The stability of these metal-complex combinations is primarily influenced by the type of chelator, the metal involved, and the coordination geometry. Metals such as Platinum Pt (II), Gadolinium Gd (II) , Palladium Pd (II) and Gold can undergo chelation, leading to various biomedical applications, particularly in oncology. Chelated metal complexes can act through multiple main mechanisms: DNA Interaction: Many metal complexes demonstrate a strong affinity for DNA, leading to the formation of covalent bonds with nucleobases. Platinum-based agents, like cisplatin, disrupt DNA replication and transcription, prompting apoptosis in cancer cells. Reactive Oxygen Species (ROS) Production: Certain chelated metals can induce oxidative stress by generating ROS, destroying cellular components such as damaged molecules of  lipids, proteins, and also damaged DNA. This mechanism is exploited in therapies to induce cell death, particularly in tumor cells. Targeted Drug Delivery: Chelated metal complexes can be engineered for targeted delivery. By attaching ligands or antibodies, these complexes can preferentially bind to cancer cell receptors, ensuring localized treatment and minimizing systemic toxicity. Some Platinum Pt 0II) derived metal complexes are fundamental for their anticancer action: Cisplatin (Cis Diammine-Dichloro-Platinum(II)) is an essential  Platinum-based chemotherapeutic agent which forms strong covalent bonds with DNA, causing cross-linking and ultimately inducing apoptosis. That chelated Platinum Pt (II) complex is widely used to treat various cancers, including testicular, ovarian, bladder, and lung cancers. Carboplatin  (1,1-Cyclobutanedicarboxylic acid), represents a second-generation platinum-based Pt (II) drug, which interacts with DNA but has a more favorable side effect profile and is less susceptible to drug resistance. It is  Often used in ovarian cancer treatment and in combination chemotherapy for lung cancer. Oxaliplatin, Platinum (Pt II) ethanedioate - 1,2-cyclohexanediamine (1:1:1), is another platinum-based agent is frequently used in combinatory therapies. Induces DNA damage through the formation of cross-links, particularly in cancer cells resistant to Cisplatin. It is primarily used in effective treatment of colorectal cancer. Ongoing research aims to refine these complexes to enhance selectivity, reduce side effects, and overcome resistance mechanisms. Furthermore, the development of multifunctional chelated metal complexes that combine therapeutic and imaging capabilities represents a significant advancement in personalized medicine. These innovations promise to improve treatment efficacy, provide real-time monitoring, and tailor therapies to individual patient profiles.

Gastrointestinal (GI) cancers—such as colorectal, gastric, and esophageal carcinomas—pose significant clinical challenges due to high mortality rates, drug resistance, and toxicity associated with conventional chemotherapies. In-response to these challenges, chelated metal complexes have gained increasing attention as promising chemotherapeutic agents owing to their unique multimodal mechanisms and potential for targeted, less toxic therapy. The clinical success of the platinum (Pt) anticancer drug cisplatin (4) is an excellent example of how to advance a serendipitous discovery to a pharmaceutical. At present, three Pt-based anticancer compounds, cisplatin (4) carboplatin (5), and oxaliplatin (6), have been approved and are used worldwide in clinical practice .However, despite their clinical successes as chemotherapeutics, Pt-based drugs have some limitations: they are not active against many common types of cancer, drug resistance is common, and they cause a deplorable range of side effects such as nerve damage, hair loss, and nausea. In search of alternative metal-based anticancer agents, Ruthenium Ru (III) compounds have turned out to be the most promising candidates.

Since Dwyer et al first developed a series of bioactive Ru polypyridyl complexes 1–3 in 1952  Ruthenium (Ru) has been a prominent subject in the search for therapeutic and diagnostic agents, and a number of bioactive Ru complexes have been reported. The major research field is the synthesis of new Ru(II) and Ru(III) complexes as potential anticancer agents and the investigation of their mechanism of action. Most of the Ruthenium Ru compounds tested for their cytotoxicity in different tumor cells have also been assessed in terms of their antimicrobial activity. Another area of growth is the study of the interactions between DNA and Ru complexes owing to the recent expansion of their roles such as chemical and stereoselective probes of nucleic acid structures, molecular light switching and bioimaging, and DNA bioanalysis agents. The structurally complex three-dimensional architectures of metal complexes are ideal templates for constructing DNA interaction systems. As a result, Ru complexes have received attention by virtue of their unique binding ability to DNA, together with their rich photophysical, photochemical, and electrochemical properties. [by: Sang Yeul Lee, Chul Young Kim & Tae-Gyu Nam, “Ruthenium Complexes as Anticancer Agents: A Brief History and Perspectives”, Drug Design, Development and Therapy Volume 14, 2020, pp. 5375-5392].

Main anticancer mechanism of Ruthenium (III) complexes. Ruthenium (III) complexes target cancer cells by triggering various mechanisms, such as disrupting mitochondria to cause energy depletion and oxidative stress, interfering with DNA replication and transcription, and promoting cell death through apoptosis. They can selectively accumulate in cancer cells, often by mimicking iron and binding to transferrin receptors, which increases their concentration inside tumor cells and reduces toxicity to healthy cells. Some complexes also exhibit anti-angiogenic properties and can inhibit tumor growth and metastasis. Positively charged ruthenium complexes can accumulate in the negatively charged mitochondria of cancer cells, disrupting the mitochondrial membrane potential and impairing energy production through oxidative phosphorylation. This can lead to increased reactive oxygen species (ROS) production and cell death. Some complexes are designed to penetrate the cell nucleus and bind to DNA, distorting its structure or interfering with its replication and transcription. Some can even induce photo-crosslinking in DNA, leading to cell apoptosis. By inducing DNA damage, mitochondrial dysfunction, or other cellular stresses, ruthenium complexes can activate programmed cell death pathways. Certain complexes can interfere with cancer cell metabolism, for example, by blocking the Warburg effect (increased glycolysis) and reducing the production of immunosuppressive lactate, a key feature of many cancers .

Transition metal complexes—particularly those containing Platinum (Pt), Ruthenium (Ru), Copper (Cu), and Gallium (Ga)—have demonstrated potent anticancer properties. For example, Ruthenium (III)  complexes, like NAMI-A (Imidazolium-trans-tetrachloro(dimethylsulfoxide)imidazoleruthenium(III); a new redox-effective anticancer candidate KP1019 [Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)]  have shown selective anti-metastatic activity in preclinical models of colorectal and gastric cancers, working by disrupting mitochondrial function, inducing apoptosis, and modulating the tumor microenvironment. These complexes exhibit much lower toxicity than traditional Platinum agents such as Cisplatin, which, despite their efficacy, are limited by severe side effects like nephrotoxicity and neurotoxicity. [by : Peng Liu, Shangbo Zhou, Zhijun Zhou , Zihan Jin , Wei Chen , Zihang Li , Jiaqi Xu , Feng Chen, You Li, Yingfei Wen, Shiqiang Zhang, Changhua Zhang , Binbin Li , Jing Zhao , Hengxing Chen, “Discovery and antitumor evaluation of a mitochondria-targeting ruthenium complex for effective cancer therapy”, Cancer Letters, Volume 616, 28 April 2025, 217582; by: Ke Lin, Zi-Zhuo Zhao, Hua-Ben Bo, Xiao-Juan Hao,^, Jin-Quan Wang, “Applications of Ruthenium Complex in Tumor Diagnosis and Therapy”, Front. Pharmacol., Section. Cancer Molecular Targets and Therapeutics, Volume 9,  19 November 2018; by: Sang Yeul Lee, Chul Young Kim & Tae-Gyu Nam, “Ruthenium Complexes as Anticancer Agents: A Brief History and Perspectives”, Drug Design, Development and Therapy Volume 14, 2020, pp. 5375-5392].

A number of Ruthenium (III) Ru-based anticancer agents have been developed to date, yet none of them are in clinical use as effective anticancer drugs. Successful entries to clinical trials of NAMI-A (7), KP1019 (8), NKP1339* (9) and TLD1443* (10) together with many reports on the promising in vitro and in vivo activities of other types of Ru complexes have caused Ru-based chemotherapeutics to be seen as a major area in anticancer drug research (Figure 3)). Despite their structural similarity, NAMI-A and KP1019 have shown quite different in vitro and in vivo activities. NAMI-A showed antiangiogenic and anti-metastatic activities in secondary tumors whereas KP1019 is active in a broad spectrum of primary tumors. NKP1339, a sodium salt version of KP1019, was initially developed as a precursor in the formulation of KP1019 but reevaluated as a clinical candidate owing to its higher aqueous solubility, which allows for the clinical application of large doses to patients.TLD1433 (10) entered Phase I and phase 2a clinical trials for bladder cancer treatment with Photodynamic Therapy (PDT ). 

NKP1339* is also known as \ sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)], a ruthenium-based anticancer drug currently under clinical investigation. It is also sometimes referred to by other names, including IT-139 and BOLD-100 (which is a Cesium salt version of NKP-1339)

(TLD-1433* is the code name for the drug Ruvidar™ (or Rutherrin), a Ruthenium (III)-based photodynamic compound used in cancer therapy, specifically for Non-Muscle Invasive Bladder Cancer (NMIBC)., as indicated by its chemical formula: C₄₉H₃₈Cl₂N₈RuS₃ [by: Maryam Taghizadeh Shool,  Hadi Amiri Rudbari,  Tania Gil-Antón Gil-Antón, José V. Cuevas Vicario, Begona Garcia, Natalia Busto, Nakisa Moini, Olivier Blacque, “The effect of halogenation of salicylaldehyde on antiproliferative activities of {∆/Λ-[Ru(bpy)2(X,Y-sal)]BF4} complexes”, Dalton Transactions 51 (1), April 2022; by: Enzo Alessio , Luigi Messori , “NAMI-A and KP1019/1339, Two Iconic Ruthenium Anticancer Drug Candidates Face-to-Face: A Case Story in Medicinal Inorganic Chemistry “, Molecules, 2019 May 24;24(10):1995. doi: 10.3390/molecules2410199]

Comparative Mechanism of Action and Effectiveness of  the New Anticancer Ruthenium Ru (III ) complexes . The ruthenium-based anticancer agent NAMI-A (ImH[trans-RuCl₄(dmso)(Im)], where Im = imidazole) has been shown to interact with RNA in vivo and in vitro. Similarly, structured drug KP1019 (IndH[trans-RuCl₄(Ind)₂], where Ind = indazole) binds to RNA as well. Fluorescence spectroscopy was employed to assay the interactions between either NAMI-A or KP1019 and tRNA^Phe through an intrinsic fluorophore wybutosine (Y) base and by extrinsic displacement of the intercalating agent ethidium bromide. In both the intrinsic Y-base and extrinsic ethidium bromide studies, KP1019 exhibited tighter binding to phenylalanine-specific tRNA (tRNA^Phe) than NAMI-A. In the ethidium bromide study, reducing both drugs from Ru^III to Ru^II resulted in a significant decrease in binding. It is suggested that  suggest that the relatively large heteroaromatic indazole ligands of KP1019 intercalate in the π-stacks of tRNA^Phe within structurally complex binding pockets. In addition, NAMI-A appears to be sensitive to destabilizing electrostatic interactions with the negative phosphate backbone of t-RNA^Phe. Interactions with additional tRNA molecules and other types of RNA require further evaluation to determine the role of RNA in the mechanisms of action for KP1019 and to better understand how Ru drugs fundamentally interact with biomolecules that are more structurally sophisticated than short DNA oligonucleotides. To the best of our knowledge, this is the first study to report KP1019 binding interactions with RNA.  [ by: Dwyer BG., Johnson E., Cazares E., McFarlane Holman KL., Kirk SR. ”Ruthenium anticancer agent KP1019 binds more tightly than NAMI-A to tRNA^Phe”, Journal of Inorganic Biochemistry, 24 Feb 2018, 182: 177-183; by: Enzo Alessio , Luigi Messori , “NAMI-A and KP1019/1339, Two Iconic Ruthenium Anticancer Drug Candidates Face-to-Face: A Case Story in Medicinal Inorganic Chemistry “, Molecules, 2019 May 24;24(10):1995. doi: 10.3390/molecules2410199].

Anticancer mechanism of action assigned to  NKP-1339 (sodium trans-[tetrachlorobis(1H-indazole) ruthenate (III)] from Figure 3. It is also known by synonyms such as IT-139, KP1339, and its more recent trade name, BOLD-100).. NKP-1339  is one of the most promising investigational non-platinum metal drugs in clinical development against solid malignancies. NKP-1339 is a redox Ruthenium-based effective anticancer drug that functions through a unique "activation-by-reduction" mechanism inside the tumor. It is activated by being reduced from Ruthenium(III) to Ruthenium(II) in the hypoxic environment of a tumor, disrupting the cell's redox balance and inducing apoptosis via the mitochondrial pathway. The drug also benefits from tumor-targeting via serum proteins like Albumin and Transferrin, which exploit the Enhanced Permeability and Retention (EPR) effect.  Recently, NKP-1339 was evaluated in a clinical phase A trial regarding its safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics. The high tumor targeting potential of NKP-1339 is probably based on delivery to tumor sites by serum proteins such as albumin and transferrin as well as on the activation of the compound in the reductive tumor milieu. The reduction of Ruthenium (III) to Ruthenium (II) is favored under hypoxic condition (frequently occurring in solid tumors) and is followed by severe disruption of the cellular redox balance and induction of apoptosis via the mitochondrial pathway. [by: Robert Trondl , Petra Heffeter, Michael A Jakupec, Walter Berger, Bernhard K Keppler, “NKP-1339, a first-in-class anticancer drug showing mild side effects and activity in patients suffering from advanced refractory cancer,”, BMC Pharmacol Toxicol 2012 Sep 17;13 (Suppl 1): A 82. doi: 10.1186/2050-6511-13-S1-A82]

Mechanism of Copper (II) complexes targeting cancer cells. Similarly, Copper (II) -based complexes like Casiopeínas specific compounds within the family named, such as Cu[(4,7-dimethyl-1,10-phenanthroline)(glycinato)] nitrate (Cas-II-Gly) or Cu[(4,4′-dimethyl-2,2′-bipyridine)(acetylacetonate)(H₂O)] nitrate (Cas-III-ia). The general formula for the family is [Cu(N-N)(N-O)] where the specific ligands (N-N, N-O, or O-O) determine exactly their  names,  have exhibited promising antiproliferative effects by generating reactive oxygen species (ROS) that cause DNA damage in Gastrointestinal (GI) tumor cells. Notably, research demonstrated that Cu (II) complexes with organic ligands could substantially inhibit growth of gastric cancer cell lines by inducing Oxidative Stress, leading to apoptosis without harming normal cells. inducing apoptosis through mechanisms like activating caspases and increasing (Reactive Oxygen Species) ROS production, and by disrupting cell cycle progression and cell migration. These Copper (II) -based compounds can also damage DNA and cause mitochondrial dysfunction, leading to cell death. Some research suggests Casiopeínas may also possess liver-protective functions while still being cytotoxic to cancer cells, making them a promising therapeutic candidate.

Advances in ligand design, such as incorporating tumor-targeting moieties (e.g., folate or * RGD peptides), have improved the selectivity and bioavailability of these complexes. For instance, a Platinum (II) complex conjugated with a folate ligand efficiently targeted folate receptor-overexpressing gastric cancer cells, resulting in enhanced cytotoxicity and reduced off-target effects in vitro and in vivo.

Furthermore, nanotechnology-based delivery systems—such as liposomal encapsulation and nanoparticle conjugation—have been employed to enhance the tumor-selective accumulation of metal complexes. Liposomes and lipid nanoparticles are common lipid-based drug delivery systems and play important roles in cancer treatment and vaccine manufacture. Although significant progress has been made with these lipid-based nanocarriers in recent years, efficient clinical translation of active targeted liposomal nanocarriers remains extremely challenging In the past ten  years, Targeted liposomes, stimuli-responsive strategy and combined therapy in cancer treatment were developed and highlighted. Advances of liposome and lipid nanoparticle as nanocarriers and innovative applications in nucleic acid delivery and tumor vaccination were discovered and developed [by: Zhe Cheng, Huichao Huang, Meilong Yin, Huaizheng Liu“Applications of liposomes and lipid nanoparticles in cancer therapy: current advances and prospects”, Exp Hematol Oncol. 2025 Jan 31; 14:11].

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Gastric cancer (GC) results from deregulated cell growth in the stomach. Despite significant efforts and recent advancements in the treatment of gastric cancer, it remains a life-threatening disease. This is in part due to the chemotherapy failure resulting from multi-drug resistance (MDR) in the associated Gastric cancer cells (GCC). These cells can acquire MDR through different mechanisms. Perhaps the most important mechanism would be the increased drug efflux by ATP-binding cassette (ABC) transporters, which reduces the intracellular concentration of the chemotherapy drugs. Recently, nanoparticle-based drug delivery systems (nano-DDS) have been emerged to reverse multi-drug resistance (MDR) by altering the mechanisms through which the drugs may function. Nano-DDSs are also highly regarded because of their potential to considerably enhance the pharmacological profile of chemotherapy drugs, improving drug solubility, and decrease their adverse effects.( Kazem Nejati , Mojgan Rastegar , Farzaneh Fathi, Mehdi Dadashpour, AmirAhmad Arabzadeh ,” Nanoparticle-based drug delivery systems to overcome gastric cancer drug resistance”, Journal of Drug Delivery Science and Technology, Volume 70, April 2022, 103231).  Nanoparticle drug delivery systems have proved anti-tumor effects; however, they are not widely used in tumor therapy due to insufficient ability to target specific sites, multidrug resistance to anti-tumor drugs, and the high toxicity of the drugs. With the development of RNAi technology, nucleic acids have been delivered to target sites to replace or correct defective genes or knock down specific genes. Also, synergistic therapeutic effects can be achieved for combined drug delivery, which is more effective for overcoming multidrug resistance of cancer cells. These combination therapies achieve better therapeutic effects than delivering nucleic acids or chemotherapeutic drugs alone, so the scope of combined drug delivery has also been expanded to three aspects: drug-drug, drug-gene, and gene-gene [by: “Daoyuan Chen, Xuecun Liu, Xiaoyan Lu, Jingwei Tian,  Nanoparticle drug delivery systems for synergistic delivery of tumor therapy” Front. Pharmacol., 16 February 2023 Sec. Pharmacology of Anti-Cancer Drugs Volume 14 – 2023, pp 1-21].

. A platinum-based nano-formulation demonstrated increased tumor uptake and reduced systemic toxicity in colorectal cancer models, paving the way for clinical translation This  platinum-based nano-formulation shows promise for colorectal cancer by increasing drug concentration in tumors while lowering side effects in the body. This is achieved through nanotechnology, which allows for more targeted delivery of the drug, making it a potential candidate for future clinical use.  [ by: Buhle Buyana, Tobeka Naki , Sibusiso Alven, Blessing Atim Aderibigbe “Nanoparticles Loaded with Platinum Drugs for Colorectal Cancer Therapy”; Int J Mol Sci. 2022 Sep 24;23(19):11261]. By improving tumor targeting, the nanoparticle formulation is designed to deeply accumulate in the tumor, increasing the concentration of the Platinum-based drug specifically at the site of the cancer. By confining the drug to the tumor, the formulation minimizes its exposure to healthy, non-cancerous cells, which helps reduce the severe side effects often associated with traditional platinum-based chemotherapy, such as nausea and anemia. Preclinical studies suggest that the formulation has strong anti-tumor activity, which may be due to a combination of improved drug delivery and the way the nanoparticles interact with cancer cells. The improved efficacy and safety profile in preclinical models indicate that this nanotechnology-based approach could be a viable and effective treatment option for patients with colorectal cancer in the future. [ by: Buhle Buyana, Tobeka Naki , Sibusiso Alven, Blessing Atim Aderibigbe “Nanoparticles Loaded with Platinum Drugs for Colorectal Cancer Therapy”; Int J Mol Sci. 2022 Sep 24;23(19):11261; by: Liping Chen,  Qingqing Li^, , “Nanomaterials in the diagnosis and treatment of gastrointestinal tumors: New clinical choices and treatment strategies”, Materials Today Bio, Volume 32, June 2025, 101782].

Many of these complexes effectively induce apoptosis through Reactive Oxygen Species (ROS) production, DNA cross-linking, or inhibition of enzymes-like thioredoxin reductase. For example, Ruthenium complexes can selectively target dehydrogenases within tumor cells, disrupting cellular metabolism. Despite very promising preclinical results, few chelated metal complexes have advanced to clinical testing of Gastrointestinal (GI) cancers. Challenges such as resistance mechanisms, stability in biological fluids, and detailed toxicity profiles remain. Nevertheless, ongoing research combining ligand innovation, targeted delivery, and combination therapies promises to overcome these barriers. In conclusion, chelated metal complexes represent a versatile, effective and very potent class of anticancer agents, with demonstrated potential against Gastrointestinal (GI) malignancies. Their ability to be tailored for selectivity and reduced toxicity underscores their promise as next-generation therapeutics. Continued research focused on optimizing their biological activity and delivery systems will be crucial for successful clinical translation, potentially transforming the therapeutic landscape for GI cancer patients.

*RGD peptides = are a sequence of three amino acids (Arginine, Glycine and Aspartic acid, that play a crucial role in cell adhesion by binding to receptors called integrins on the cell surface. Found in natural proteins like fibronectin and vitronectin, synthetic RGD peptides are used in medicine and biotechnology for applications such as substantially improving tissue regeneration, delivering drugs to specific targets like cancer cells, and creating diagnostic imaging agents.