Supramolecular metal-based nanoparticles for drug delivery and cancer therapy

Although conventional cancer therapies such as chemotherapy and radiotherapy prevail in clinic, they tend to have narrow therapeutic windows. Many chemotherapies have unfavorable pharmacokinetics while radiotherapy incurs radiotoxicity to normal tissues surrounding tumors. The chemical tunability of supramolecular metal-based nanoparticles (SMNPs) enables the incorporation of various therapeutics, including hydrophilic and hydrophobic chemotherapeutic drugs, photosensitizers, radiosensitizers, and biological therapeutics for more effective delivery to tumors. In this mini-review, we highlight recent advances in SMNPs, namely nanoscale coordination polymers and nanoscale metal–organic frameworks, for drug delivery and cancer therapy. We particularly focus on innovative uses of metal clusters, ligands, pores, and surface modifications to load various therapeutics into SMNPs and critical evaluations of the anticancer efficacies of SMNPs.     

New metal complexes as potential therapeutics

The many activities of metal ions in biology have stimulated the development of metal-based therapeutics. Cisplatin, as one of the leading metal-based drugs, is widely used in treatment of cancer, being especially effective against genitourinary tumors such as testicular. Significant side effects and drug resistance, however, have limited its clinical applications. Biological carriers conjugated to cisplatin analogs have improved specificity for tumor tissue, thereby reducing side effects and drug resistance. Platinum complexes with distinctively different DNA binding modes from that of cisplatin also exhibit promising pharmacological properties. Ruthenium and gold complexes with antitumor activity have also evolved. Other metal-based chemotherapeutic compounds have been investigated for potential medicinal applications, including superoxide dismutase mimics and metal-based NO donors/scavengers. These compounds have the potential to modulate the biological properties of superoxide anion and nitric oxide.     

Metal Complexes in Cancer Treatment: Journey So Far

Metal complexes in cancer therapy have attracted much interest mainly because metals exhibit unique characteristics, such as redox activity, metal-ligand interaction, structure and bonding, Lewis acid properties etc. In 1965, Barnett Rosenberg serendipitously discovered the metal-based compound cisplatin, an outstanding breakthrough in the history of metal-based anticancer complexes and led to a new area of anticancer drug discovery. Many metal-based compounds have been studied for their potential anticancer properties. Some of these compounds have FDA approval for clinical use, while others are now undergoing clinical trials for cancer therapy and detection. In the present study, we have highlighted the primary mode of action of metallic complexes and all FDA-approved/under clinical trial drugs with reference to cancer treatment. This review also focuses on recent progress on metal-based complexes such as platinum, ruthenium, iron, etc. with potential anticancer activities.     

Fluorescent metal-based complexes as cancer probes

The ability to track drugs inside of cells and tumours has been highly valuable in cancer research and diagnosis. Metal complexes add attractive features to fluorescent drugs, such as targeting and specificity, solubility and uptake or photophysical properties. This review focuses on the latest fluorescent metal-based complexes, their cellular targets, photophysical properties and possible anticancer effects.     

Challenges and opportunities in the development of metal-based anticancer theranostic agents

Around 10 million fatalities were recorded worldwide in 2020 due to cancer and statistical projections estimate the number to increase by 60% in 2040. With such a substantial rise in the global cancer burden, the disease will continue to impose a huge socio-economic burden on society. Currently, the most widely used clinical treatment modality is cytotoxic chemotherapy using platinum drugs which is used to treat variety of cancers. Despite its clinical success, critical challenges like resistance, off-target side effects and cancer variability often reduce its overall therapeutic efficiency. These challenges require faster diagnosis, simultaneous therapy and a more personalized approach toward cancer management. To this end, small-molecule ‘theranostic’ agents have presented a viable solution combining diagnosis and therapy into a single platform. In this review, we present a summary of recent efforts in the design and optimization of metal-based small-molecule ‘theranostic’ anticancer agents. Importantly, we highlight the advantages of a theranostic candidate over the purely therapeutic or diagnostic agent in terms of evaluation of its biological properties.     

Approaching tumour therapy beyond platinum drugs: status of the art and perspectives of ruthenium drug candidates

The study of metal complexes for the treatment of cancer diseases has resulted in the identification of some unique properties of ruthenium-based compounds. Among these inorganic-based agents, two of them, namely the ruthenium(III) drugs NAMI-A and KP1019 have undertaken with some success the clinical evaluations of phase I and preliminary phase II trials in patients. Here we highlight the strategies that have led to the discovery of metal-based (NAMI-A and KP1019) and of organometallic (RM175, RAPTA-T, RDC11 and DW1/2) ruthenium-based complexes, and we report their main biological/pharmacological characteristics and expectations for further development.     

Coordination conjugates of therapeutic proteins with drug carriers: a new approach for versatile advanced drug delivery

We present here a general system for the coordination attachment of therapeutic proteins to a drug delivery system and its application in combined therapy. Proof of concept is demonstrated by the synthesis and testing of the targeted drug delivery system for cytostatics, which is based on a combination of the drug carrier Zn-porphyrin-cyclodextrin conjugates and their supramolecular coordination complexes with immunoglobulins. This system can be as readily used for a variety of therapeutic and targeting proteins including PAs, MAs, lectins, and HSA. Moreover, it allows combined photodynamic therapy, cell targeted chemotherapy and immunotherapy. When tested in a mouse model with human C32 carcinoma, the therapeutic superiority of the coordination assembly nanosystem was shown in comparison with the efficacy of building blocks used for the construction of the system.     

Mitochondria as a target of third row transition metal-based anticancer complexes

In pursuit of better treatment options for malignant tumors, metal-based complexes continue to show promise as attractive chemotherapeutics due to tunability, novel mechanisms, and potency exemplified by platinum agents. The metabolic character of tumors renders the mitochondria and other metabolism pathways fruitful targets for medicinal inorganic chemistry. Cumulative understanding of the role of mitochondria in tumorigenesis has ignited research in mitochondrial targeting metal-based complexes to overcome resistance and inhibit tumor growth with high potency and selectivity. Here, we discuss recent progress made in third row transition metal-based mitochondrial targeting agents with the goal of stimulating an active field of research toward new clinical anticancer agents and the elucidation of novel mechanisms of action.     

Supramolecular platinum complexes for cancer therapy

The rise of supramolecular chemistry offers new tools to design therapeutics and delivery platforms for biomedical applications. This review aims to highlight the recent developments that harness host-guest interactions and self-assembly to design novel supramolecular Pt complexes as anticancer agents and drug delivery systems. These complexes range from small host-guest structures to large metallosupramolecules and nanoparticles. These supramolecular complexes integrate the biological properties of Pt compounds and novel supramolecular structures, which inspires new designs of anticancer approaches that overcome problems in conventional Pt drugs. Based on the differences in Pt cores and supramolecular structures, this review focuses on five different types of supramolecular Pt complexes, and they include host-guest complexes of the FDA-approved Pt(II) drugs, supramolecular complexes of nonclassical Pt(II) metallodrugs, supramolecular complexes of fatty acid-like Pt(IV) prodrugs, self-assembled nanotherapeutics of Pt(IV) prodrugs, and self-assembled Pt-based metallosupramolecules.     

New trends for metal complexes with anticancer activity

Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs. This has, for instance, led to the clinical application of chemotherapeutic agents for cancer treatment, such as cisplatin. The use of cisplatin is, however, severely limited by its toxic side-effects. This has spurred chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. Recent trends in the field are discussed in this review. These include the more selective delivery and/or activation of cisplatin-related prodrugs and the discovery of new non-covalent interactions with the classical target, DNA. The use of the metal as scaffold rather than reactive centre and the departure from the cisplatin paradigm of activity towards a more targeted, cancer cell-specific approach, a major trend, are discussed as well. All this, together with the observation that some of the new drugs are organometallic complexes, illustrates that exciting times lie ahead for those interested in 'metals in medicine'.     

Methods to identify protein targets of metal-based drugs

Metal-based anticancer agents occupy a distinct chemical space due to their particular coordination geometry and reactivity. Despite the initial DNA-targeting paradigm for this class of compounds, it is now clear that they can also be tuned to target proteins in cells, depending on the metal and ligand scaffold. Since metallodrug discovery is dominated by phenotypic screenings, tailored proteomics strategies were crucial to identify and validate protein targets of several investigative and clinically advanced metal-based drugs. Here, such experimental approaches are discussed, which showed that metallodrugs based on ruthenium, gold, rhenium and even platinum, can selectively and specifically target proteins with clear-cut down-stream effects. Target identification strategies are expected to support significantly the mechanism-driven clinical translation of metal-based drugs.     

Electron-transfer activated metal-based anticancer drugs

Platinum(II)-based anticancer drugs play an essential role in the clinic today, and a number of coordination compounds with other metals are in current development as promising antitumor drugs. Probably the most prominent non-platinum metal-based drugs are those of ruthenium. Various strategies have been applied for the design of novel drugs with an improved toxicological profile, and one of them involves the preparation of metal complexes in inert high oxidation states [e.g. Pt(IV), Ru(III)]. Three platinum(IV) and two ruthenium(III) drugs have already reached clinical trials. Ideally, hypoxia-selective drugs are delivered to the target environment without prior reduction or major transformation via substitution reactions at the metal center. A (selective) reduction has been proposed to activate the prodrugs by formation of active species, which react with the target more readily and lead ultimately to apoptosis. Investigations on the electrochemical behavior of platinum(IV) and ruthenium(III) cytotoxins and the establishment of preliminary structure-property relationships are therefore of current importance. Herein, we present recent results in the field of metal-centered electron-transfer activated Ru(III), Pt(IV) and Co(III) drugs with regard to design and targeting strategies, prediction of redox potentials in aqueous medium, labilization and enhanced reactivity with potential biological targets upon reduction, and correlations between electrochemical parameters and anticancer activity.     

Polyether ionophores—promising bioactive molecules for cancer therapy

The natural polyether ionophore antibiotics might be important chemotherapeutic agents for the treatment of cancer. In this article, the pharmacology and anticancer activity of the polyether ionophores undergoing pre-clinical evaluation are reviewed. Most of polyether ionophores have shown potent activity against the proliferation of various cancer cells, including those that display multidrug resistance (MDR) and cancer stem cells (CSC). The mechanism underlying the anticancer activity of ionophore agents can be related to their ability to form complexes with metal cations and transport them across cellular and subcellular membranes. Increasing evidence shows that the anticancer activity of polyether ionophores may be a consequence of the induction of apoptosis leading to apoptotic cell death, arresting cell cycle progression, induction of the cell oxidative stress, loss of mitochondrial membrane potential, reversion of MDR, synergistic anticancer effect with other anticancer drugs, etc. Continued investigation of the mechanisms of action and development of new polyether ionophores and their derivatives may provide more effective therapeutic drugs for cancer treatments.     

Unique platinum-DNA interactions may lead to more effective platinum-based antitumor drugs

Platinum coordination compounds are among the most utilized anticancer agents, even though platinum has not been determined to be an essential trace element in any living organism. The success of platinum-based drugs has catalyzed research on other metal-containing agents that can be used to achieve therapeutic goals that cannot be achieved with organic compounds. The antitumor activities of recently reported platinum(ii) complexes indicate that further modification of platinum coordination compounds will lead to the development of anticancer agents with higher efficacies against chemotherapy-insensitive tumors.     

Dual role of autophagy for advancements from conventional to new delivery systems in cancer

Autophagy, a programmed cell-lysis mechanism, holds significant promise in the prevention and treatment of a wide range of conditions, including cancer, Alzheimer's, and Parkinson's disease. The successful utilization of autophagy modulation for therapeutic purposes hinges upon accurately determining the role of autophagy in disease progression, whether it acts as a cytotoxic or cytoprotective factor. This critical knowledge empowers scientists to effectively manipulate tumor sensitivity to anti-cancer therapies through autophagy modulation, while also circumventing drug resistance. However, conventional therapies face limitations such as low bioavailability, poor solubility, and a lack of controlled release mechanisms, hindering their clinical applicability. In this regard, innovative nanoplatforms including organic and inorganic systems have emerged as promising solutions to offer stimuli-responsive, theranostic-controlled drug delivery systems with active targeting and improved solubility. The review article explores a variety of organic nanoplatforms, such as lipid-based, polymer-based, and DNA-based systems, which incorporate autophagy-inhibiting drugs like hydroxychloroquine. By inhibiting the glycolytic pathway and depriving cells of essential nutrients, these platforms exhibit tumor-suppressive effects in advanced forms of cancer such as leukemia, colon cancer, and glioblastoma. Furthermore, metal-based, metal-oxide-based, silica-based, and quantum dot-based nanoplatforms selectively induce autophagy in tumors, leading to extensive cancer cell destruction. Additionally, this article discusses the current clinical status of autophagy-modulating drugs for cancer therapy with valuable insights of progress and potential of such approaches.     

Quantitative measurement of the reduction of platinum(IV) complexes using X-ray absorption near-edge spectroscopy (XANES)

The platinum(II) drugs cisplatin, carboplatin and oxaliplatin are usefully employed against a range of malignancies, but toxicities and resistance have spurred the search for improved analogs. This has included investigation of the platinum(IV) oxidation state, which provides greater kinetic inertness. It is generally accepted that Pt(IV) complexes must be reduced to Pt(II) for activation. As such, the ability to monitor reduction of Pt(IV) complexes is critical to guiding the design of candidates, and providing mechanistic understanding. Here we report in full that the white line height of X-ray absorption near-edge spectra (XANES) of Pt complexes, normalized to the post-edge minima, can be used to quantitatively determine the proportion of each oxidation state in a mixture. A series of Pt(IV) complexes based on the Pt(II) complexes cisplatin and transplatin were prepared with chlorido, acetato or hydroxido axial ligands, and studies into their reduction potential and cytotoxicity against A2780 human ovarian cancer cells were performed, demonstrating the relationship between reduction potential and cytotoxicity. Analysis of white line height demonstrated a clear and consistent difference between Pt(II) (1.52 ± 0.05) and Pt(IV) (2.43 ± 0.19) complexes. Reduction of Pt(IV) complexes over time in cell growth media and A2780 cells was observed by XANES, and shown to correspond with their reduction potentials and cytotoxicities. We propose that this method is useful for monitoring reduction of metal-based drug candidates in complex biological systems.     

A mechanistic approach for the DNA binding of chiral enantiomeric L- and D-tryptophan-derived metal complexes of 1,2-DACH: cleavage and antitumor activity

A new chiral series of potential antitumor metal-based complexes 1-3(a and b) of L- and D-tryptophan have been synthesized and thoroughly characterized. Both enantiomers of 1-3 bind DNA noncovalently via phosphate interaction with slight preference of metal center for covalent coordination to nucleobases. The K(b) values of L-enantiomer, however, possess higher propensity for DNA binding in comparison with the D-enantiomeric analogs. The relative trend in K(b) values is as follows: 2(a) > 2(b) > 3(a) > 1(a) > 3(b) > 1(b). These observations together with the findings of circular dichoric and fluorescence studies reveal maximal potential of L-enantiomeric form of copper complex to bind DNA, thereby exerting its therapeutic effect. The complex 2a exhibits a remarkable DNA cleavage activity with pBR322DNA in the presence of different activators such as H(2) O(2) , ascorbic acid, 3-mercaptopropionic acid, and glutathione, suggesting the involvement of active oxygen species for the DNA scission. In vitro anticancer activity of complexes 1-3(a) were screened against 14 different human carcinoma cell lines of different histological origin, and the results reveal that 2a shows significant antitumor activity in comparison with both 1a and 3a and is particularly selective for MIAPACA2 (pancreatic cancer cell line).