicated that CP@GDY/DSPE-PEG could capture endogenous CO2 and photo-catalytically reduce it into CO. It was reported that CO could enhance intracellular adenosine triphosphate (ATP), thus the ATP level was measured and is shown in Fig. 2c. The result was contrary to conjecture and showed declining ATP levels when treated with CP@GDY/DSPE-PEG. We speculated that there was 1% O2 providing CP@GDY/DSPE-PEG to produce ROS under hypoxia conditions, which disturbed the intracellular level.


image file: d1qm00677k-f2.tif
Fig. 2 (a) CO production rates for PFP@GDY/DSPE-PEG and PBF@GDY/DSPE-PEG in hypoxia condition and pure carbon dioxide. (b) CLSM image of 4T1 cells with treatment of CP@GDY/DSPE-PEG in the presence of Fl-CO after irradiation. The scale bar is 50 μm. (c) ATP level of 4T1 cells measured using the ATP kit assay.

Prior to studying the anticancer activity, the distribution of CP@GDY/DSPE-PEG inside 4T1 cells was investigated by confocal laser scanning microscopy (CLSM). As shown in Fig. 3a and b, the fluorescence of PFP@GDY/DSPE-PEG (blue emission) and PBF@GDY/DSPE-PEG (red emission) merged well with that of the lysosomal tracker but not for the mitochondrial tracker, indicating that the nanocatalyst is mainly located at the lysosome. To confirm that CP@GDY/DSPE-PEG could catalytically reduce CO2 into CO for hypoxia cancer therapy, the cell viability with irradiation treatment was studied using the MTT assay. As shown in Fig. 4a and b, CP@GDY/DSPE-PEG showed obvious anticancer influence on the viability of 4T1 cells with increasing concentration of the nanocatalyst. In comparison with CP@GDY/DSPE-PEG, PFP and PBF only showed slight cytotoxicity towards 4T1 cells because of the hypoxia condition offering insufficient O2 for CPs to kill cancer cells via PDT. Nevertheless, CP@GDY/DSPE-PEG could transform endogenous CO2 into CO for continuous hypoxia cancer therapy.


image file: d1qm00677k-f3.tif
Fig. 3 Co-localization analysis of PFP@GDY/DSPE-PEG (a), and PBF@GDY/DSPE-PEG (b) in 4T1 cells. Scale bar is 30 μm.

image file: d1qm00677k-f4.tif
Fig. 4 MTT assay of 4T1 cells treated with PBF and PBF@GDY/DSPE-PEG (a), PFP and PFP@GDY/DSPE-PEG (b) in hypoxia condition. (c) Loss of mitochondrial membrane potential verified by JC-1 assay. The scale bar is 40 μm.

The generated CO could interfere with mitochondrial respiration to induce cell apoptosis. To further explore the anticancer mechanism of CP@GDY/DSPE-PEG, the membrane potential of mitochondria was measured using a mitochondrial membrane potential probe, JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl benzimidazole carbonyl cyanine iodide). When JC-1 enters the cells and is distributed in the normal mitochondrial matrix with high membrane potential, it formed aggregation and emitted red fluorescence. For cells during the process of apoptosis, JC-1 presented decrement of the mitochondrial membrane potential, dispersed well, and emitted green fluorescence. As shown in Fig. 4c, negligible green fluorescence was observed in 4T1 cells treated with CP@GDY/DSPE-PEG nanocatalyst without light irradiation. Under light irradiation, much intensive green fluorescence was observed, proving CP@GDY/DSPE-PEG induced cell apoptosis. The catalytic production of CO interferes with the normal physiological metabolism of mitochondria in the cell, showing a decreased mitochondrial membrane potential.

Conclusions

In conclusion, this work provides new CPs/GDY nanocatalysts to in situ reduce endogenous CO2 to CO for hypoxia cancer therapy. The nanocatalysts were constructed through an assembly of CPs with GDY, which could photocatalyze CO2 into CO at a rate of 23 μmol h−1 gmat−1 for PFP@GDY/DSPE-PEG and 31 μmol h−1 gmat−1 for PBF@GDY/DSPE-PEG under hypoxia condition, respectively. The catalytically generated CO inside the cells induces the loss of mitochondrial potential, and the ATP level was also affected in 4T1 cells, leading to cancer cell apoptosis. This work diversifies the research field of gas therapeutics, especially hypoxic tumor treatments.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This study was financially supported by the National Natural Science Foundation of China (No. 21373243, 21473220).

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Footnote

Electronic supplementary information (ESI) available: Detailed experimental procedures and Fig. S1–S4. See DOI: 10.1039/d1qm00677k

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