Platinum Anticancer Drugs Research Articles

A brief review on bioactivity of platinum therapeutics

The present review includes a brief introduction over deferent platinum anticancer drugs and their mechanism of action as well as their applications and limitations. Various recently studied Pt(II) complexes are also discussed herein. It also highlights the different possible DNA binding mode for a chemical substance as well as intracellular or extracellular platinum-sulfur interactions.

Improved method for quantification of intact oxaliplatin by ultra high performance liquid chromatography-inductively coupled plasma mass spectrometry: Applications to clinical and speciation studies

Interest is increasing in the use of different liquid chromatography techniques coupled online to mass spectrometry for the quantification of platinum anticancer drugs in human plasma to inform cancer chemotherapy. We developed, validated and studied the application of a method for quantification of intact oxaliplatin in human plasma using ultra high performance liquid chromatography hyphenated to inductively coupled plasma mass spectrometry (UHPLC-ICP-MS). Plasma samples were processed instantly after collection from patients to preserve oxaliplatin speciation by methanol-deproteinization, and storage of diluted supernatants (plasma:methanol 1:2 v/v) at −80 °C. UHPLC separation of intact oxaliplatin and internal standard (carboplatin) was achieved using a C18 column and linear gradient mobile phase (Mobile phase A: water-methanol (97:3 v/v), 0.075 mM sodium dodecyl sulfate, 9.79 nM thallium adjusted to pH 2.5 with trifluoromethanesulfonic acid; Mobile phase B: 100 % methanol (v/v)) with ICP-MS detection to monitor platinum and thallium at m/z 195 and 205, respectively. The limit of quantification was 50 nM in methanol-deproteinized diluted plasma (1:2 v/v). Linearity was established for calibration standards ranging from 50 to 500 nM made in methanol-deproteinized diluted plasma (1:2 v/v), and for dilution of higher concentration samples in blank matrix containing internal standard (final dilution 1:29 v/v). Intra-day and inter-day accuracy ranged from 96.8 to 103 % of nominal concentration and precision from 0.62 to 2.49 % coefficient of variation. Recovery was complete and a matrix effect confirmed the requirement for matrix-matched standards. Intact oxaliplatin was stable during storage for at least 473 days, and during analysis, in methanol-deproteinized diluted plasma (1:2 v/v). The method was applied to determining the plasma concentrations of intact oxaliplatin in patients undergoing cancer chemotherapy, and studies of oxaliplatin degradation in vitro. This improved method based on UHPLC-ICP-MS will allow more specific, efficient and reliable quantification of intact oxaliplatin in human plasma.

Anticancer platinum-drug delivered by mesenchymal stromal cells improves its activity on glioblastoma

BackgroundGlioblastoma multiforme (GBM) is nowadays the most aggressive tumor affecting brain in adults with a very poor prognosis due to the limited therapies and the systemic cytotoxicity. Among the different new drugs, recently has been reported the in vitro anti-glioma activity of a new cationic platinum(II) complex bearing 8-aminoquinoline as chelating ligand (Pt-8AQ). The purpose of this research work was to confirm the activity of Pt-8AQ on U87-GM spheroid and to investigate the ability of Mesenchymal Stromal Cells (MSCs) to incorporate and release Pt-8AQ in its active form. The MSCs were primed with Pt-8AQ under optimized conditions and the secretome was analyzed for evaluating the cytotoxic activity of Pt-8AQ and the presence of Extracellular Vesicles (Evs).ResultsThe principal results showed that Pt-8AQ incorporated by MSCs was released in the secretome and exerted a significant higher anticancer activity with respect to the free drug. The release of Pt-8AQ did not occur in Evs, as demonstrated for other drugs, but it could be delivered bound to some specific carriers able to enhance its bioavailability and efficacy. Some hypotheses are discussed to explain this surprisingly finding out that, however, it needs more investigations.ConclusionsThe major conclusions are that cell mediated drug delivery systems could provide a potential approach to facilitate the GBM therapy by intra-tumoral administration of cells loaded with Pt-8AQ, being MSCs able to integrate it into the tumor mass and exert high therapeutic efficacy in situ. The increased efficacy of Pt-8AQ delivered by MSCs even suggests to deeper investigate a possible direct use of MSCs secretome both in situ and/or by systemic administration, being secretome able to pass the blood–brain tumor.

Pegylated magnetic carbon nanotubes for efficient and safe delivery of poorly water-soluble platinum anticancer drugs

In this work, a new PEGylated magnetic carbon nanotube was developed for efficient and safe delivery of poorly water-soluble platinum anticancer drugs. Nanocarriers based on PEGylated magnetic carbon nanotubes were chemically synthesized through simple methods and finally platinum(II) complex conjugated to the synthesized delivery system (carbon nanotubes/polyethyleneglycol@Fe3O4/CPTMS@Cis-dichloro-bis(5-(4-pyridyl)-5-phenylhydantoin)platinum(II)) (CNTs/PEG@M/CPTMS@CisPt(II)). This nanomaterial was characterized by Transmission electron microscopes (TEM), Scanning electron microscopy (SEM), Energy-dispersive X-ray spectroscopy (EDS), X-Ray diffraction analysis (XRD), Ultraviolet–visible (UV–Vis) spectroscopy, Inductively coupled plasma mass spectrometry (ICP-MS), Fourier-transform infrared spectroscopy (FT-IR), Elemental mapping, Raman spectroscopy, and Nuclear Magnetic Resonance (NMR) analysis. The pattern of drug release from the CNTs/PEG@M/CPTMS@CisPt(II) was affected by pH at a certain temperature and time. In vitro cytotoxicity studies shown that despite the acceptable biocompatibility of the drug-free carrier, the drug-conjugated carrier has a good efficiency in limiting the growth and killing cancer cells. These findings revealed that CNTs/PEG@M/CPTMS@CisPt(II) carrier may provide a promising approach for delivery of the anticancer drugs to cancer cells.

Structural changes in DNA by binding mitochondrion-targeted monofunctional platinum(II) complexes using molecular dynamics simulation study

Triphenylphosphonium (Ph3P+, TPP) is a highly effective mitochondrial targeting group, an example of using which on mitochondrion-targeted monofunctional platinum(II) agent as anticancer drug was OPT, with the –CH2Ph3P+ group at ortho position of the pyriplatin pyridine ring. To study how carrier ligands might affect the efficacy of OPT, we constructed two platinum(II) agents with bulky bidentate ligands based on OPT. DNA structural changes caused by these three platinum(II) agents using molecular dynamics simulations were analysed. Data regarding DNA conformational changes including helical parameter, base stacking, average structure, and principal component analyses has been obtained. We found that TPP-based monofunctional platinum(II) complexes with bulky carrier ligands may induce more significant DNA conformational changes. These results are beneficial for developing highly efficient mitochondrion-targeted platinum anticancer drugs with carrier ligands of different steric hindrance.

Overcoming Cancer Resistance to Platinum Drugs by Inhibiting Cholesterol Metabolism

AbstractDrug resistance is a serious challenge for platinum anticancer drugs. Platinum complexes may get over the drug resistance via a distinct mechanism of action. Cholesterol is a key factor contributing to the drug resistance. Inhibiting cellular cholesterol synthesis and uptake provides an alternative strategy for cancer treatment. Platinum(IV) complexes FP and DFP with fenofibric acid as axial ligand(s) were designed to combat the drug resistance through regulating cholesterol metabolism besides damaging DNA. In addition to producing reactive oxygen species and active platinum(II) species to damage DNA, FP and DFP inhibited cellular cholesterol accumulation, promoted cholesterol efflux, upregulated peroxisome proliferator‐activated receptor alpha (PPARα), induced caspase‐1 activation and gasdermin D (GSDMD) cleavage, thus leading to both apoptosis and pyroptosis in cancer cells. The reduction of cholesterol significantly relieved the drug resistance of cancer cells. The double‐acting mechanism gave the complexes strong anticancer activity in vitro and in vivo, particularly against cisplatin‐resistant cancer cells.

Overcoming Cancer Resistance to Platinum Drugs by Inhibiting Cholesterol Metabolism.

Drug resistance is a serious challenge for platinum anticancer drugs. Platinum complexes may get over the drug resistance via a distinct mechanism of action. Cholesterol is a key factor contributing to the drug resistance. Inhibiting cellular cholesterol synthesis and uptake provides an alternative strategy for cancer treatment. Platinum(IV) complexes FP and DFP with fenofibric acid as axial ligand(s) were designed to combat the drug resistance through regulating cholesterol metabolism besides damaging DNA. In addition to producing reactive oxygen species and active platinum(II) species to damage DNA, FP and DFP inhibited cellular cholesterol accumulation, promoted cholesterol efflux, upregulated peroxisome proliferator-activated receptor alpha (PPARα), induced caspase-1 activation and gasdermin D (GSDMD) cleavage, thus leading to both apoptosis and pyroptosis in cancer cells. The reduction of cholesterol significantly relieved the drug resistance of cancer cells. The double-acting mechanism gave the complexes strong anticancer activity in vitro and in vivo, particularly against cisplatin-resistant cancer cells.

Graph Energy Variants and Topological Indices in Platinum Anticancer Drug Design: Mathematical Insights and Computational Analysis with DFT and QTAIM

In this paper, we present a new approach that explores the application of graph energy variants in chemistry, specifically in the development of platinum anticancer drugs. While previous energy variants have been proposed without considering their direct relevance to chemistry, our study focuses on two key aspects. First, we investigate the correlation between seven degree-based and four distance-based topological indices and their corresponding energies in platinum anticancer drugs. Furthermore, we mathematically analyze the properties of these energies, establishing upper and lower bounds that can be generalized to other structures. Second, we examine the possibility of utilizing the energies of these topological indices as structural descriptors. Our research showcases promising results, suggesting potential improvements in the future manufacturing of anticancer drugs. In addition, we employ density functional theory D F T calculations to optimize the molecular structures of platinum anticancer drugs and identify local reactive sites using Fukui functions. Quantum theory of atoms in molecules Q T A I M was carried out at the bond critical point B C P , to reveal the nature of the intermolecular interactions in the investigated ten Pt anticancer drugs, especially, the nature of bonds between Pt atoms and their bond atoms. Overall, this study presents an innovative approach that bridges graph energies, topological indices, and DFT with the properties (physical and chemical) of platinum anticancer drugs, offering insights into their molecular properties and potential for enhanced drug design.

Probing Disaccharide Binding to Triplatin as Models for Tumor Cell Heparan Sulfate (GAG) Interactions.

In this study, we have used [1H, 15N] NMR spectroscopy to investigate the interactions of the trinuclear platinum anticancer drug triplatin (1) (1,0,1/t,t,t or BBR3464) with site-specific sulfated and carboxylated disaccharides. Specifically, the disaccharides GlcNS(6S)-GlcA (I) and GlcNS(6S)-IdoA(2S) (II) are useful models of longer-chain glycosaminoglycans (GAGs) such as heparan sulfate (HS). For both the reactions of 15N-1 with I and II, equilibrium conditions were achieved more slowly (65 h) compared to the reaction with the monosaccharide GlcNS(6S) (9 h). The data suggest both carboxylate and sulfate binding of disaccharide I to the Pt with the sulfato species accounting for <1% of the total species at equilibrium. The rate constant for sulfate displacement of the aqua ligand (kL2) is 4 times higher than the analogous rate constant for carboxylate displacement (kL1). There are marked differences in the equilibrium concentrations of the chlorido, aqua, and carboxy-bound species for reactions with the two disaccharides, notably a significantly higher concentration of carboxylate-bound species for II, where sulfate-bound species were barely detectable. The trend mirrors that reported for the corresponding dinuclear platinum complex 1,1/t,t, where the rate constant for sulfate displacement of the aqua ligand was 3 times higher than that for acetate. Also similar to what we observed for the reactions of 1,1/t,t with the simple anions, aquation of the sulfato group is rapid, and the rate constant k-L2 is 3 orders of magnitude higher than that for displacement of the carboxylate (k-L1). Molecular dynamics calculations suggest that extra hydrogen-bonding interactions with the more sulfated disaccharide II may prevent or diminish sulfate binding of the triplatin moiety. The overall results suggest that Pt-O donor interactions should be considered in any full description of platinum complex cellular chemistry.

In Vitro Binding of Platinum Anticancer Drugs to DNA Observed Directly by Polyacrylamide Gel Electrophoresis: A Multiweek Undergraduate Laboratory Investigation

In Vitro Binding of Platinum Anticancer Drugs to DNA Observed Directly by Polyacrylamide Gel Electrophoresis: A Multiweek Undergraduate Laboratory Investigation

Corrigendum to: Searching for the Magic Bullet: Anticancer Platinum Drugs Which Can Be Accumulated or Activated in the Tumor Tissue.

An article was published in the journal "Anti-Cancer Agents in Medicinal Chemistry", Volume 7, No. 01, 2007, pp: 55-73 [1]. The first author is requesting an alteration in the name. Details of a correction are provided here. The original name published was Markus Galanski. The request is to change the name to Mathea Sophia Galanski. The original article can be found online at: https://www.eurekaselect.com/article/3359.

Impact of HMGB1 binding on the structural alterations of platinum drug-treated single dsDNA molecule

High mobility group B1 (HMGB1) is an architectural protein that recognizes the DNA damage sites formed by the platinum anticancer drugs. However, the impact of HMGB1 binding on the structural alterations of the platinum drug-treated single dsDNA molecules has remained largely unknown. Herein, the structural alterations induced by the platinum drugs, the mononuclear cisplatin and it's analog the trinuclear BBR3464, have been probed in presence of HMGB1, by atomic force microscopy (AFM) and AFM-based force spectroscopy. It is observed that the drug-induced DNA loop formation enhanced upon HMGB1 binding, most likely as a result of HMGB1-induced increase in DNA conformational flexibility that allowed the drug-binding sites to come close and form double adducts, thereby resulting in enhanced loop formation via inter-helix cross-linking. Since HMGB1 enhances DNA flexibility, the near-reversible structural transitions as observed in the force-extension curves (for 1 h drug treatment), generally occurred at lower forces in presence of HMGB1. The DNA structural integrity was largely lost after 24 h drug treatment as no reversible transition could be observed. The Young's modulus of the dsDNA molecules, as estimated from the force-extension analysis, increased upon drug treatment, due to formation of the drug-induced covalent cross-links and consequent reduction in DNA flexibility. The Young's modulus increased further in presence of HMGB1 due to HMGB1-induced enhancement in DNA flexibility that could ease formation of the drug-induced covalent cross-links. To our knowledge, this is the first report that shows an increase in the stiffness of the platinum drug-treated DNA molecules in presence of HMGB1.

Platinum-Based Nanoformulations for Glioblastoma Treatment: The Resurgence of Platinum Drugs?

Current therapies for treating Glioblastoma (GB), and brain tumours in general, are inefficient and represent numerous challenges. In addition to surgical resection, chemotherapy and radiotherapy are presently used as standards of care. However, treated patients still face a dismal prognosis with a median survival below 15-18 months. Temozolomide (TMZ) is the main chemotherapeutic agent administered; however, intrinsic or acquired resistance to TMZ contributes to the limited efficacy of this drug. To circumvent the current drawbacks in GB treatment, a large number of classical and non-classical platinum complexes have been prepared and tested for anticancer activity, especially platinum (IV)-based prodrugs. Platinum complexes, used as alkylating agents in the anticancer chemotherapy of some malignancies, are though often associated with severe systemic toxicity (i.e., neurotoxicity), especially after long-term treatments. The objective of the current developments is to produce novel nanoformulations with improved lipophilicity and passive diffusion, promoting intracellular accumulation, while reducing toxicity and optimizing the concomitant treatment of chemo-/radiotherapy. Moreover, the blood-brain barrier (BBB) prevents the access of the drugs to the brain and accumulation in tumour cells, so it represents a key challenge for GB management. The development of novel nanomedicines with the ability to (i) encapsulate Pt-based drugs and pro-drugs, (ii) cross the BBB, and (iii) specifically target cancer cells represents a promising approach to increase the therapeutic effect of the anticancer drugs and reduce undesired side effects. In this review, a critical discussion is presented concerning different families of nanoparticles able to encapsulate platinum anticancer drugs and their application for GB treatment, emphasizing their potential for increasing the effectiveness of platinum-based drugs.

Nanoparticle-Based Combination Therapy for Ovarian Cancer.

Ovarian cancer is one of the most common malignant tumors in gynecology with a high incidence. Combination therapy, eg, administration of paclitaxel followed by a platinum anticancer drug is recommended to treat ovarian cancer due to its advantages in, eg, reducing side effects and reversing (multi)drug-resistance compared to single treatment. However, the benefits of combination therapy are often compromised. In chemo and chemo/gene combinations, co-deposition of the combined therapeutics in the tumor cells is required, which is difficult to achieve due to dramatic pharmacokinetic differences between combinational agents in free forms. Moreover, some undesired properties such as the low-water solubility of chemodrugs and the difficulty of cellular internalization of gene therapeutics also hinder the therapeutic potential. Delivery of dual or multiple agents by nanoparticles provides opportunities to tackle these limits. Nanoparticles encapsulate hydrophobic drug(s) to yield aqueous dispersions facilitating its administration and/or to accommodate hydrophilic genes facilitating its access to cells. Moreover, nanoparticle-based therapeutics can not only improve drug properties (eg, in vivo stability) and ensure the same drug disposition behavior with controlled drug ratios but also can minimize drug exposure of the normal tissues and increase drug co-accumulation at targeted tissues via passive and/or active targeting strategies. Herein, this work summarizes nanoparticle-based combination therapies, mainly including anticancer drug-based combinations and chemo/gene combinations, and emphasizes the advantageous outcomes of nanocarriers in the combination treatment of ovarian cancer. In addition, we also review mechanisms of synergetic effects resulting from different combinations.

Determination of platinum anticancer drugs in occupational settings by ICP-MS

Objective: To establish an inductively coupled plasma mass spectrometry (ICP-MS) for platinum antineoplastic drugs in the environment. Methods: The platinum antineoplastic drugs in the environmental table were eluted by wiping and collecting pure water, and the supernatant was taken by centrifugation and inductively coupled plasma mass spectrometry for detection. Results: The concentration range of 0-8.0 μg/L was good, the correlation coefficient was 1.000, the detection limit was 0.0006 μg/L, the lower quantitative limit was 0.002 μg/L, the method precision was between 0.9%-1.3%, and the sample standard recovery rate was between 97.0%-98.5%. Conclusion: This method has low detection limit, high accuracy and precision, and simple sample pretreatment, which is suitable for the determination of platinum antineoplastic drugs in environmental tables.

Potent Ruthenium-Ferrocene Bimetallic Antitumor Antiangiogenic Agent That Circumvents Platinum Resistance: From Synthesis and Mechanistic Studies to In Vivo Evaluation in Zebrafish.

Emergence of resistance in cancer cells and dose-limiting side effects severely limit the widespread use of platinum (Pt) anticancer drugs. Multi-action hybrid anticancer agents that are constructed by merging two or more pharmacophores offer the prospect of circumventing issues of Pt drugs. Herein, we report the design, synthesis, and in-depth biological evaluation of a ruthenium-ferrocene (Ru-Fc) bimetallic agent [(η6-p-cymene)Ru(1,1,1-trifluoro-4-oxo-4-ferrocenyl-but-2-en-2-olate)Cl] and its five analogues. Along with aquation/anation chemistry, we evaluated the in vitro antitumor potency, Pt cross-resistance profile, and in vivo antiangiogenic properties. A structure activity analysis was performed to understand the impact of Fc, CF3, and p-cymene groups on the anticancer potency of the Ru-Fc hybrid. Finally, in addition to assessing cellular uptake and intracellular distribution, we demonstrated that the Ru-Fc hybrid binds to nucleophilic biomolecules and produces reactive oxygen species, which causes mitochondrial dysfunction and induces ER stress, leading to poly(ADP-ribose) polymerase-mediated necroptotic cell death.

Blood Components as Carriers for Small-Molecule Platinum Anticancer Drugs.

The efficacy of platinum drugs is limited by severe side effects, drug resistance, and poor pharmacokinetic properties. Utilizing long-lasting blood components as drug carriers is a promising strategy to improve the circulation half-lives and tumor accumulation of platinum drugs. Non-immunogenic blood cells such as erythrocytes and blood proteins such as albumins, which have long lifespans, are suitable for the delivery of platinum drugs. In this concept, we briefly summarize the strategies of applying blood components as promising carriers to deliver small-molecule platinum drugs for cancer treatment. Examples of platinum drugs that are encapsulated, non-covalently attached, and covalently bound to erythrocytes and plasma proteins such as albumin and apoferritin are introduced. The potential methods to increase the stability of platinum-based thiol-maleimide conjugates involved in these delivery systems are also discussed. This concept may enlighten researchers with more ideas on the future development of novel platinum drugs that have excellent pharmacokinetic properties and antitumor performance in vivo.

Effect of cisplatin on respiratory activity in neonatal rats.

One side effect of cisplatin, a cytotoxic platinum anticancer drug, is peripheral neuropathy; however, its central nervous system effects remain unclear. We monitored respiratory nerve activity from the C4 ventral root in brainstem and spinal cord preparations from neonatal rats (P0-3) to investigate its central effects. Bath application of 10-100μM cisplatin for 15-20min dose-dependently decreased the respiratory rate and increased the amplitude of C4 inspiratory activity. These effects were not reversed after washout. In separate perfusion experiments, cisplatin application to the medulla decreased the respiratory rate, and application to the spinal cord increased the C4 burst amplitude without changing the burst rate. Application of other platinum drugs, carboplatin or oxaliplatin, induced no change of respiratory activity. A membrane potential analysis of respiratory-related neurons in the rostral medulla showed that firing frequencies of action potentials in the burst phase tended to decrease during cisplatin application. In contrast, in inspiratory spinal motor neurons, cisplatin application increased the peak firing frequency of action potentials during the inspiratory burst phase. The increased burst amplitude and decreased respiratory frequency were partially antagonized by riluzole and picrotoxin, respectively. Taken together, cisplatin inhibited respiratory rhythm via medullary inhibitory system activation and enhanced inspiratory motor nerve activity by changing the firing property of motor neurons.

Ruthenium Complexes as Potential Cancer Cell Growth Inhibitors for Targeted Chemotherapy

AbstractThe effective clinical use of the three generation platinum anticancer drugs, cisplatin, carboplatin, and oxaliplatin, has sparked interest in metallodrugs; however, drug resistance and side effects have hampered their continued use and effects. Ruthenium(III) complexes have been successfully used in clinical research, and their anticancer mechanisms have been extensively reported during the last few decades. Ruthenium(II) complexes have also received a lot of attention as anticancer alternatives, but only a few of them have been thoroughly investigated. The development of ruthenium compounds as target‐specific chemotherapeutic drugs has received a lot of attention in recent years. Indeed, a few reviews summarising the research on cancer targeting ruthenium complexes have been published previously. We looked at studies on the target specific mechanism of action of ruthenium complexes for numerous organelles endoplasmic reticulum, nucleus, mitochondria,), DNA, intracellular proteins, and certain enzymes (carbonic anhydrase, TopoisomeraseI), all of which are upregulated in cancer cells and provide a specific mechanism for cancer cell death. This review will provide readers with a general overview of the different ruthenium complexes available for targeted chemotherapy, as well as information to aid in the design and creation of new anticancer ruthenium complexes research.

Highly Promising an Anti-Cancer Drugs : Metal Complex Bearing Sulfur Chelating Ligand, A Hypothetical Design

In anticancer chemotherapy, drug targeting and delivery methods depend on agents with selective access to cancer cells to deliver drugs to the target, and approaches to finding such agents often depend on novel design strategies employing bioactive vectors. Platinum-based complexes are extremely important drugs for the treatment of cancer. Recently synthesized complexes of Pt (IV) have been shown to have several advantages, such as they are safer, can be used orally, are highly anti-cancer effective, there is no cross-resistance to cisplatin, and their effectiveness is compared with commonly used Pt (II) compounds such as cisplatin and oxaliplatin. A molecular mimicry model for the generation of new active drugs may be synthesized by the 3,5-ditert-butyl-2-hydroxy-benzylaminocysteine (DTHBAC) where a cysteine group and two tertiary butyl groups attached to the phenol aromatic ring can be coordinated with platinum. This appropriate ligand with the platinum complex is fit for the anticancer drug. Based on the present modeling, it can be recommended in the management of patients, and from this perspective, the status of the platinum anticancer drug field will develop over the next decade. Moreover, the authors have no doubt that this will benefit patients in the future and will be widely used in cancer treatment for years to come.&#x0D; Keywords: Drug design, Anti-cancer, Cisplatin, Complex, Chelate.