Atomic-precise Pt2Cu4 cluster-based fluorescent sensor for rapid interleukin-6 detection.

Levonorgestrel protected Pt2Cu4 clusters were assembled with a polymer to prepare nanobeads (NBs) with intense red fluorescence. An immunofluorescence sensor based on Pt2Cu4NBs was established for the rapid and sensitive detection of interleukin-6 (IL-6) owing to its significance in inflammatory diseases, with a limit of detection of 42.66 pg mL-1. IL-6 spiked in serum was also accurately detected.

Impact of Hydrophobic Chains in Five-Coordinate Glucoconjugate Pt(II) Anticancer Agents.

This study describes new platinum(II) cationic five-coordinate complexes (1-R,R') of the formula [PtR(NHC)(dmphen)(ethene)]CF3SO3 (dmphen = 2,9-dimethyl-1,10-phenanthroline), containing in their axial positions an alkyl group R (methyl or octyl) and an imidazole-based NHC-carbene ligand with a substituent R' of variable length (methyl or octyl) on one nitrogen atom. The Pt-carbene bond is stable both in DMSO and in aqueous solvents. In DMSO, a gradual substitution of dmphen and ethene is observed, with the formation of a square planar solvated species. Octanol/water partitioning studies have revealed the order of hydrophobicity of the complexes (1-Oct,Me > 1-Oct,Oct > 1-Me,Oct > 1-Me,Me). Their biological activity was investigated against two pairs of cancer and non-cancer cell lines. The tested drugs were internalized in cancer cells and able to activate the apoptotic pathway. The reactivity of 1-Me,Me with DNA and protein model systems was also studied using UV-vis absorption spectroscopy, fluorescence, and X-ray crystallography. The compound binds DNA and interacts in various ways with the model protein lysozyme. Remarkably, structural data revealed that the complex can bind lysozyme via non-covalent interactions, retaining its five-coordinate geometry.

State of art in the chemistry of nucleoside-based Pt(II) complexes.

After the fortuitous discovery of the anticancer properties of cisplatin, many Pt(II) complexes have been synthesized, to obtain less toxic leads which could overcome the resistance phenomena. Given the importance of nucleosides and nucleotides as antimetabolites, studying their coordinating properties towards Pt(II) ions is challenging for bioorganic and medicinal chemistry. This review aims to describe the results achieved so far in the aforementioned field, paying particular attention to the synthetic aspects, the chemical-physical characterization, and the biological activities of the nucleoside-based Pt(II) complexes.

Brief Research on the Biophysical Study and Anticancer Behavior of Pt(II) Complexes: Their DNA/BSA Binding, Molecular Docking, and Cytotoxic Property.

The potent bidentate carrier ligand 2-picolylamine (pic) has been used to synthesize Pt(II) complexes to know their bioactivity and anticancer property as reflected by PASS prediction software. The dichloro Pt(II) complex [Pt(pic)Cl2], Pt-1, and its hydrolyzed diaqua complex [Pt(pic)(OH2)2]2+, Pt-2, were synthesized. The thiol-containing Pt(II) complexes [Pt(pic)(l-cys)]+, Pt-3, and [Pt(pic)(L-ac-l-cy)]+, Pt-4, were synthesized from Pt-2, which was obtained from hydrolysis of Pt-1. Their biomolecular interactions with BSA and DNA were executed by spectroscopic methods, and their cytototoxic property was tested by the MTT assay. In vitro biomolecular interactions of Pt(II) complexes with BSA and DNA were investigated by different spectroscopic and viscosity measurement methods for their pharmacokinetic and pharmacodynamic importance. The conformational change of BSA in the presence of a drug candidate was studied by Förster resonance energy transfer calculation and synchronous and three-dimensional fluorescence spectroscopic studies. A theoretical approach on optimization structures, highest occupied molecular orbital-lowest unoccupied molecular orbital energy, global reactivity parameters, time-dependent density functional theory, and molecular docking with BSA and DNA was executed to strengthen and support the experimental observations. In vitro cytotoxic profiles of the complexes like the anticancer activity and their level of reactive oxygen species production were brought under consideration on A549 cancer cells and the normal human embryonic kidney cell line HEK-293. The cytotoxic property was compared with that of the recognized anticancer drug cisplatin.

Antitumor effects of new glycoconjugated PtII agents dual-targeting GLUT1 and Pgp proteins.

A novel and highly efficient dual-targeting PtII system was designed to improve the drug delivery capacity and selectivity in cancer treatment. The dual-targeting monofunctional PtII complexes (1-8) having glycosylated pendants as tridentated ligand were achieved by introducing glycosylation modification in the thioaminocarbazone compounds with potential lysosomal targeting ability. The structures and stability of 1-8 were further established by various techniques. Molecular docking studies showed that 2 was efficiently docked into glucose transporters protein 1 (GLUT1) and P-glycoprotein (Pgp) proteins with the optimal CDocker-interaction-energy of -64.84 and -48.85 kcal mol-1. Complex 2 with higher protein binding capacity demonstrated significant and broad-spectrum antitumor efficacy in vitro, even exhibiting a half maximal inhibitory concentration (IC50) value (∼10 µM) than cisplatin (∼17 µM) against human lung adenocarcinoma cells (A549). The inhibitor experiment revealed GLUT-mediated uptake of 2, and the subcellular localization experiment in A549 also proved that 2 could be localized in the lysosome, thereby causing cell apoptosis. Moreover, cellular thermal shift assay (CETSA) confirmed the binding of 2 with the target proteins of GLUT1 and Pgp. The above results indicated that 2 represents a potential anticancer candidate with dual-targeting functions.

Platinum complexes as inhibitors of DNA repair protein Ku70 and topoisomerase IIα in cancer cells.

Ku70 protein and topoisomerase IIα (Topo IIα) are promising targets of anticancer drugs, which play critical roles in DNA repair and replication processes. Three platinum(II) complexes, [PtCl(NH3)2(9-(pyridin-2-ylmethyl)-9H-carbazole)]NO3 (OPPC), [PtCl(NH3)2(9-(pyridin-3-ylmethyl)-9H-carbazole)]NO3 (MPPC), and [PtCl(NH3)2(9-(pyridin-4-ylmethyl)-9H-carbazole)]NO3 (PPPC), were designed as inhibitors of Ku70 and Topo IIα. Their antitumor activity and inhibitory efficacy on Ku70 and Topo IIα were investigated on cellular and molecular levels. OPPC exhibited high antiproliferative activity against various cancer cell lines, with acute toxicity to mice being lower than that of cisplatin. Moreover, OPPC could enter cancer cells effectively and cause DNA damage, which was evidenced by the enhanced expression of γ-H2AX, Chk1/2 phosphorylation, p53 and cell cycle arrest. OPPC also downregulated the DNA damage repair protein Ku70 and inhibited the formation of Ku70 foci-the central points or loci of Ku70, which would suppress DNA repair and induce a nonhomologous end joining response in cancer cells. More importantly, these complexes showed inhibition towards Topo IIα; in particular, OPPC was more effective than MPPC and PPPC. In the Topo IIα knockdown cells, Ku70 and Topo IIα were directly associated with the DNA damage and apoptotic response. The molecular docking provided detailed structural insights into the interactions of the complexes with Topo IIα. This study demonstrates that the cytotoxicity of these complexes is associated with the DNA damage and repair pathways mediated by Ku70 and Topo IIα; OPPC is an effective inhibitor of Ku70 and Topo IIα and restrains cancer cells via a mechanism utterly distinct from that of cisplatin.

Photophysical, photooxidation, and biomolecule-interaction of meso-tetra(thienyl)porphyrins containing peripheral Pt(II) and Pd(II) complexes. Insights for photodynamic therapy applications.

We report the synthesis and characterization of two novel tetra-cationic porphyrins, containing Pt(II) or Pd(II) polypyridyl complexes attached at the peripheral position of N4-macrocycle. Compounds were characterized through elemental analysis, molar conductivity, cyclic voltammetry, and spectroscopy analysis. Photophysical and photobiological parameters were also evaluated. Also, the binding capacity of each porphyrin with human serum albumin (HSA) was determined by UV-Vis, steady-state, and time-resolved fluorescence spectroscopy, combined with molecular docking calculations. The results suggest that the interaction of these compounds is spontaneous, weak to moderate, and probably occurs at site III (subdomain IB) by non-covalent forces, including van der Waals and H-bonding. Moreover, porphyrins containing peripheral complexes improve their interactions with biomolecules, show good photostability, generate reactive oxygen species under white light studied by electron paramagnetic resonance (EPR) analysis, and promote photo-damage of HSA.

Synthesis, crystal structure, and in vitro evaluation of the anticancer activity of new Pt (Pd) complexes with 1-[(dimethylamino)methyl]-2-naphthol ligand.

The synthesis of new Pt(II) and Pd(II) complexes with 1-aminomethyl-2-naphtol ligands has been first performed. The adducts of [PtCl4]2- and [PdCl4]2- anions with the 1-aminomethyl-2-naphtol NH cation were synthesized. The structure for four Pt (Pd)-containing compounds was investigated using X-ray diffraction. The obtained compounds were examined for in vitro cytotoxic activity against Jurkat and K562 human leukemia cells, lymphoma U937cells, A2780 and the cisplatin-resistant A2780cis lines of human ovarian cancer, and normal fibroblasts. Study of induction of apoptosis and the effect of new palladium and platinum complexes on the cell cycle was carried out. The cells showed a higher sensitivity to Pt(II) compounds than to Pd(II) ones. All the synthesized metal complexes show much more antitumor activity compared with a platinum-containing cisplatin drug.

Photodynamic control of Aedes aegypti larvae with environmentally-friendly tetra-platinated porphyrin.

This work evaluated the photosensitizing activity of isomeric tetra-cationic porphyrins with peripheral [Pt(bpy)Cl]+ to control the larval population of Aedes aegypti by photodynamic action. The photolarvicidal activity of the tetra-platinated porphyrins at meta and para position (3-PtTPyP and 4-PtTPyP) was evaluated under blue (450 nm), green (525 nm), and red (625 nm) light illumination at 55.0 J cm-2. The meta isomer presented an efficient photolarvicidal activity even at a low concentration (1.2 ppm) in the presence of light, while the para counterpart was inactive regardless of the concentration and illumination. The different responses were related to the improved optical features and higher water solubility of 3-PtTPyP compared to 4-PtTPyP. Additionally, the potential environmental toxicity of 3-PtTPyP was tested in a plant model (Allium cepa test), with no toxicity detected for all used concentrations (1.2 to 12 ppm). Hence, this work reveals that 3-PtTPyP has a great potential to be employed to photodynamically control the insect vector population in an environmentally safe way.

Plasmonic AuPt@CuS Heterostructure with Enhanced Synergistic Efficacy for Radiophotothermal Therapy.

Integrating multifunctional nanostructures capable of radiotherapy and photothermal ablation is an emerging alternative in killing cancer cells. In this work, we report a novel plasmonic heterostructure formed by decorating AuPt nanoparticles (NPs) onto the surfaces of CuS nanosheets (AuPt@CuS NSs) as a highly effective nanotheranostic toward dual-modal photoacoustic/computed tomography imaging and enhanced synergistic radiophotothermal therapy. These heterostructures can confer higher photothermal conversion efficiency via the local electromagnetic enhancement as well as a greater radiation dose deposition in the form of glutathione depletion and reactive oxygen species generation. As a result, the depth of tissue penetration is improved, and hypoxia of the tumor microenvironment is alleviated. With synergistic enhancement in the efficacy of photothermal ablation and radiotherapy, the tumor can be eliminated without later recurrence. It is believed that these multifunctional heterostructures will play a vital role in future oncotherapy with the enhanced synergistic effects of radiotherapy and photothermal ablation under the guided imaging of a potential dual-modality system.

The Role of Low-Energy Electron Interactions in cis-Pt(CO)2Br2 Fragmentation.

Platinum coordination complexes have found wide applications as chemotherapeutic anticancer drugs in synchronous combination with radiation (chemoradiation) as well as precursors in focused electron beam induced deposition (FEBID) for nano-scale fabrication. In both applications, low-energy electrons (LEE) play an important role with regard to the fragmentation pathways. In the former case, the high-energy radiation applied creates an abundance of reactive photo- and secondary electrons that determine the reaction paths of the respective radiation sensitizers. In the latter case, low-energy secondary electrons determine the deposition chemistry. In this contribution, we present a combined experimental and theoretical study on the role of LEE interactions in the fragmentation of the Pt(II) coordination compound cis-PtBr2(CO)2. We discuss our results in conjunction with the widely used cancer therapeutic Pt(II) coordination compound cis-Pt(NH3)2Cl2 (cisplatin) and the carbonyl analog Pt(CO)2Cl2, and we show that efficient CO loss through dissociative electron attachment dominates the reactivity of these carbonyl complexes with low-energy electrons, while halogen loss through DEA dominates the reactivity of cis-Pt(NH3)2Cl2.

Ruthenium(II) and Platinum(II) Complexes with Biologically Active Aminoflavone Ligands Exhibit In Vitro Anticancer Activity.

Continuing our studies on the mechanisms underlying the cytotoxicity of potential drugs, we have described several aspects of the in vitro anticancer activity of ruthenium(II) and platinum(II) complexes with bioactive, synthetic aminoflavone ligands. We examined the mechanism of proapoptotic activity of cis-dichlorobis(3-imino-2-methoxyflavanone)ruthenium(II), cis-dichlorobis(3-imino-2-ethoxyflavanone)ruthenium(II), and trans-dichlorobis(3-aminoflavone)platinum(II). Cisplatin was used as a reference compound. The cytotoxicity was investigated by MTT assay. The mechanism of proapoptotic activity of the tested compounds was investigated by evaluation of caspase-8 activity, cytometric analysis of annexin-V positive cells, and mitochondrial potential loss measurement. The results showed that ruthenium compounds break partially or completely the cisplatin resistance by activating the caspase 8-dependent apoptosis pathway and loss of mitochondrial membrane potential. Platinum compounds also have a cytostatic effect, but their action requires more exposure time. Potential mechanisms underlying drug resistance in the two pairs of cancer cell lines were investigated: total glutathione content, P-glycoprotein activity, and differences in the activity of DNA repair induced by nucleotide excision. Results showed that cisplatin-resistant cells have elevated glutathione levels relative to sensitive cells. Moreover, they indicated the mechanisms enabling cells to avoid apoptosis caused by DNA damage. Pg-P activity has no effect on the development of cisplatin resistance in the cell lines described.

Combination of starvation therapy and Pt-NP based chemotherapy for synergistic cancer treatment.

Platinum nanoparticles (Pt-NPs) have been developed for enhanced toxicity against tumor cells. However, the therapeutic effect of Pt-NPs was severely limited by the lack of cellular uptake of Pt-NPs and an oxidative environment. The combination of starvation therapy with Pt-NP based chemotherapy in a well-designed nano-system is expected to eliminate tumors. Therefore, GOx and Pt-NPs were coated with PLGA to obtain a functional nano-system (GOx-Pt-NS), which increased the cellular uptake of Pt-NPs. The accumulation of GOx-Pt-NS in tumors increased significantly via the enhanced permeability and retention (EPR) effect of nanoparticles. In addition, protection of the GOx-Pt-NS overcame several drawbacks of GOx such as poor stability, short in vivo half-life, immunogenicity, and systemic toxicity. Glucose oxidase (GOx) elevated the gluconic acid ROS levels in tumor cells, resulting in an acidic and oxidative environment. The acidic and oxidative environment enhanced the conversion of Pt2+via Pt NPs as well as DNA-binding ability. Finally, combining GOx based starvation therapy with Pt-NP based chemotherapy was expected to eliminate tumors more efficiently through a synergistic strategy.

Functionalized azobenzene platinum(II) complexes as putative anticancer compounds.

The synthesis and characterization of four platinum(II) complexes using azobenzenes conveniently functionalized as ligands has been carried out. The characteristic photochemical behavior of the complexes due to the presence of azobenzene-type ligands and the role of the ligands in the activation of the complexes has been studied. Their promising cytotoxicity observed in HeLa cells prompted us to study the mechanism of action of these complexes as cytostatic agents. The interaction of the compounds with DNA, studied by circular dichroism, revealed a differential activity of the Pt(II) complexes upon irradiation. The intercalation abilities of the complexes as well as their reactivity with common proteins present in the blood stream allows to confirm some of the compounds obtained as good anticancer candidates.

Arsenoplatin-Ferritin Nanocage: Structure and Cytotoxicity.

Arsenoplatin-1 (AP-1), the prototype of a novel class of metallodrugs containing a PtAs(OH)2 core, was encapsulated within the apoferritin (AFt) nanocage. UV-Vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy measurements confirmed metallodrug encapsulation and allowed us to determine the average amount of AP-1 trapped inside the cage. The X-ray structure of AP-1-encapsulated AFt was solved at 1.50 Å. Diffraction data revealed that an AP-1 fragment coordinates the side chain of a His residue. The biological activity of AP-1-loaded AFt was comparatively tested on a few representative cancer and non-cancer cell lines. Even though the presence of the cage reduces the overall cytotoxicity of AP-1, it improves its selectivity towards cancer cells.

Prediction of the hydrophobicity of platinum(IV) complexes based on molecular surface properties.

A quantitative structure-property relationship (QSPR) study was performed for predicting the hydrophobicity of Pt(IV) complexes. Two four-parameter equations, one based solely on structural descriptors derived from electrostatic potentials (ESPs) on molecular surface, and the other integrated ESP descriptors with molecular surface area (AS), were firstly constructed. Mechanistic interpretations of the structural descriptors introduced were elucidated in terms of solute-solvent intermolecular interactions. Subsequently, several up-to-date modeling techniques, including support vector machine (SVM), least-squares support vector machine (LSSVM), random forest (RF) and Gaussian process (GP), were utilized to build the nonlinear models. Systematical validations including leave-one-out cross-validation, the validation for test set, as well as a more rigorous Monte Carlo cross-validation were performed to verify the reliability of the constructed models. The predictive performances of the four different nonlinear modeling methods follow the order of LSSVM≈GP > RF > SVM. The pure-ESP-based models are generally inferior to the AS-integrated ones. Comparisons with previous results were made.

Functional Platinum(II) Complexes with Four-Photon Absorption Activity, Lysosome Specificity, and Precise Cancer Therapy.

Multiphoton materials are in special demand in the field of photodynamic therapy and multiphoton fluorescence imaging. However, rational design methodology for these brands of materials is still nascent. This is despite transition-metal complexes favoring optimized nonlinear-optical (NLO) activity and heavy-atom-effected phosphorescent emission. Here, three four-photon absorption (4PA) platinum(II) complexes (Pt1-Pt3) are achieved by the incorporation of varied functionalized C^N^C ligands with high yields. Pt1-Pt3 exhibit triplet metal-to-ligand charge-transfer transitions at ∼460 nm, which are verified multiple times by transient absorption spectra, time-dependent density functional theory calculations, and low-temperature emission spectra. Further, Pt1-Pt3 undergo 4PA. Notably, one of the complexes, Pt2, has maximum 4PA cross-sectional values of up to 15.2 × 10-82 cm8 s3 photon-3 under excitation of a 1600 nm femtosecond laser (near-IR II window). The 4PA cross sections vary when Pt2 is binding to lecithin and when it displays its lysosome-specific targeting behavior. On the basis of the excellent 4PA property of Pt2, we believe that those 4PA platinum(II) complexes have great potential applications in cancer theranostics.

Mustards-Derived Terpyridine-Platinum Complexes as Anticancer Agents: DNA Alkylation vs Coordination.

The development of bifunctional platinum complexes with the ability to interact with DNA via different binding modes is of interest in anticancer metallodrug research. Therefore, we report platinum(II) terpyridine complexes to target DNA by coordination and/or through a tethered alkylating moiety. The platinum complexes were evaluated for their in vitro antiproliferative properties against the human cancer cell lines HCT116 (colorectal), SW480 (colon), NCI-H460 (non-small cell lung), and SiHa (cervix) and generally exhibited potent antiproliferative activity although lower than their respective terpyridine ligands. 1H NMR spectroscopy and/or ESI-MS studies on the aqueous stability and reactivity with various small biomolecules, acting as protein and DNA model compounds, were used to establish potential modes of action for these complexes. These investigations indicated rapid binding of complex PtL3 to the biomolecules through coordination to the Pt center, while PtL4 in addition alkylated 9-ethylguanine. PtL3 was investigated for its reactivity to the model protein hen egg white lysozyme (HEWL) by protein crystallography which allowed identification of the Nδ1 atom of His15 as the binding site.

Novel Platinum(II) Complex-based Luminescent Probe for Detection of Hypochlorite in Cancer Cells.

Hypochlorite (ClO⁻) is of great importance either for the metabolism of living organisms or as disinfectant in daily life. However, improper concentration levels of ClO⁻ lead to serious health problems including erythrocyte damage, cardiovascular problems, neuron degeneration, lung/kidney injury and cancer. Therefore, a sensitive and selective detection method is required for the visualization and measurement of ClO⁻. In this work, a novel platinum(II) complex-based luminescent probe Pt-CHO was synthesized and utilized to detect ClO⁻. This "turn-off" probe exhibits high sensitivity, excellent selectivity, good pH stability, low limit of detection and instantaneous response ability. Moreover, the luminescent response is caused by the oxidation of aldehyde into carboxyl groups combined with the coordination of hydroxyl groups at the Pt center, which is rarely reported. The cell imaging of HeLa cells proved the considerable potential of the probe for ClO⁻ imaging in living cells.

Rational Design of Near-Infrared-Absorbing Pt(II)-Chelated Azadipyrromethene Dyes as a New Generation of Photosensitizers for Synergistic Phototherapy.

Pt(II) photosensitizers are emerging as novel Pt anticancer agents for cancer photodynamic therapy (PDT) to avoid uncontrollable toxicity of cisplatin. However, the application of Pt(II) photosensitizers is limited by tumor hypoxia and the poor penetration depth of excitation light. To overcome these drawbacks, exploiting the next generation of Pt anticancer agents is of urgent need. According to theoretical calculations, novel near-infrared (NIR)-absorbing Pt(II)-chelated azadipyrromethene dyes (PtDP-X, where X = N, C, and S) were designed. Importantly, spin-orbit coupling of the Pt atom could promote the intersystem crossing of a singlet-to-triplet transition for converting oxygen to singlet oxygen (1O2), and the azadipyrromethene skeleton could provide a strong photothermal effect. As expected, PtDP-X exhibited intense NIR absorption and synergistic PDT and photothermal effects with low dark cytotoxicity. Furthermore, water-soluble and biocompatible PtDP-N nanoparticles (PtDP-N NPs) were prepared that achieved effective tumor cell elimination with low side effects under 730 nm light irradiation in vitro and in vivo. This pioneering work could push the exploitation of NIR-absorbing metal-chelated azadipyrromethene dyes, so as to promote the positive evolution of phototherapy agents.