Applications of Boron cluster Supramolecular Frameworks as Metal-free Chemodynamic Therapy Agents

doi:10.21203/rs.3.rs-2630546/v1

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Applications of Boron cluster Supramolecular Frameworks as Metal-free Chemodynamic Therapy Agents

https://doi.org/10.21203/rs.3.rs-2630546/v1

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published 14 Sep, 2023

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Chemodynamic therapy (CDT) is a highly targeted approach to treat cancer since it converts hydrogen peroxide into harmful hydroxyl radicals (•OH) through Fenton or Fenton-like reactions in tumor microenvironments. However, the systemic toxicity of metal-based CDT agents has limited their clinical use due to harmful side effects and low efficiency. Herein, we generate a novel CDT agent: 2,4,6-tri(4-pyridyl)-1,3,5-triazine (TPT)/ [closo-B₁₂H₁₂]²⁻(TPT@ B₁₂H₁₂), which is metal-free and may avoid cumulative toxicity during long-term therapy. We investigated the Fenton-like catalytic activity and anti-melanoma effects of the synthesized boron cluster supramolecular framework TPT@B₁₂H₁₂, and the results showed that it could effectively suppress the melanoma growth both in vitro and in vivo through ROS generation. The favorable properties of the TPT@B₁₂H₁₂ system were rationalized by means of quantum chemistry DFT calculations revealing that TPT@B₁₂H₁₂ substantially decreases the activation barrier compared to the effective Fe²⁺ ion commonly used in Fenton reactions. This study highlights the great clinical translational potential of TPT@B₁₂H₁₂ as a CDT agent, potentially serving as a prelude to the rapid development of metal-free CDT agents.

Biological sciences/Chemical biology/Biocatalysis

Biological sciences/Biochemistry/Chemical modification

Boron cluster Supramolecular Frameworks

Fenton-like catalytic activity

Chemodynamic therapy

Melanoma

Malignant tumors are one of the leading causes of death in the world, showing complexity, diversity and heterogeneity that largely challenge contemporary therapeutic approaches. Compared to normal cells, cancer cells are characterized with abnormal proliferation, metabolic activity, and mitochondrial dysfunction, which can be specifically summarized as mild acidity,¹ hypoxia,² abnormal vessels,³ overproduction of hydrogen peroxide and GSH,^4,5 and consumption of a large amount of nutrients.⁶

It has been demonstrated that tumor cells with excessive H₂O₂ levels could exert a profound effect on the development and progression of tumors.^7,8 In 1983, the British scientist H. J. H. Fenton discovered a reaction, in which H₂O₂ oxidizes various organic substances under the catalysis of iron ions in acidic media; subsequently, this reaction has been coined as the Fenton reaction.⁹ Similarly, some transition metal ions (Mn, Cu, Ag, Au, etc.) can also trigger Fenton-like process, which could convert over-expressed H₂O₂ into highly toxic •OH radicals under acidic tumor microenvironments.¹⁰ Based on these findings, a chemodynamic therapy (CDT) effect was proposed¹¹, which was defined as the transformation of endogenous H₂O₂ by means of the Fenton or Fenton-like reactions into the harmful •OH radical which in turn can induce tumor cells apoptosis by causing DNA damage and proteins inactivation.¹² It is here notable that as CDT demonstrates its anti-tumor effects depending on the high expression of H₂O₂ in the tumor microenvironment (TME) it is highly selective and specific with less damage to normal tissue. Therefore, CDT has become a powerful anti-tumor treatment strategy. At present, transitional metal Fenton materials, especially iron-based materials, are the basis of CDT therapy. However, the systemic toxicity of such materials (such as nervous system abnormalities, organ metabolic function loss), have limited its clinical applicaiton.^13,14 Continuous exposure to excessive iron intake can cause iron deposition in various tissues, ultimately leading to tissue damage and even peripheral organ failure,^14–16 especially organs like liver, heart, and pancreatic beta cells.^16–18 In particular, the anti-tumor treatment may significantly increase the risk of exposure to high levels of toxic iron without excessive iron input.^19,20 This covert and chronically neglected exposure may enhance organ toxicity and increase the probability of secondary malignancies and organ failure.²¹

Triazine compounds, an important class of six-membered aromatic heterocyclic compounds with three nitrogen atoms, are widely used in the construction of heterocycles and many natural products,²² antitumor,²³ antibacterial,²⁴ photo degradation²⁵ and catalytic fields.²⁶ Recently, several efforts to activate oxygen with triazine have been explored. For example, Han et al. developed a covalent triazine framework (CTF) with urea by a grafting method. The apparent enhancement of charge separation/transport and proton transfer was attributed to the ability of the triazine unit to accumulate photogenerated electrons and perform as a photoreduction site for the two-electron oxygen reduction reaction(ORR), while the accumulation of holes in the thiourea site accelerated the kinetics of water oxidation, thus cooperating to promote the production of H₂O₂ in oxygen and water mixtures.²⁷ Zhang et al. reported a metal-free covalent organic framework (COF)-based photocatalyst. Due to good porosity, high density of photoactive triazine components and partially interrupted π-conjugation, producing a suitable band gap could be produced. Moreover, an efficient charge separation and transfer due to the AA stacking, and abundant reaction centers, is shown to enhance its degradation activity for organic pollutants.²⁸ Although triazines have some potential applications in the activation of oxygen/dihydrogen peroxide, there is only a few relevant literature reporting possibilities of the triazine compounds to influence H₂O₂ in TME providing anti-tumor effects.

The dodecahydro-closo-dodecaborate anion [closo-B₁₂H₁₂]²⁻ is an icosahedron with a significant degree of symmetry, which has been the subject for various research studies such as supramolecular construction,²⁹ Boron neutron capture therapy³⁰ (BNCT), broadband membrane carriers³¹ and in situ synthesis of nanomaterials.^32,33 Our group has been working on a series of nonmetallic materials, on supramolecular assemblies based on boron clusters with applications in optical, and on electrical and thermal catalysis.^34–37 Recently, supramolecular polymer-2,4,6-tri(4-pyridyl)-1,3,5-triazine (TPT)/[closo-B₁₂H₁₂]2− (TPT@ B₁₂H₁₂) was investigated as an efficient bifunctional carrier for the nano-gold-catalyzed selective reduction of nitrobenzene under visible light. We found that TPT@B₁₂H₁₂ exhibited radical-generated photochromic properties under UV radiation attributed to the preference of closo-[B₁₂H₁₂]²⁻ as an electron donor, which allowed an e⁻ transfer to the excellent electron acceptor (TPT) under suitable conditions.³⁸

Based on the fact that toxic side effects limit the contemporary clinical applications of common Fenton materials,^11,39 we provide in this wok an anti-tumor strategy based on the versatile TPT@ B₁₂H₁₂ materials that can combine highly anti-tumor efficiency with low toxicity.

Synthesis and Characterization of TPT@B₁₂H₁₂

Detailed information on catalyst preparation can be found in the Experimental Section. Fourier transform infrared spectra (Fig. 1a) revealed that characteristic peaks corresponding to stretching vibration of the B-H bond near 2480 cm^− 1 in the spectra of Cs₂B₁₂H₁₂ and TPT@B₁₂H₁₂, while TPT@B₁₂H₁₂ exhibited a series of characteristic peaks of TPT at 1600 − 750 cm^− 1, indicating that TPT@B₁₂H₁₂ was successfully obtained. Indeed, originating from the anion-cation Coulombic attraction, the bonds of hydrogen and B-H...π have enhanced the interaction between closo-[B₁₂H₁₂]2- and TPT, thus contributing to the robust properties of TPT@B₁₂H₁₂. The transformation of TPT@B₁₂H₁₂ before and after UV irradiation can be observed from powder X-ray diffraction (PRXD) (Fig. 1b), that shows slight alteration of several characteristic peaks between 2θ = 10–15° and 22–30° after UV irradiation. Electron paramagnetic resonance (EPR) spectrum (Fig. 1c) demonstrated that the EPR signal was rather weak at the illumination time of 0 min, and the peak of the radical signal corresponding to [B₁₂H₁₂]-· appeared near G = 3490. Notably, compared with the pure free radical signal of [B₁₂H₁₂]-· (Figure S1) in our previous literature³², the [B₁₂H₁₂]-· free radical signal of TPT@B₁₂H₁₂ had a blue shift. Similarly, the free radical signal of [B₁₂H₁₂]-· gradually enhanced and blue shifted when the irradiation time was prolonged. When the illumination time was 12h, a significant signal of the boron cluster free radical appears at G = 3480 while the corresponding intensity was not significantly strengthened. Solid UV-vis spectra of TPT@B₁₂H₁₂ under different radiation indicated that TPT@B₁₂H₁₂ had response to light containing ultraviolet (Fig. 1d). Upon extended exposure to visible light, two UV-vis signals were observed around 535 nm and 725 nm. Moreover, after a short UV irradiation, the intensities of the two peaks notably increased in comparison with TPT@B₁₂H₁₂ under visible light conditions. These results indicated that TPT@B₁₂H₁₂ had a significant response in the UV region. Meanwhile, the color of the TPT@B₁₂H₁₂ solid gradually changed from light yellow to dark purple with the increase of UV-containing illumination time (Figure S2). Therefore, the charge transfer to TPT in the presence of UV light and the accompanying boron cluster radical generation led to a photochromic effect. X-ray photoelectron spectra (XPS) of TPT@B₁₂H₁₂ before and after UV illumination revealed that the B1s spectrum changed from a single characteristic peak (186.70 eV) to two characteristic peaks corresponding to 186.89 and 187.35 eV, respectively (Fig. 1e and f). Despite the presence of a series of changes, the field emission scanning electron micrographs (FESEM) and high-resolution transmission electron micrographs (HRTEM) indicated no significant structural changes of TPT@B₁₂H₁₂ after illumination, thus keeping its rod-like structures (Fig. 1g-i). Element distribution and the energy-dispersive X-ray spectroscopy (EDS) spectrum of TPT@B₁₂H₁₂ demonstrated that the three elements B, C, N were distributed rather homogeneously (Fig. 1j and k).

To elucidate the nature of catalytic efficiency of the developed catalyst TPT@B₁₂H₁₂, we have performed a set of calculations. It is well-known from the literature that hydrogen peroxide decomposes when it acquires an electron, like in the Fenton reaction.⁴⁰ In our case, an electron transfers form the anion to the cation upon light absorption forming a radical pair Cat^•2+ An^•–. Herein, Cat^•2+ tends to release the electron back; thus, this species is expected to demonstrate the catalytic activity.

The calculations of spin density distribution in Cat^•2+ reveal the preferable location on one pyridinium cycle (Fig. 2a). Sterically, such location of the unpaired spin is very convenient since the pyridinium cycles are directed towards the most morphologically important surfaces (Fig. 2b). All other stable surfaces of the studied crystalline catalyst are illustrated in Figure S1 in the ESI. Thus, we have compared activation barriers for the hydrogen peroxide decomposition with and without catalyst (Fig. 2c). Note all the discussed energies include the zero-point vibrational energy correction term. As one can see, our catalyst decreases the activation barrier more than 3.5 times being more effective than the Fe²⁺ ion (the Fenton reaction), which decreases the barrier about twice.

The corresponding optimized geometries of R', TS' and P' are presented in Figure S2 in the ESI. We should stress that the level of P' is much higher than that of P, which is due to the presence of a further stage of the Fenton process. Herein, we ignore this fact for the time being since the first stage already has a higher barrier compared to our catalyst (Fig. 2c). Meanwhile, the structural changes of the H₂O₂…HN moiety are illustrated in Fig. 2d. As one can see, a simultaneous process of the O–O bond elongation and the hydrogen atom abstraction is observed and a subsequent formation of a hydroxyl radical and a water molecule takes place. Obviously, further chemical transformations include the water molecule desorption and hydroxylation of a benzene molecule. We assume here a synchronous process of the HO• addition and H• detachment near the bare nitrogen, which should immediately acquire the latter regenerating the native structure of the catalyst. The proposed scheme of the whole catalytic cycle looks thus as follows:

Cat^•2+ + H₂O₂ = [Cat-H] ²⁺ + OH^• + H₂O

An EPR test of TPT@B₁₂H₁₂/H₂O₂ system was carried out to verify the outcome of the calculations. The results observed here demonstrated that TPT@B₁₂H₁₂ was stimulated by UV light irradiation and consequently has the capacity to decompose H₂O₂ into OH^• (Fig. 2e).

TPT@B₁₂H₁₂ induced ROS-dependent apoptosis of melanoma in vitro

As mentioned above, TPT@B₁₂H₁₂ can decompose H₂O₂ to produce hydroxyl radical (•OH) with ultraviolet radiation. Hence, we sought to determine whether TPT@B₁₂H₁₂ triggers ROS production in tumor cells. We firstly investigated the effect of ultraviolet radiation on the ROS generation in cells, and found that the ROS levels generated by the B16 cells (murine melanoma cells) were dependent on the pre-treatment duration by ultraviolet radiation (Fig. 3a and 3b). We then determine the effect of dose on the ROS generation by the cells. The results from the DCFH-DA staining showed that TPT@B₁₂H₁₂ increased the production of ROS in B16 cells in a dose-dependent manner (Fig. 3c-3f).

To determine the cytotoxicity of the ROS produced by the TPT@B₁₂H₁₂, we performed the cell viability assay and confirmed that TPT@B₁₂H₁₂ significantly suppress the cell viability of B16 in a dose-dependent manner (Fig. 4a and 4b). Longer exposure of TPT@B₁₂H₁₂ to the ultraviolet radiation led to higher cytotoxicity (Figure S6). Vitally, the ROS scavenger N-acetyl-L-cysteine (NAC) could significantly decrease the ROS levels (Figure S5) and rescue the cytotoxicity of TPT@B₁₂H₁₂ (Fig. 4b), suggesting that TPT@B₁₂H₁₂ mediated cell cytotoxicity through ROS generation. Since ROS could trigger the cell apoptosis via mitochondrial related apoptotic cascade,⁴² we evaluated whether TPT@B₁₂H₁₂ could induce B16 cell apoptosis and affect the functions of mitochondrial. With flow cytometry, we confirmed that TPT@B₁₂H₁₂ could lead to a dose-dependent apoptosis (Fig. 4c and 4d, FITC+). With a JC-1 probe, we verified TPT@B₁₂H₁₂ treatment dramatically increased the accumulation of JC-1 monomers in B16 cells, indicating the decreased of mitochondrial membrane potential (Fig. 4e and 4f). Collectively, these data indicated that TPT@B₁₂H₁₂ lead to apoptosis of B16 through triggering the ROS generation.

ROS modulation is a widely used anti-tumor strategy based on the fact that H₂O₂ plays an important role in the tumor proliferation, invasion and metastasis,⁴³ making tumor cells more vulnerable to oxidative stress by H₂O₂ compared to normal cells.⁴⁴ CDT exerts its anti-tumor effect depending on the high level of H₂O₂, suggesting that CDT is selective to tumor cells.¹⁰ These data indicates that TPT@B₁₂H₁₂ can produce a high levels of ROS. This property is sufficient to induce tumor cell apoptosis, making TPT@B₁₂H₁₂ a novel kind of effective CDT agent.

TPT@B₁₂H₁₂ significantly suppressed melanoma growth in vivo

The antitumor effects of TPT@B₁₂H₁₂ were evaluated in the animal model. C57BL/6 mice were subcutaneously injected with 0.5×10⁶ B16 cells, and when tumor volumes reached 100 mm³, mice were randomly divided into 2 groups, one group mice were administrated with saline, and the other group with TPT@B₁₂H₁₂ (20 mg/kg, every three days, i.p. injection). The tumor volumes were monitored during treatment. All mice were sacrificed at the day22. The blood, serum, and organs including kidney, livers, heart, spleen, and lung samples were harvested (Fig. 5a). TPT@B₁₂H₁₂ could significantly inhibit melanoma tumor growth (Fig. 5b and 5c). The side effects assessment of TPT@B₁₂H₁₂ were evaluated with the blood, serum, and important organs. TPT@B₁₂H₁₂ administration rarely affected the mice body weight (Fig. 5d). There was no significant difference for the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine (CREA) between the two groups (Fig. 5e). Cells counting including white blood cell (WBC), lymphocyte (LYM), neutrophil (NEUT), hemoglobin (HGB) and blood platelet (PLT) indicated that TPT@B₁₂H₁₂ has limited hematologic toxicity (Fig. 5f). Consistently, HE staining showed that TPT@B₁₂H₁₂ could promote melanoma cell death and showed no obvious toxicity in important organs, including the heart, liver, spleen, lung, and kidney (Fig. 5g). These data support that TPT@B₁₂H₁₂ inhibited B16 tumor growth with limited side effects.

As mentioned, metal-based Fenton materials may have systemic toxicity problems, such as nervous system abnormalities and organ metabolic function loss.^13,14 Currently, most CDT agents are iron-based materials, and iron overload is an important problem in the process of drug administration. The bioavailability of iron is scarce and the excretion of excess iron is very slow.^45–47 Long-term exposure to excess iron may cause organ toxicity, secondary malignancies, and even organ failure.^15,16,21 At the same time, the use of iron-based agents in cancer patients need a careful consideration, since patients who are undergoing cancer treatment are at high risk for iron loading, especially under the condition of transfusion and chemotherapy which can suppress erythropoiesis and increased exposure to toxic non-transferrin-bound iron.^19,20,48,49 As patients with tumors usually are receiving continuous treatment, this situation can make physicians neglect the complications induced by iron toxicity.²¹ Other metallic agents (Cu, Mn, etc.) also face the same risk in clinical use.^50–52 Thus, TPT@B₁₂H₁₂ is a metal-free catalyst with a limited biological toxicity and its use does obviously not cause any of the above mentioned concerns about the accumulation of metal toxicity in the body and subsequent organ failure.

In this study, we constructed a novel metal-free CDT agent TPT@B₁₂H₁₂ and confirmed its anti-tumor effects both in vitro and vivo. Mechanismly, TPT@B₁₂H₁₂ mediated cell apoptosis through triggering the ROS generation. More importantly, TPT@B₁₂H₁₂ showed rarely side effects on important organs and normal cells, indicating a significant clinical potential. Meanwhile, a theoretical analysis supported that TPT@B₁₂H₁₂ substantially decreases the activation barrier compared to the Fe²⁺ ion commonly used in Fenton reactions. This study indicates a new direction for the development and clinical application of CDT agents and motivates upcoming research of metal-free CDT agents with high efficiency, high selectivity and low toxicity.

Acknowledgments

The work was financially supported by National Natural Science Foundation (22179100), Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province (CXPJJH122006-1014), Hubei Provincial Natural Science Foundation (2022CFB616), and Fundamental Research Funds for the Central Universities (413000404).

Author Contributions

Conceptualization, Tianhe Huang, Haibo Zhang, and Yongchang Wei; Methodology, Tianhe Huang, Haibo Zhang, and Yongchang Wei; Investigation, Xiaoran Xu, Xuefan Deng, Yi Li, Shiyin Xia, Pan Liu, and Xinyu Wang; Analysis, Xiaoran Xu, Xuefan Deng, Yi Li, Shiyin Xia, Pan Liu, and Xinyu Wang; Writing – Original Draft, Xiaoran Xu, Xuefan Deng; Writing – Review & Editing, Glib Baryshnikov, Sergey V. Bondarchuk, Hans Ågren, Tianhe Huang, Haibo Zhang, and Yongchang Wei; Funding Acquisition, Tianhe Huang, Haibo Zhang, and Yongchang Wei. Supervision, Tianhe Huang, Haibo Zhang, and Yongchang Wei.

Declaration of Competing Interest

The authors report no declarations of interest.

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Applications of Boron cluster Supramolecular Frameworks as Metal-free Chemodynamic Therapy Agents

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