Photodynamic Therapy of Hypoxic Tumors with Ir(Ⅲ) Complexes

Zilin Zhu; Zhongxian Fan; Mengzhao Miao; Huaiyi Huang

doi:10.7536/PC200878

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (9) : 1473-1481 DOI: 10.7536/PC200878

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Photodynamic Therapy of Hypoxic Tumors with Ir(Ⅲ) Complexes

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Abstract

Photodynamic therapy has become a new method to treat cancer because of noninvasive, controllable features and less drug resistance compared with chemotherapy. The photo-sensitization pathway involves the photoactivation of molecular oxygen by photosensitizer. However, due to the hypoxic environment of solid tumors, the photodynamic therapeutic effect of traditional photosensitizers is severely suppressed. Metallic Ir(Ⅲ) complexes exhibit excellent photo-physical and photo-chemical properties which make them ideal next-generation photosensitizers for photodynamic therapy. It has been reported that some novel Ir(Ⅲ) complexes show excellent photodynamic therapy effect towards hypoxic tumors. In this review, we focus on the recent studies on the application of Ir(Ⅲ) complexes to photodynamic therapy under hypoxia. Furthermore, the applications of Ir(Ⅲ) complexes containing nanocomposite system for hypoxic photodynamic therapy are also summarized, with the hope to provide guidance for the development of novel and efficient photosensitizers for hypoxic tumor.

Contents

1 Introduction

2 Photodynamic therapy(PDT)based on iridium complexes

2.1 Type I PDT in the hypoxic environment

2.2 Type II PDT in the hypoxic environment

3 Nanocomposite system for PDT of hypoxic tumors

3.1 Up-conversion nanocomposite system

3.2 Polymer nanocomposite system

4 Conclusion and outlook

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Keywords

iridium complexes / hypoxia / photodynamic therapy / nanocomposite system

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Zilin Zhu, Zhongxian Fan, Mengzhao Miao, Huaiyi Huang. Photodynamic Therapy of Hypoxic Tumors with Ir(Ⅲ) Complexes. Progress in Chemistry, 2021, 33(9): 1473-1481 DOI:10.7536/PC200878

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1 Introduction

Cancer is still a major threat to human health because of its high mortality, easy recurrence, strong invasion and metastasis^[1]. A large number of studies have shown that hypoxia is one of the common characteristics of the tissue microenvironment of solid tumors^[2]. In solid tumors, due to the rapid proliferation of tumor cells, incomplete development and uneven distribution of blood vessels, the internal oxygen supply of solid tumors is insufficient, which eventually leads to the existence of hypoxic areas in tumors. Severe tumor hypoxia can lead to a significant decline in the efficacy of non-surgical treatment of cancer, leading to tumor metastasis, recurrence and drug resistance, so hypoxia has become a major problem in the treatment of cancer^[3⇓~5].

Photodynamic Therapy (PDT) has a good application prospect in the field of medicine because of its non-invasive, controllable and not easy to produce drug resistance, especially in the field of cancer treatment as an alternative or complementary Therapy to traditional treatment methods^[6⇓~8]. Photodynamic effect involves the light-activated reaction between Photosensitizer (PS) and molecular Oxygen, which can induce the production of Reactive Oxygen Species (ROS) to selectively kill tumor cells, destroy tumor blood vessels and activate the host immune system^[9,10]. According to the photoactivation pathway, PDT can be divided into two types: type I PDT involves electron transfer between photosensitizer and biomolecules, which is less dependent on oxygen; Type II PDT involves energy transfer between photosensitizer and molecular oxygen, and kills tumor cells by producing singlet oxygen (¹O₂), which is completely dependent on intracellular oxygen concentration^[11,12]. Type II photosensitizers are highly dependent on oxygen concentration in the treatment process, and will consume a large amount of oxygen, aggravating the degree of tumor hypoxia. However, most porphyrin-based PDT is mainly based on the type II photoreaction pathway, resulting in a close correlation between the efficacy of PDT and the local oxygen concentration of tumor tissue. In addition, the oxygen consumption during PDT will further aggravate the hypoxia state of tumors, which seriously restricts the photosensitization process and greatly reduces the efficacy of PDT.

In recent years, researchers have done a lot of research on the limitation of PDT efficacy and the poor prognosis of PDT caused by tumor hypoxia. The research focuses on the development of type I photosensitizers with less oxygen dependence and type II photosensitizers with high singlet oxygen quantum yield to deal with hypoxic tumors. Compared with traditional organic photosensitizers such as porphyrins, iridium complexes have unique advantages: (1) long-lived triplet excited States in microseconds, which still have strong singlet oxygen quantum yield under hypoxic conditions; (2) Good photophysical and photochemical properties can be obtained by structural modification or ligand modification^[13,14]. Therefore, the reasonable design of iridium photosensitizers for photodynamic therapy shows great potential in the field of comprehensive diagnosis and treatment of hypoxic tumors.

In this paper, the recent progress in photodynamic therapy of hypoxic tumors with iridium complexes is reviewed. Firstly, the application of iridium complexes in photodynamic therapy of type I and type II in hypoxic environment is summarized, which provides reference for the rational development of new and efficient photosensitizers. At the same time, the construction of nanocomposite system based on metal iridium complexes and its application in photodynamic therapy of hypoxic tumors were also discussed.

2 Photodynamic therapy based on iridium complex

2.1 Hypoxic environment type I photodynamic therapy

The research of photodynamic therapy has been focused on designing efficient photosensitizers to produce more ¹O₂ to kill tumor cells. However, the production of ¹O₂ requires the participation of oxygen, and improving the quantum yield of ¹O₂ in hypoxic tumors is still an obstacle to the development of new type II photosensitizers^[15⇓~17]. Type I photodynamic therapy is less dependent on oxygen and can produce toxic free radicals under hypoxic conditions. Therefore, in order to overcome the inherent contradiction between the efficacy of PDT and the demand for oxygen, researchers have been committed to the development and design of PDT based on type I photoreaction pathway. Type I PDT involves intracellular electron transfer. When the photosensitizer is excited by light to form a triplet state, the triplet excited photosensitizer can transfer electrons with some biomolecules (such as reducing coenzymes, amino acids and nitrogenous bases) in cancer cells to produce free radicals.Then it can further react with molecular oxygen to produce superoxide radicals, hydrogen peroxide radicals and hydroxyl radicals, thus killing tumor cells and inhibiting tumor hypoxia^[18⇓~20]. The generation of active oxygen is accompanied by the generation of some toxic free radicals independent of oxygen, such as the direct generation of toxic free radicals by the reaction between metal complexes and biomolecules or the generation of toxic carbon free radicals by the initiation of complexes, and its mechanism is also widely studied.

2.1.1 Form superoxide radical with molecular oxygen

Superoxide radical is one of the major and highly toxic reactive oxygen species, which is considered to be the main oxidant of cancer therapy and the adjuvant of synergistic chemotherapy^[21⇓~23]. Excessive superoxide free radicals in vivo can react with proteins, DNA and lipids, causing irreversible damage to cellular components, leading to cellular metabolic dysfunction^[24,25]. More importantly, intracellular superoxide dismutase (SOD) can initiate the disproportionation reaction and catalyze superoxide radicals to produce hydrogen peroxide and oxygen^[26,27]. The accumulation of hydrogen peroxide will further convert into more toxic hydroxyl radicals, which will significantly aggravate oxidative damage and improve anti-cancer efficacy. To some extent, O₂ can be recovered in these cascades of biological reactions, thus contributing to the improvement of tumor hypoxia^{[23⇓⇓⇓⇓~28]}. Therefore, the development of photosensitizers that can induce the production of superoxide radicals will open up a new way for the treatment of hypoxic solid tumors.

Ruiz and Kasparkova et al. Designed and synthesized three series of octahedral iridium complexes 1 ~ 3 (Fig. 1), and studied their phototoxicity in HeLa cell model under normoxic and hypoxic conditions^[29]. They found that complexes 1 C, 2 C and 3C showed strong phototoxicity in human cervical cancer HeLa cell model, in which 1 C and 2 C preferentially localized to the endoplasmic reticulum, while 3C localized to the mitochondria. When they studied iridium complex 3, they found that iridium complex 3B was the most phototoxic. However, complex 3B is only involved in the generation of superoxide radicals and not in the generation of ¹O₂, and 3A and 3C are only involved in the formation of a small amount of ¹O₂. Therefore, they concluded that the generation of superoxide radicals was the main cause of phototoxicity after treatment of cells with complex 3. March Marchán et al. reported a cyclometallated iridium complex 4A and 4B that can be coupled to a fluorophore (fig. 2)^[30]. These complexes had no significant dark toxicity in HeLa cells, but under blue and green light irradiation, cell death was significantly correlated with the production of intracellular superoxide radicals, even under hypoxic conditions. Based on the above studies, type I photodynamic therapy photosensitizers can improve the therapeutic effect in hypoxic tumors.

2.1.2 Formation of toxic free radicals with biomolecules

Most of the metal complexes in the photodynamic effect are based on the type II photochemical process, which produces ¹O₂ in cooperation with oxygen under the excitation of light^[31,32]. When oxygen-dependent photoreaction pathways are not suitable for hypoxic tumors, it is of great significance to develop oxygen-independent type I photosensitizers. Studies have found that some modified iridium complexes have high oxidation activity, which can transfer electrons with biomolecules under light irradiation and produce toxic free radicals, thus killing tumor cells^[33,34].

Elias et al. Developed bicyclometalated iridium complexes 5a-d (fig. 3) capable of photoreacting with biomolecules, which can transfer electrons from guanine residues of DNA under visible light irradiation and produce toxic free radicals (oxidized guanine residues) to block DNA replication and transcription^[35,36]. In addition to extensive experimental and theoretical studies of the photophysical properties of these complexes, they characterized their photoreactivity toward redox-active targets and related biological targets (guanine bases) models. The results show that the excited iridium complex can undergo photoinduced electron transfer with guanine to form a stable photoproduct, which causes irreversible damage to guanine. Next, they verified the phototoxicity of iridium complexes 5B and 5d in related biological models, and found that even under hypoxic conditions, drugs accumulated in mitochondria, which could induce a sharp decline in cell viability under corresponding light irradiation. Among them, in the study of these two complexes, they found that 5d has a low ¹O₂ quantum yield and a high oxygen-independent type I photodynamic effect, so iridium complex 5d is expected to become a promising candidate for type I photodynamic therapy. These results lay a foundation for the development of new type I photosensitizers.

2.1.3 Formation of carbon free radical

Usually involving photoinduced electron transfer of biomolecules, reaction with oxygen will result in the production of different types of free radicals. Although the treatment of hypoxic tumors is less dependent on oxygen and has obvious curative effect, it still needs the presence of oxygen, so researchers have been committed to the development of oxygen-independent photosensitizers.

Sadler et al. designed an octahedral cyclometalated iridium complex 6 (fig. 4) with photocatalytic activity, which is phototoxic to both normoxic and hypoxic cancer cells^[37]. The complex can photocatalytically oxidize an important 1,4-dihydronicotinamide adenine dinucleotide (NADH) coenzyme in living cells, generates NAD carbon free radicals in a biological medium at a high conversion rate, destroys the redox balance in the cells, and can kill cancer cells in a hypoxic state. They found that the complex localizes to mitochondria and induces NADH depletion, intracellular redox imbalance and immunogenic apoptotic cancer cell death under light irradiation by photocatalyzing NADH to disrupt electron transport. Iridium complex 6 has a light-controlled oxygen-independent immunogenic apoptosis mechanism, which can be used as a novel targeted anti-cancer drug, and the strategy of photocatalytic redox imbalance provides a new direction for efficient hypoxic photodynamic therapy.

In this context, Chao Hui et al. Designed and synthesized an iridium complex 7 with anthraquinone groups (Fig. 5), which can be located in the mitochondria of tumor cells as an initiator for the generation of carbon radicals^[38]. Under normoxic conditions, the anthraquinone group of complex 7 is not reduced, but under hypoxic conditions, it can be reduced to anthracenediol by reductase, and then carbon radicals are produced under two-photon excitation, which leads to the loss of mitochondrial membrane potential and cell death. The PDT effect of complex 7 under hypoxic conditions was also demonstrated in tumor multicellular spheroids and in vivo. The complex has a good prospect as a candidate drug for clinical trials due to mitochondrial targeting and hypoxia-activated two-photon excitation characteristics and efficient photodynamic therapy efficiency in vivo.

2.2 Photodynamic therapy in hypoxic environment

Type II photodynamic therapy involves energy transfer between the triplet excited state of the photosensitizer and the ground state of the O₂, producing toxic singlet oxygen (¹O₂)^[39]. Although this process is completely dependent on oxygen, most of the photosensitizers reported so far are based on the type II photoreaction pathway, which causes tumor cell death by producing ¹O₂. Therefore, the development of type II photosensitizers that can improve the quantum yield of ¹O₂ and the design of efficient combination therapy are also of great significance in the photodynamic therapy of hypoxic tumors. Here, we will take iridium complexes as an example to discuss how to improve the efficacy of PDT.

2.2.1 Targeted mitochondria

In recent years, researchers have been working to develop PDT agents that target organelles and to evaluate their PDT effects^[40⇓~42]. For example, nucleus-targeted PDT agents can cause great damage to cancer cells, but because of the risk of genetic variation, they have begun to turn to other organelles^[40]. Mitochondria and lysosomes, as indispensable organelles, play important roles in cellular respiration and digestion, respectively^[43,44]. More importantly, they are closely related to apoptosis. Therefore, PDT agents targeting mitochondria and lysosomes can rapidly destroy the biological functions of organelles under light activation, leading to the death of tumor cells. However, researchers have found that photosensitizers that target mitochondria are more effective in the treatment of hypoxic tumors.

Zhao Qiang et al. designed and synthesized two iridium complexes 8A and 8B targeting cell mitochondria and lysosomes respectively (Fig. 6)^[45,46]. Both complexes exhibit long-lived and oxygen-sensitive phosphorescence. They evaluated the phototoxicity of the complexes to cells under normoxic and hypoxic conditions. The results showed that under hypoxic conditions, HeLa cells treated with mitochondria-targeted complexes and irradiated with light maintained lower respiration rates and higher levels of ¹O₂. Therefore, compared with the complexes targeting lysosomes, especially under hypoxic conditions, the complexes targeting mitochondria have better PDT effect, which indicates that the photosensitizers targeting mitochondria may have higher practical potential in photodynamic therapy.

However, mitochondria-targeted iridium complexes can inhibit mitochondrial respiration and increase the oxygen content in mitochondria, thus improving the yield of ¹O₂, but the quantum yield of ¹O₂ is still low in the treatment of hypoxic tumors. Therefore, based on the previous research, they successfully introduced the electron-withdrawing anthraquinone group into the C ^ N ligand, and designed and synthesized iridium complexes 9 a ~ d (Fig. 7) containing anthraquinone group, which can effectively adjust the excited state energy level. The energy gap of complex 9a is in the range of 1. 63 ~ 2.21 eV, which is consistent with the energy gap of O₂, and the HOMO energy is less than-5. 51 eV. Compared with the iridium complexes 9 B ~ d, the complex 9 a has the highest fluorescence quantum yield and can specifically target the mitochondria of tumor cells.Meanwhile, the complex 9 a shows high ¹O₂ quantum yield in both solution and in living tumor cells, and has low dark toxicity and high phototoxicity. The results of PDT experiments showed that the iridium complex 9 a had a good therapeutic effect under both normoxic and hypoxic conditions. Therefore, it is of great significance to develop excellent PDT photosensitizers based on cyclometallated iridium complexes through reasonable ligand modification.

2.2.2 Combination therapy

PDT lacks selectivity for cancer cells, resulting in higher photosensitizer dose requirements and increased systemic toxicity. In addition, congenital defects in tumor vasculature and persistent oxygen consumption in PDT increase the possibility of tumor hypoxia, which hinders the efficacy of PDT and increases the risk of cancer recurrence^[47⇓~49]. In response, PDT-related multimodal therapies using fine nanostructured photosensitizers have been extensively studied in the quest to eradicate cancer cells. However, nanomaterials may have unstable properties due to complex modifications^[50⇓~52]. Therefore, the researchers further explored whether specific combination therapies could improve the therapeutic effect of cancer cells.

Cancer cells, unlike normal cells, are largely powered by glycolysis, reducing their dependence on oxygen and further giving them an advantage in survival under hypoxic conditions^[53,54]. Studies have reported that the use of dichloroacetic acid (DCA) can reverse the glycolytic phenotype of cancer cells, which has great prospects for promoting cancer-specific drug sensitization. In addition, PDT targeting mitochondria can rapidly disrupt redox homeostasis and trigger apoptosis, potentially overcoming multidrug resistance. Chao Hui et al. Prepared a series of DCA-bound iridium complexes 10 a-d (Fig. 8), which can accumulate in mitochondria, selectively induce metabolic changes in cancer cells, and play a role in the combined treatment of mitochondria-targeted DCA chemotherapy and PDT^[55]. They found that complex 10a showed excellent therapeutic effects in both monolayer cells and hypoxic tumor multicellular spheres, so DCA and two-photon active iridium complexes can play a synergistic role through rational molecular engineering, thus enhancing cancer treatment.

He et al. Designed and synthesized an iridium complex 11 (fig. 9) targeting cell mitochondria, which can produce photoacid under light irradiation, and also produce two iridium complexes that can sensitize the formation of ¹O₂^[56]. They found that photoacid and ¹O₂ work together to damage mitochondria and effectively kill cancer cells even under hypoxic conditions. Therefore, compared to other oxygen independent PDT agents, the iridium complex not only induces oxygen independent photodynamic damage, but also fully utilizes the oxygen present in the tumor to induce ¹O₂ related damage in cancer cells. This study demonstrates that dual mode (oxygen independent and oxygen dependent) PDT photosensitizers are a promising strategy for the treatment of hypoxic tumors.

3 Nanocomposite system for photodynamic therapy of hypoxic tumor

In the course of PDT treatment, the increase of oxygen consumption will further aggravate the hypoxia state of tumor tissue, forming a vicious circle and limiting the effect of PDT^[57⇓~59]. In recent years, in the field of PDT, efforts have been made to overcome the limitations of the hypoxic tumor microenvironment, and various nanosystems have been explored to alleviate the hypoxia of tumors. So far, there are three main strategies to solve the above problems: (1) using nanoparticles (such as MnO₂, TiO₂, biological enzymes, etc.) As catalysts to generate oxygen in situ in tumors with acidic environment and high concentration of hydrogen peroxide; (2) direct delivery of oxygen to the tumor site using oxygen carriers such as perfluorocarbons and hemoglobin; And (3) adopt nano materials such as C₃N₄ or CaO₂ and that like to decompose in situ to generate oxygen^[60⇓~62]. However, there are still some problems in this research field. For example, insufficient endogenous H₂O₂ in tumor tissue often leads to inefficient oxygen production, and oxygen carriers have limited oxygen carrying capacity^[63,64]. Therefore, improving the efficacy of PDT remains a great challenge, and new strategies are needed to overcome tumor hypoxia. For example, a nanoplatform targeting tumor hypoxia was designed to turn PDT-induced tumor hypoxia into a therapeutic advantage. Here, we will take iridium complexes as an example to explore how to enhance the effect of photodynamic therapy by applying them to the construction of upconversion and polymer nanocomposite systems.

3.1 Upconversion nanocomposite system

For most photosensitizers, the light that excites them is generally in the ultraviolet-visible region, where tissue penetration is weak. Beyond this region, the energy will decay sharply, so that the ROS produced is not enough to produce a strong photodynamic effect^[65,66]. Only in the near-infrared window (700-1000 nm), the light can penetrate the tissue more strongly and reach deeper tissue layers. Although researchers have been trying to synthesize new photosensitizers and shift their absorption maxima to the near-infrared region, there are few reports based on this and they are still in the early stage of development^[67,68]. In recent years, researchers have proposed an ingenious method, using upconversion nanoparticles as converters to effectively convert low-energy near-infrared light with high penetration into high-energy ultraviolet visible light, which matches the excitation wavelength of existing photosensitizers, so as to excite photosensitizers to exert photodynamic effects. In addition, upconversion nanoparticles can also be used as drug carriers for photosensitizers to deliver them to tumor sites, effectively accumulating preferentially at tumor sites.

Photosensitizers with long-lived triplet excited States are suitable for cancer therapy, especially metal-based photosensitizers, which have immeasurable potential^[69]. However, in most cases, the triplet excited state of iridium complexes usually shows a relatively short lifetime and weak absorption in the near infrared, which limits its application in the deep treatment of tumor tissues. Therefore, the iridium complex is covalently coupled to the surface of the upconversion nanoparticles to realize the near-infrared light excitation PDT. However, overcoming hypoxia remains a serious challenge in photodynamic therapy.

Zhang and Gou et al. Designed a nano-platform for tumor hypoxia to transform PDT-induced tumor hypoxia into a therapeutic advantage^[70]. They designed and synthesized a long-lived triplet-excited cyclometalated iridium complex 12, covalently bound it to upconversion nanoparticles for near-infrared photodynamic therapy, and then encapsulated the synthesized UCNP @ Ir with a biocompatible Pluronic F127 (F127). After that, YC-1 (HIF-1α inhibitor) was physically adsorbed on the hydrophobic layer of the surface of the up-converted nanoparticles, and the UCNP @ IrYCF127 nano-platform for tumor hypoxia was successfully synthesized. The results showed that the synthesized UCNP @ IrYCF127 exhibited high ¹O₂ production even under hypoxia. Under the irradiation of near-infrared light, the iridium complex generates ¹O₂, which fully consumes oxygen and aggravates the hypoxia of tumor tissues, thus leading to the up-regulation of HIF-1α for subsequent HIF-1-targeted tumor therapy (fig. 10). Among them, the biological evaluation showed that the therapeutic efficiency of UCNP @ IrYCF127 nano-drug was higher than that of UCNP @ IrF127, which indicated that YC-1 played an important role in improving the PDT effect of UCN P @ IrYCF127. Therefore, this work proposes an excellent strategy to overcome the hypoxia barrier in PDT, which is expected to promote the development of clinically applicable PDT nanoplatforms.

3.2 Polymer nanocomposite system

Polymer nanoparticles have attracted great attention as drug delivery systems for cancer detection and therapy due to their excellent water solubility and biocompatibility^[71]. The use of polymer carriers can improve the efficiency of targeting tumors, reduce the dosage of complexes, increase the availability of metal complexes, and thus reduce the side effects caused by excessive dosage of complexes. In addition, macromolecular delivery systems containing multiple compounds enable Multi-Action and multi-target delivery, or the combination of therapeutic and diagnostic tools to provide diagnostic agents.

Zhao Qiang et al. designed and synthesized negatively charged hyperbranched phosphorescent conjugated polymer dots (13/PSMA dots) with iridium complex 13 as the core for hypoxia imaging and efficient photodynamic therapy (Fig. 11)^[72]. They chose oxygen-sensitive red phosphorescent iridium complex as the core, oxygen-insensitive blue fluorescent 9,9-dioctylfluorene as the conjugated backbone of hyperbranched conjugated polymer, and introduced polystyrene-maleic anhydride (PSMA) into phosphorescent conjugated polymer dots by co-precipitation method to make them negatively charged, which ensured their water solubility and biocompatibility. Due to the inclusion of an iridium complex in the nanoprobe, which has phosphorescent properties and high singlet oxygen quantum yield, the potential application of PDT under imaging guidance was confirmed by real-time fluorescence imaging and MTT method to measure light-induced apoptosis and death of cells in situ. These results suggest that the development of a diagnostic and therapeutic platform based on phosphorescent polymer dots will be a promising strategy for the treatment of cancer.

4 Conclusion and prospect

This review summarizes the recent progress in photodynamic therapy of hypoxic tumors with iridium complexes. Although iridium complexes have excellent optical properties and good cell permeability, there are few reports on the application of iridium complexes in photodynamic therapy of hypoxic tumors. Most of the iridium complexes have focused on developing type II photosensitizers, designing targeted mitochondria or improving the quantum yield of ¹O₂ through specific combination therapy strategies, but the ¹O₂ produced are still insufficient to deal with malignant tumors.Therefore, researchers began to develop photosensitizers with new mechanisms of action (such as type I mechanism) or design nano-platforms for tumor hypoxia for photodynamic therapy of hypoxic tumors, in order to overcome the problems caused by tumor hypoxia. Although there are some challenges in the application of iridium complexes in photodynamic therapy of hypoxic tumors, the excellent optical properties of iridium complexes are destined to have a bright future in this field.With the rapid development of many disciplines, it is believed that iridium complexes will be more widely used in photodynamic therapy of hypoxic tumors in the future.

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