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In this study, we report a novel platinum–doxorubicin conjugate that demonstrates superior therapeutic indices to cisplatin, doxorubicin, or their combination, which are commonly used in cancer treatment. This new molecular structure (1) was formed by conjugating an amphiphilic Pt(IV) prodrug of cisplatin with doxorubicin. Due to its amphiphilic nature, the Pt(IV)–doxorubicin conjugate effectively penetrates cell membranes, delivering both cisplatin and doxorubicin payloads intracellularly. The intracellular accumulation of these payloads was assessed using graphite furnace atomic absorption spectrometry and fluorescence imaging. Since the therapeutic effects of cisplatin and doxorubicin stem from their ability to target nuclear DNA, we hypothesized that the amphiphilic Pt(IV)–doxorubicin conjugate (1) would effectively induce nuclear DNA damage toward killing cancer cells. To test this hypothesis, we used flow the cytometric analysis of phosphorylated H2AX (γH2AX), a biomarker of nuclear DNA damage. The Pt(IV)–doxorubicin conjugate (1) markedly induced γH2AX in treated MDA-MB-231 breast cancer cells, showing higher levels than cells treated with either cisplatin or doxorubicin alone. Furthermore, MTT cell viability assays revealed that the enhanced DNA-damaging capability of complex 1 resulted in superior cytotoxicity and selectivity against human cancer cells compared to cisplatin, doxorubicin, or their combination. Overall, the development of this amphiphilic Pt(IV)–doxorubicin conjugate represents a new form of combination therapy with improved therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Rhenium(V) oxo complexes of general formula [ReO(OMe)(N^N)Cl2], where N^N = 4,7-diphenyl-1,10-phenanthroline, 1, or 3,4,7,8-tetramethyl-1,10-phenanthroline, 2, effectively kill cancer cells by triggering necroptosis, a non-apoptotic form of cell death. Both complexes evoke necrosome (RIP1-RIP3)-dependent intracellular reactive oxygen species (ROS) production and propidium iodide uptake. The complexes also induce mitochondrial membrane potential depletion, a possible downstream effect of ROS production. Apparently, 1 and 2 are the first rhenium complexes to evoke cellular events consistent with programmed necrosis in cancer cells. Furthermore, 1 and 2 display low acute toxicity in C57BL/6 mice and reasonable stability in fresh human blood.

This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(IV) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(II) cage that can host four Pt(IV) prodrug guest molecules. Relying on host-guest interactions between adamantyl units tethered to the Pt(IV) molecules and the cage, four prodrugs could be encapsulated within one cage. This host-guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host-guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cells lines, whereas the cage or the Pt(IV) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.

This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(IV) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(II) cage that can host four Pt(IV) prodrug guest molecules. Relying on host-guest interactions between adamantyl units tethered to the Pt(IV) molecules and the cage, four prodrugs could be encapsulated within one cage. This host-guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host-guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cells lines, whereas the cage or the Pt(IV) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.

The effect of a newly developed osmium(VI) nitrido complex, 1, on breast cancer stem cells (CSCs) is reported. The complex displays selective toxicity for HMLER breast cancer cells enriched with CD44-positive, CSC-like cells over the same cells having reduced CSC character. Remarkably, 1 also reduces the proportion of CSCs within a heterogeneous breast cancer cell population and irreversibly inhibits the formation of free-floating mammospheres to an extent similar to that of salinomycin, a natural product that targets CSCs. Detailed mechanistic studies reveal that in breast cancer cells 1 induces DNA damage and endoplasmic reticulum stress, the latter being responsible for the CSC selectivity. The anti-CSC properties of 1 provide a strong impetus for the development of new metal-based compounds to target CSCs and to treat chemotherapy-resistant and relapsed tumors.

Albumin is the most abundant protein in human serum and drugs that are administered intravenously inevitably interact with it. We present here a series of platinum(IV) prodrugs designed specifically to enhance interaction with human serum albumin (HSA) for drug delivery. This goal is achieved by asymmetrically functionalizing the axial ligands of the prodrug so as to mimic the overall features of a fatty acid. Systematic variation of the length of the aliphatic tail tunes the cellular uptake and, consequently, the cytotoxicity of cis,cis,trans-[Pt(NH3)2Cl2(O2CCH2CH2COOH)(OCONHR)], 4, where R is a linear alkyl group. Investigation of an analogue bearing a fluorophore conjugated to the succinate ligand confirmed that these compounds are reduced by biological reductants with loss of the axial ligands. Intracellular release of cisplatin from 4 was further confirmed by observing the characteristic effects of cisplatin on the cell cycle and morphology following treatment with the prodrug. The most potent member of series 4, for which R is a hexadecyl chain, interacts with HSA in a 1:1 stoichiometry to form the platinum-protein complex 7. The interaction is non-covalent and extraction with octanol completely removes the prodrug from an aqueous solution of HSA. Construct 7 is robust and can be isolated following fast protein liquid chromatography. The nature of the tight interaction was investigated computationally, and these studies suggest that the prodrug is buried below the surface of the protein. Consequently, complexation to HSA is able to reduce the rate of reduction of the prodrug by ascorbate. The lead compound from series 4 also exhibited significant stability in whole human blood, attributed to its interaction with HSA. This favorable redox profile, in conjunction with the established nonimmunogenicity, biocompatibility, and enhanced tumor accumulation of HSA, produces a system that holds significant therapeutic potential.

Although iron is a bio-essential metal, dysregulated iron acquisition and metabolism result in production of reactive oxygen species (ROS) due to the Fenton catalytic reaction, which activates ferroptotic cell death pathways. The lipophilic Fe(III)-chelator chlorquinaldol (L; i.e., 5,7-dichloro-8-hydroxy-2-methylquinoline) strongly favors the formation of a highly stable binuclear Fe(III) complex [(L2Fe)2(μ-O)] (1) that can mimic the function of the Fe(III)-transferrin complex in terms of the strong binding to Fe(III) and facile release of Fe(II) when the metal center is reduced. It should be noted that the cellular uptake of 1 is not transferrin receptor-mediated but enhanced by the high lipophilicity of chlorquinaldol. Once 1 is transported across the cell membrane, Fe(III) can be reduced by ferric reductase or other cellular antioxidants to be released as Fe(II), which triggers the Fenton catalytic reaction, thus harnessing the anticancer activity of iron. As the result, this transferrin-inspired iron-delivery strategy significantly reduces the cytotoxicity of 1 in normal human embryonic kidney cells (HEK 293) and the hemolytic activity of 1 in human red blood cells (hRBCs), giving rise to the unique tumor-specific anticancer activity of this Fe(III) complex. [ABSTRACT FROM AUTHOR]