Redesigning Coordination Chemistry for Cancer Therapy: Advances in Non-platinum Metal-based Anticancer Agents

Elaboration of new generations of more effective and safer metal-based anticancer agents, has been stimulated by the severe side effects encountered by patients undergoing chemotherapeutic treatments. In this search, ruthenium complexes have shown encouraging potential, demonstrating a wide antiproliferative profile against cancer cells. Seminal studies conducted in our labs have resulted in the development of ruthenium(II)-based new anticancer agents, which showed distinct cytotoxicity mechanisms. First, a substitutionally-inert bis(dppz)-Ru(II) complex has been synthetized that impairs the mitochondrial membrane potential of cells leading to apoptosis. A follow- up structure-activity relationship analysis investigating the impact of lipophilicity, charge and size-based modification revealed the presence of carboxylic acid functionality as indispensable to confer cytotoxicity to the Ru(II) complex. This complex was successfully inactivated by protecting the carboxylate functionality with a photolabile protecting group. The anticancer activity could be regained by UV-A irradiation (2.58 J/cm2). Second, a seemingly harmless ruthenium(II) complex was prepared. It targets the cell nucleus and causes significant damage to DNA, such as single-strand breaks (SSBs) and purines oxidation upon UV-A irradiation (1.29 J/cm2). After 24 h, double- strand breaks (DSBs) are also created that lead overall to cell death. Collectively, these findings are an important progress towards developing a new class of metal-based anticancer agents, which have the potential to overcome the drawbacks of the current platinum-based drugs.

Photodynamic therapy (PDT) is an effective tumor treatment that involves the administration of a photosensitizer to generate cytotoxic 1O2 [reactive oxygen species (ROS)] from molecular oxygen that is produced from energy absorption following tumor irradiation at specific wavelengths. Ferroptosis is induced by the disruption of the glutathione peroxidase 4 (GPX4) antioxidant system, leading to lipid peroxidation. We hypothesized that talaporfin sodium-photodynamic therapy (TS-PDT)-generated ROS would lead to ferroptosis via accumulation of lipid peroxidation. Cell viability assay in TS-PDT-treated cells in combination with a ferroptosis inhibitor (ferrostatin-1: Fer-1) or ferroptosis inducers (imidazole ketone erastin: IKE, Ras-selective lethal 3: RSL3) was performed. Accumulation of lipid peroxidation, GPX4 antioxidant system and cystine/glutamate antiporter (system xc-) activity in TS-PDT-treated cells was investigated. In xenograft mice, the antitumor effect of TS-PDT in combination with ferroptosis inducers (IKE or sorafenib) was examined. TS-PDT-induced cell death was partly suppressed by Fer-1 and accompanied by lipid peroxidation. TS-PDT combined with IKE or RSL3 enhanced the induction of cell death. TS-PDT inhibited cystine uptake activity via system xc-. In vivo, the combination of TS-PDT and ferroptosis inducers (IKE or sorafenib) reduced tumor volume. This study found that the mechanism underlying TS-PDT-induced ferroptosis constitutes direct lipid peroxidation by the generated ROS, and the inhibition of system xc-, and that the combination of a ferroptosis inducer with TS-PDT enhances the antitumor effect of TS-PDT. Our findings suggest that ferroptosis-inducing therapies combined with PDT may benefit cancer patients.

Oral leukoplakia (OLK) is the most representative oral potentially malignant disorder, with a high risk of malignant transformation and unclear mechanisms of occurrence. Recently, photodynamic therapy (PDT) has exhibited great potential in the treatment of OLK. However, the efficacy of PDT is difficult to predict and varies from person to person. Ferroptosis-related pathways are upregulated in many cancers, and ferroptosis induction is considered to be a potential synergistic strategy for various antitumor therapies, but its role in OLK treatment remains unclear. This study aimed to determine whether ferroptosis induction can enhance the efficacy of PDT in OLK treatment. Our study revealed that solute carrier family 7 member 11 (SLC7A11), a component of a crucial amino acid transporter and a key negative regulator of ferroptosis, was found to be highly expressed in OLK patients with no response to PDT. 5-Aminolevulinic acid (ALA)-PDT is known to cause apoptosis and necrosis, but ferroptosis also occurred under ALA-PDT in OLK cells in our study. Using erastin to induce ferroptosis enhanced the efficacy of ALA-PDT on OLK cells by disrupting the antioxidant system and further elevating intracellular reactive oxygen species levels, leading to increased apoptosis. Furthermore, this combined modality also enhanced the efficacy of ALA-PDT on 4-nitroquinoline-1-oxide (4NQO)–induced OLK lesions in mice. In summary, ferroptosis induction may serve as a potential strategy to enhance the efficacy of ALA-PDT for OLK treatment.

Ferroptosis: A novel cell death modality as a synergistic therapeutic strategy with photodynamic therapy.

Photodynamic therapy (PDT) induced lipid peroxidation reaction can lead to necrosis and apoptosis of extrahepatic cholangiocarcinoma (ECC) cells, reducing the tumor load. However, the depth of action of PDT is shallow, and its therapy efficacy is weak, making it difficult to achieve eradication even with multiple treatments. This study aims to investigate the mechanism and main pathways of ferroptosis in cholangiocarcinoma under Hematoporphyrin-mediated photodynamic therapy, and to compare the effects of different ferroptosis inducers on photodynamic therapy-induced ferroptosis in cholangiocarcinoma. To provide an experimental basis for selecting appropriate ferroptosis-inducing agents and synergizing with photodynamic therapy during the clinical perioperative period. The Cell Counting Kit-8 (CCK-8) was used to examine the cytotoxicity of cholangiocarcinoma cells following PDT. Flow cytometry was used to detect apoptotic cell percentage and cell cycle changes to assess the enhanced photodynamic production of reactive oxygen species (ROS) by different ferroptosis inducers, confocal imaging was used to de-assay ROS content. Western blot analysis was employed to detect the expression of GPX4 、FSP1、ASCL4 and SLC7A11. Furthermore, a fluorescence spectrophotometric assay was used to quantify the alterations in lipid peroxides (MDA, LPO, GSH, and Fe2+). The combination of PDT with Lenvatinib or Erastin resulted in increased ROS levels, and decreased GSH content, tumor cells were inhibited in the G2 phase, and the proportion of apoptotic cells increased. Additionally, GPX4, FSP1, and SLC7A11 protein expression decreased, whereas ASCL4 increased This was accompanied by heightened levels of Fe2+, LPO, and MDA. Induction of the ferroptosis pathway was observed to enhance the therapeutic efficacy of PDT. Our findings suggest that Erastin or Lenvatinib can enhance the induction of ferroptosis in cholangiocarcinoma cells by photodynamic therapy by increasing intracellular ROS and inhibiting intracellular antioxidant pathways.

Ferroptosis promotes 5-aminolevulinate acid-based photodynamic therapy in cervical cancer.

Rare-earth elements (REEs), which include the entire lanthanide series together with scandium and yttrium, have unique electronic configurations and coordination chemical properties that provide them with special magnetic, optical, and redox abilities. Generally used for diagnostic imaging and theranostic applications, increasing evidence emphasizes their potential as direct anticancer agents. This review aims to present a thorough investigation of the studies published in the last ten years that focus on the intrinsic anticancer properties of REE-based molecular complexes and nanostructures, without discussing their recognized imaging functions. Rare-earth compounds exhibit selective cytotoxicity against malignant cells via mechanisms that mainly include modulations in the generation of reactive oxygen species, mitochondrial dysfunctions, interaction with DNA molecules, apoptosis, and ferroptosis induction, as well as radiosensitization. Molecular complexes that are based on the trivalent coordination chemistry of REEs enable them to target biomolecules like DNA and serum albumin. Nanostructured systems, on the other hand, render tumors more responsive to treatment by improving the cellular uptake, enabling surface functionalization, and controlling ROS generation. Terbium, thulium, yttrium, scandium, ytterbium, cerium, erbium, dysprosium, and europium show different levels of anticancer activity in both in vitro and in vivo cancer models. They often exert more toxicity in tumor cells than in normal tissues, thus exhibiting selective anticancer effects. The findings collectively underscore the therapeutic potential of REE-based compounds as novel metal-based anticancer agents and advocate for additional mechanistic and translational research to enhance their clinical applicability.

Ferroptosis, a regulated form of non‐apoptotic cell death driven by iron‐dependent lipid peroxidation, has emerged as a promising approach for overcoming therapy‐resistant cancers. A multifunctional lipid nanoparticle (LNP) platform was developed to integrate ferroptosis induction with photodynamic therapy (PDT) for synergistic anticancer effects. By partially substituting cholesterol in conventional DLin‐MC3‐DMA (MC3)‐based LNPs with cholesterol—polyethylene glycol (PEG)–pheophorbide a (CPP), we engineered photosensitizing lipid nanoparticles (PLNPs) capable of delivering glutathione peroxidase 4 (GPX4)‐targeting small interfering RNA (siRNA). Upon laser irradiation, the PLNPs generate reactive oxygen species (ROS) through PDT, while siRNA‐mediated GPX4 silencing promotes ferroptosis by disrupting cellular antioxidant defenses. The PLNPs demonstrate favorable physicochemical characteristics, efficient gene silencing, and potent ROS production. In vitro experiments in 4T1 and EO771 breast cancer cells reveal enhanced cytotoxicity under combined treatment, underscoring the synergistic interaction between PDT‐induced oxidative stress and ferroptotic cell death. In vivo, the PLNPs exhibit prolonged tumor retention, effective GPX4 knockdown, and significant tumor growth inhibition, with minimal systemic toxicity. Overall, this work introduces a dual‐function nanoplatform that potentiates photodynamic cancer therapy through ferroptosis induction and offers a versatile strategy for developing next‐generation combination treatments targeting aggressive tumors.

Resistance to apoptosis-inducing chemotherapy is a major factor contributing to treatment failure and poor survival outcomes in high-grade serous ovarian cancer (HGSOC). Ferroptosis, a regulated form of cell death driven by lipid peroxidation, has emerged as a promising effector mechanism because it remains available in HGSOC cells with impaired apoptosis signaling. While most research has focused on pharmacological ferroptosis inducers, there is growing interest in strategies that could trigger lipid autoxidation through externally delivered energy, such as photons. Photodynamic therapy (PDT), which utilizes light and light-activatable photosensitizers to generate reactive molecular species, offers a means of initiating lipid peroxidation with a high degree of precision and minimal systemic toxicities. However, the precise lipid targets of PDT, the influence of varying tumor lipidomic landscapes, and the role of ferroptosis sensitivity on PDT-lipid interactions have yet to be elucidated. In this study, we systematically compare PDT to ferroptosis induced by the inhibition of glutathione peroxidase 4, focusing on lipid redox states and composition in HGSOC cell lines. While PDT was similarly effective in both ferroptosis-sensitive and -resistant cells, its effects on cellular lipidomes differed markedly. PDT robustly induced lipid radical formation in both cell types; however, a dose-dependent accumulation of lipid hydroxides and hydroperoxides was only observed in ferroptosis-sensitive cells rich in unsaturated phospholipids. Further analysis revealed a significant overlap in lipid oxidation targets between PDT and ferroptosis. Notably, in both cell types, and in vivo, PDT upregulated ceramides, a lipid class strongly associated with mitochondrial apoptosis. In summary, PDT exhibited comparable efficacy in both ferroptosis-sensitive and -resistant cells by triggering a combination of lipid peroxidation and ceramide upregulation, suggesting the activation of both ferroptosis and apoptosis pathways. Further studies are needed to explore the role of PDT-induced lipidomic changes in the initiation of various cell death pathways and in overcoming chemoresistance in HGSOC.

Singlet oxygen ((1)O2), as a reactive oxygen species, has garnered serious attention in physical, chemical, and biological studies. In this paper, we designed and synthesized a new type of singlet-oxygen generation system by exchanging cationic ruthenium complexes (RCs) into anionic bio-MOF-1. The resulting bio-MOF-1&RCs can be used as effective photocatalysts for generation of singlet oxygen under both single-photon and two-photon excitation. Especially, the excellent two-photon absorption (TPA) behavior of bio-MOF-1&RCs aroused our interest greatly because their two-photon absorption band lies in the optical window of biological tissue. Here, we measured the ability of bio-MOF-1&RCs to generate (1)O2 by irradiation under both 490 and 800 nm wavelength light in DMF. 1,3-Diphenylisobenzofuran (DPBF) and 2',7'-dichlorofluorescein (DCFH) were used as typical (1)O2 traps to detect and evaluate the efficiency of generation of (1)O2 under single-photon and two-photon excitation, respectively. Results indicated that bio-MOF-1&[Ru(phen)3](2+) was able to effectively generate (1)O2 under both conditions. Our work creates a novel synergistic TPA system with the excellent photophysical properties of RCs and the unique microporous structure benefit of MOFs, which may open a new avenue for creation of a cancer treatment system with both photodynamic therapy and chemotherapy.

Historical perspective, Thomas J. Dougherty, et al. Part 1 Molecular and cellular effects of photodynamic therapy: fluorescence and photodynamic effects of phthalocyanines and porphyrins in cells, Johan Moan, et al photodynamic therapy - membrane and enzyme photobiology, Tom M.A.R. Dubbleman, et al cellular targets of photodynamic therapy as a guide to mechanisms, Russell Hilf cellular stress responses following photodynamic therapy, Stefan W. Ryter, et al basic photobiology and mechanisms of action of phthalocyanines, Ehud Ben-Hur cationic sensitizers, combination therapies, and new methodologies, Allan R. Oseroff bacterial and viral photodynamic inactivation, Zvi Malik, et al. Part 2 Tissue effects of photodynamic therapy: determinants for photodynamic tissue destruction, David A. Bellnier and Barbara W. Henderson photosensitizing dyes related to hematoporphyrin derivative - structure-activity relationships, David Kessel, et al phthalocyanines and related compounds - structure activity relationships, Benoit Paquette and Johan E. van Lier reduced porphyrins as photosensitizers - synthesis and biological effects, Alan R. Morgan low density lipoproteins-liposome delivery systems for tumour photosensitizers in vivo, Giulio Jori photosensitizer delivery mediated by macro-molecular carrier systems, Tayyaba Hasan normal tissue damage following photodynamic therapy - are there biological advantages?, Hugh Barr and Stephen G. Bown. Part 3 Clinical applications of photodynamic therapy: clinical photodynamic therapy - the continuing evolution, Stuart L. Marcus photodynamic therapy in treatment of early cancer, Yoshihiro Hayata and Harubumi Kato palliation for endobronchial tumours in lung cancer, Anne-Marie Regal innovative photodynamic therapy at the National Cancer Institute - intraoperative, intracavitary treatment, Harvey I. Pass and Thomas F. DeLaney clinical application of photodynamic therapy - German collaborative studies, Kieter Jocham, et al photodynamic therapy - an eight-year experience, James S. McCaughan, et al. Part 4 Photophysics and photodynamic therapy technology: light delivery and optical dosimetry in photodynamic therapy of solid tumours, Willem M. Star, et al the implications of photobleaching for photodynamic therapy, Lars O. Svaasand and William R. Potter laser spectroscopy in medical diagnostics, Stefan Andersson-Engels, et al.

Photodynamic therapy and ferroptosis induction have risen as vanguard oncological interventions, distinguished by their precision and ability to target vulnerabilities in cancer cells. Photodynamic therapy's non-invasive profile and selective cytotoxicity complement ferroptosis' unique mode of action, which exploits iron-dependent lipid peroxidation, offering a pathway to overcome chemoresistance with lower systemic impact. The synergism between photodynamic therapy and ferroptosis is underscored by the depletion of glutathione and glutathione peroxidase four inhibitions by photodynamic therapy-induced reactive oxygen species, amplifying lipid peroxidation and enhancing ferroptotic cell death. This synergy presents an opportunity to refine cancer treatment by modulating redox homeostasis. Porphyrin-based nanoscale metal-organic frameworks have unique hybrid structures and exceptional properties. These frameworks can serve as a platform for integrating photodynamic therapy and ferroptosis through carefully designed structures and functions. These nanostructures can be engineered to deliver multiple therapeutic modalities simultaneously, marking a pivotal advance in multimodal cancer therapy. This review synthesizes recent progress in porphyrin-modified nanoscale metal-organic frameworks for combined photodynamic therapy and ferroptosis, delineating the mechanisms that underlie their synergistic effects in a multimodal context. It underscores the potential of porphyrin-based nanoscale metal-organic frameworks as advanced nanocarriers in oncology, propelling the field toward more efficacious and tailored cancer treatments.

Extensive research into platinum-based chemotherapeutics has been underway for decades with ruthenium-based complexes emerging as interesting and potent candidates. Even still, there is no evidence of a single mechanism of action across all synthesized and tested Ru-based complexes, prompting the continuance of research in this field. In addition, the mechanism of action varies according to cell line and/or animal model and is seemingly highly individualized and personalized. In accordance with this, the ruthenium complexes are able to activate specific molecular pathways and interact with certain targets within the cell, sometimes reported simultaneously. In this review, we attempt to give a new perspective on ruthenium complexes’ anti-cancer properties and organize selected results from the past 15 years of research connecting their structure with the reported mechanism of action. These results corroborate the previously reported great potential that ruthenium complexes have on cancer in vitro. In addition, the review provides insight into Ru drugs in their clinical trials and their efficacy against cancer including a historical context on metallodrugs, particularly platinum-based complexes, and their antitumor capability.

Background: Aggregation-induced emission (AIE)-based photodynamic therapy (PDT) represents a promising strategy for cancer treatment for its capacity to activate specific cell death pathways through pronounced oxidative stress. While the activation of specific death pathways has been correlated with PDT efficiency and overall effect, the systematic coordination of oxidative stress across different cell death modalities to amplify therapeutic effects remains unexplored. Current research lacks systematic investigation into how oxidative stress coordinates multiple cell death pathways to amplify therapeutic outcomes of PDT.Methods: We developed an AIE-based nano-photosensitizer (T-T NPs) to induce multimodal cell death through PDT. The system was characterized for mitochondrial targeting capability and reactive oxygen species (ROS) generation. Mechanistic analyses were conducted to evaluate programmed cell death pathways and ferroptosis induction in tumor.Results: T-T NPs exhibited superior mitochondrial targeting and highly efficient ROS generation. This dual effect successfully triggered PANoptosis and ferroptosis. The synergistic activation of these pathways significantly enhanced PDT-mediated antitumor efficacy.Conclusion: Our findings reveal that AIE-driven PDT can orchestrate multimodal cell death in tumor through oxidative stress modulation. By concurrently activating PANoptosis and ferroptosis, this approach establishes a novel paradigm for overcoming limitations of conventional single-pathway targeted PDT.

Scaffold-leaping optimization of naphthoquinone derivatives as ferroptosis inducer against non-small lung cancer.