ABSTRACT
Current challenges in oncology are largely associated with the need to improve the effectiveness of cancer treatment and to reduce drug's side effects. An effective strategy to cope with these challenges is behind designing and developing drug delivery systems based on smart nanomaterials and approved anticancer drugs. The present study offers a novel and straightforward approach to efficiently load the cisplatin drug into the newly constructed liposome-based nanosystems as well a reliable technique for monitoring this process based on capillary electrophoresis hyphenated with inductively coupled plasma tandem mass spectrometry. The proposed drug-loading methodology comprises liposome formation via a simple ethanol-injection method and propels increased drug encapsulation using tailor-made freeze-thawing or lyophilization-hydration procedures. To optimize liposome generation and drug encapsulation, the effects of dilution medium and liposome composition (types of phospholipids and their percentage ratio) have been investigated in detail. It was shown that modest alterations of the composition of three-component phospholipid liposomes and parameters of the freeze-thawing procedure have a strong impact on the formation of cisplatin-liposome systems. The obtained cisplatin-liposome formulation features a remarkable degree of drug encapsulation, over 100â¯mg L-1, and holds promise for further preclinical development as a potent drug-delivery platform.
Subject(s)
Antineoplastic Agents , Cisplatin , Liposomes/chemistry , Phospholipids/chemistry , Drug Delivery SystemsABSTRACT
In this contribution we report the synthesis, characterization and in vitro anticancer activity of novel cyclometalated 4-phenylthiazole-derived ruthenium(II) (2a-e) and osmium(II) (3a-e) complexes. Formation and sufficient purity of the complexes were unambigiously confirmed by 1H-, 13C- and 2D-NMR techniques, X-ray diffractometry, HRMS and elemental analysis. The binding preferences of these cyclometalates to selected amino acids and to DNA models including G-quadruplex structures were analyzed. Additionally, their stability and behaviour in aqueous solutions was determined by UV-Vis spectroscopy. Their cellular accumulation, their ability of inducing apoptosis, as well as their interference in the cell cycle were studied in SW480 colon cancer cells. The anticancer potencies were investigated in three human cancer cell lines and revealed IC50 values in the low micromolar range, in contrast to the biologically inactive ligands.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Ruthenium , Humans , Molecular Structure , Models, Molecular , Cell Line, Tumor , Antineoplastic Agents/chemistry , Cell Cycle , Ruthenium/pharmacology , Ruthenium/chemistry , Coordination Complexes/chemistryABSTRACT
While platinum-based chemotherapeutic agents have established themselves as indispensable components of anticancer therapy, they are accompanied by a variety of side effects and the rapid occurrence of drug resistance. A promising strategy to address these challenges is the use of platinum(iv) prodrugs, which remain inert until they reach the tumor tissue, thereby mitigating detrimental effects on healthy cells. Typically, platinum drugs are part of combination therapy settings. Consequently, a very elegant strategy is the development of platinum(iv) prodrugs bearing a second, clinically relevant therapeutic in axial position. In the present study, we focused on gemcitabine as an approved antimetabolite, which is highly synergistic with platinum drugs. In addition, to increase plasma half-life and facilitate tumor-specific accumulation, an albumin-binding maleimide moiety was attached. Our investigations revealed that maleimide-cisplatin(iv)-gemcitabine complexes cannot carry sufficient amounts of gemcitabine to induce a significant effect in vivo. Consequently, we designed a carboplatin(iv) analog, that can be applied at much higher doses. Remarkably, this novel analog demonstrated impressive in vivo results, characterized by significant improvements in overall survival. Notably, these encouraging results could also be transferred to an in vivo xenograft model with acquired gemcitabine resistance, indicating the high potential of this approach.
ABSTRACT
As cancer cells exhibit an increased uptake of iron, targeting the interaction with iron has become a straightforward strategy in the fight against cancer. This work comprehensively characterizes the chemical properties of 6-methyl-3-{(2E)-2-[1-(2-pyridinyl)ethylidene]hydrazino}-5H-[1,2,4]triazino[5,6-b]indole (VLX600), a clinically investigated iron chelator, in solution. Its protonation processes, lipophilicity, and membrane permeability as well as its complexation with essential metal ions were investigated using UV-visible, electron paramagnetic resonance, and NMR spectroscopic and computational methods. Formation constants revealed the following order of metal binding affinity at pH 7.4: Cu(II) > Fe(II) > Zn(II). The structures of VLX600 (denoted as HL) and the coordination modes in its metal complexes [Cu(II)(LH)Cl2], [Cu(II)(L)(CH3OH)Cl], [Zn(II)(LH)Cl2], and [Fe(II)(LH)2](NO3)2 were elucidated by single-crystal X-ray diffraction. Redox properties of the iron complexes characterized by cyclic voltammetry showed strong preference of VLX600 toward Fe(II) over Fe(III). In vitro cytotoxicity of VLX600 was determined in six different human cancer cell lines, with IC50 values ranging from 0.039 to 0.51 µM. Premixing VLX600 with Fe(III), Zn(II), and Cu(II) salts in stoichiometric ratios had a rather little effect overall, thus neither potentiating nor abolishing cytotoxicity. Together, although clinically investigated as an iron chelator, this is the first comprehensive solution study of VLX600 and its interaction with physiologically essential metal ions.
Subject(s)
Coordination Complexes , Ferric Compounds , Hydrazones , Triazoles , Humans , Copper/pharmacology , Copper/chemistry , Metals/chemistry , Iron/chemistry , Ions , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Iron Chelating Agents/pharmacology , Ferrous CompoundsABSTRACT
The first-in-class ruthenium-based chemotherapeutic agent BOLD-100 (formerly IT-139, NKP-1339, KP1339) is currently the subject of clinical evaluation for the treatment of gastric, pancreatic, colorectal and bile duct cancer. A radiolabeled version of the compound could present a helpful diagnostic tool. Thus, this study investigated the pharmacokinetics of BOLD-100 in more detail to facilitate the stratification of patients for the therapy. The synthesis of [103Ru]BOLD-100, radiolabeled with carrier added (c.a.) ruthenium-103, was established and the product was characterized by HPLC and UV/Vis spectroscopy. In order to compare the radiolabeled and non-radioactive versions of BOLD-100, both complexes were fully evaluated in vitro and in vivo. The cytotoxicity of the compounds was determined in two colon carcinoma cell lines (HCT116 and CT26) and biodistribution studies were performed in Balb/c mice bearing CT26 allografts over a time period of 72 h post injection (p.i.). We report herein preclinical cytotoxicity and pharmacokinetic data for BOLD-100, which were found to be identical to those of its radiolabeled analog [103Ru]BOLD-100.
ABSTRACT
The reaction of (1R,2R)-(cyclohexane-1,2-diamine)dichloridoplatinum(II) with maleic acid unexpectedly resulted in the formation of an organometallic platinum(II) complex featuring a C,O-coordinating ligand. Additionally, a small series of close derivatives with increasing lipophilicity was synthesized. All complexes were fully characterized by multinuclear one- and two-dimensional (1H, 13C, 15N, and 195Pt) NMR spectroscopy, high resolution mass spectrometry, and in one case by X-ray diffraction. The lipophilicity and the impact on the DNA secondary structure as well as the cytotoxic properties in three human cancer cell lines (A549, SW480, and CH1/PA-1) were investigated. Unexpectedly, no clear-cut trend in cytotoxicity was observed with increasing lipophilicity. Also unexpectedly, the complexes showed only a low potential to inhibit cancer cell growth and no sign of interaction with DNA, in sharp contrast to the parent drug oxaliplatin, which seems to be caused by the low reactivity of the investigated compounds.
Subject(s)
Antineoplastic Agents , Platinum , Humans , Platinum/chemistry , Organoplatinum Compounds/chemistry , Cell Line, Tumor , Antineoplastic Agents/chemistry , DNA , Drug Screening Assays, AntitumorABSTRACT
Nano-sized ion exchangers (NIEs) combine the properties of common bulk ion-exchange polymers with the unique advantages of downsizing into nanoparticulate matter. In particular, being by nature milti-charged ions exchangers, NIEs possess high reactivity and stability in suspensions. This brief review provides an introduction to the emerging landscape of various NIE materials and summarizes their actual and potential applications. Special attention is paid to the different methods of NIE fabrication and studying their ion-exchange behavior. Critically discussed are different examples of using NIEs in chemical analysis, e.g., as solid-phase extraction materials, ion chromatography separating phases, modifiers for capillary electrophoresis, etc., and in industry (fuel cells, catalysis, water softening). Also brought into focus is the potential of NIEs for controlled drug and contrast agent delivery.
ABSTRACT
The leading first-in-class ruthenium-complex BOLD-100 currently undergoes clinical phase-II anticancer evaluation. Recently, BOLD-100 is identified as anti-Warburg compound. The present study shows that also deregulated lipid metabolism parameters characterize acquired BOLD-100-resistant colon and pancreatic carcinoma cells. Acute BOLD-100 treatment reduces lipid droplet contents of BOLD-100-sensitive but not -resistant cells. Despite enhanced glycolysis fueling lipid accumulation, BOLD-100-resistant cells reveal diminished lactate secretion based on monocarboxylate transporter 1 (MCT1) loss mediated by a frame-shift mutation in the MCT1 chaperone basigin. Glycolysis and lipid catabolism converge in the production of protein/histone acetylation substrate acetyl-coenzymeA (CoA). Mass spectrometric and nuclear magnetic resonance analyses uncover spontaneous cell-free BOLD-100-CoA adduct formation suggesting acetyl-CoA depletion as mechanism bridging BOLD-100-induced lipid metabolism alterations and histone acetylation-mediated gene expression deregulation. Indeed, BOLD-100 treatment decreases histone acetylation selectively in sensitive cells. Pharmacological targeting confirms histone de-acetylation as central mode-of-action of BOLD-100 and metabolic programs stabilizing histone acetylation as relevant Achilles' heel of acquired BOLD-100-resistant cell and xenograft models. Accordingly, histone gene expression changes also predict intrinsic BOLD-100 responsiveness. Summarizing, BOLD-100 is identified as epigenetically active substance acting via targeting several onco-metabolic pathways. Identification of the lipid metabolism as driver of acquired BOLD-100 resistance opens novel strategies to tackle therapy failure.
Subject(s)
Antineoplastic Agents , Histones , Organometallic Compounds , Humans , Histones/metabolism , Lipid Metabolism , Acetylation , Acetyl Coenzyme A/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , LipidsABSTRACT
Platinum(IV) prodrugs are highly interesting alternatives to platinum(II) anticancer therapeutics due to their increased tumor selectivity and reduced side effects. In contrast to the established theory, we recently observed that the equatorial ligand(s) of e.g. oxaliplatin(IV) complexes can be hydrolyzed with formation of [(DACH)Pt(OHeq )2 (OAcax )2 ]. In the work presented here, we investigated the reactivity and synthetic usability of this complex to be exploited as a precursor for the development of novel platinum(IV) complexes, not able to be synthesized by conventional protocols. Indeed, we could substitute the equatorial hydroxido ligand(s) e.g. by one or two monodentate biotin ligands (which would be oxidized under standard methods). The formed complexes turned out to be very stable with slow ligand release after reduction, ideal for long-circulating tumor-targeting strategies. Therefore, two platinum(IV) complexes with equatorial maleimides, capable of exploiting serum albumin as a natural nanocarrier, were synthesized as well. The complexes showed massively prolonged plasma half-life and distinctly improved anticancer activity in vivo compared to oxaliplatin. Taken together, the newly developed synthetic platform allows the simple and specific insertion of equatorial ligands into platinum(IV) complexes. This will enable the attachment of three different (bioactive) moieties generating targeted triple-action platinum(IV) prodrugs within one single platinum complex.
Subject(s)
Antineoplastic Agents , Neoplasms , Prodrugs , Humans , Platinum , Oxaliplatin , Organoplatinum Compounds , Ligands , Cell Line, TumorABSTRACT
The task-specific ionic liquid trihexyltetradecylphosphonium 3-hydroxy-2-naphthoate has been described as a suitable extraction agent for numerous metals from aqueous phases, while additionally providing reduced leaching into the used matrices. Here, we investigate the extraction properties of this extractant towards rare earth elements. Of these, La, Ce, Nd, Ho und Lu were chosen as a representative mix of light and heavy elements. Single- as well as double-element extractions were carried out under varying conditions regarding pH, temperature and extraction time. The highest extraction efficacies and minimalized precipitation of the respective metals were recorded at a pH of 2.5. Satisfactory extraction efficacies (>80%) were achieved already after 6 hours for the elements Ce, Nd and Lu in single-element extraction experiments at room temperature. Increased temperatures improved the extraction efficacy for Nd from 36% at 20 °C to 80% at 30 °C after only 2 hours. Surprisingly, this effect was not observed for Ce in single-element experiments. In double-element feed solutions containing both Ce and Nd, however, the time-dependant extraction efficacy of Ce mirrored that of Nd. The pH in the aqueous extraction matrix changed during the extraction, showing a positive correlation with the extraction efficacy and revealing the extraction mechanism to be via anion exchange. The leaching was in good agreement with literature values, showed a positive correlation with extraction efficacies, and ranged for all extractions between 0.8 and 1.2%. Remarkably, increasing the temperature from 20 °C to 30 °C had no significant influence on leaching.
ABSTRACT
The bottom-up synthesis of plasmonic NHC@CuNPs from common starting reagents, via the formation of the synthetically accessible NHC-Cu(I)-Br complex and its reduction by NH3·BH3 is reported. The resulting NHC@CuNPs have been characterized in detail by XPS, TEM and NMR spectroscopy. The stability of NHC@CuNPs was investigated under both inert and ambient conditions using UV-Vis analysis. While the NHC@CuNPs are stable under inert conditions for an extended period of time, the NPs oxidize under air to form CuxO with concomitant release of the stabilizing NHC ligand.
ABSTRACT
Platinum(iv) prodrugs are a promising class of anticancer agents designed to overcome the limitations of conventional platinum(ii) therapeutics. In this work, we present oxaliplatin(iv)-based complexes, which upon reduction, release acetylsalicylic acid (aspirin), known for its antitumor activity against colon cancer and currently investigated in combination with oxaliplatin in a phase III clinical study. Comparison with a recently reported cisplatin analog (asplatin) revealed a massive increase in reduction stability for the oxaliplatin complex in mouse serum. This was in line with the cell culture data indicating the desired prodrug properties for the newly synthesized complex. For in vivo studies, a new derivative containing an albumin-binding maleimide unit was synthesized. Indeed, distinctly longer plasma half-life as well as higher tumor accumulation in comparison to asplatin and oxaliplatin were observed, also leading to significantly higher antitumor activity and overall survival of CT26 tumor-bearing mice.
ABSTRACT
Thiosemicarbazones (TSCs) are a class of biologically active compounds with promising anticancer activity. Their typical mechanism, especially of the clinically far developed representative Triapine, is chelation of iron (Fe), with the Fe-containing enzyme ribonucleotide reductase as primary intracellular target. However, for the subclass of terminally disubstituted, nanomolar-active derivatives like Dp44mT and Me2NNMe2, recent findings suggest that the chelation, stability, and reduction properties of the copper(II) (Cu) complexes are essential for their modes of action. Consequently, it is important to elucidate whether blood serum Cu(II) is a potential metal source for these TSCs. To gain more insights, the interaction of Triapine, Dp44mT or Me2NNMe2 with purified human serum albumin (HSA) as the main pool of labile Cu(II) was investigated by UV-vis and electron paramagnetic resonance measurements. Subsequently, a size-exclusion chromatography inductively coupled plasma mass spectrometry method for the differentiation of Cu species in serum was developed, especially separating the non-labile Cu enzyme ceruloplasmin from HSA. The results indicate that the TSCs specifically chelate copper from the N-terminal Cu-binding site of HSA. Furthermore, the Cu(II)-TSC complexes were shown to form ternary HSA conjugates, most likely via histidine. Noteworthy, Fe-chelation from transferrin was not overserved, even not for Triapine. In summary, the labile Cu pool of HSA is a potential source for Cu-TSC complex formation and, consequently, distinctly influences the anticancer activity and pharmacological behavior of TSCs.
Subject(s)
Antineoplastic Agents , Thiosemicarbazones , Humans , Serum Albumin, Human , Copper/chemistry , Thiosemicarbazones/pharmacology , Thiosemicarbazones/chemistry , Chelating Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistryABSTRACT
Quaternary ammonium palmitoyl glycol chitosan (GCPQ) has already shown beneficial drug delivery properties and has been studied as a carrier for anticancer agents. Consequently, we synthesised cytotoxic platinum(IV) conjugates of cisplatin, carboplatin and oxaliplatin by coupling via amide bonds to five GCPQ polymers differing in their degree of palmitoylation and quaternisation. The conjugates were characterised by 1H and 195Pt NMR spectroscopy as well as inductively coupled plasma mass spectrometry (ICP-MS), the latter to determine the amount of platinum(IV) units per GCPQ polymer. Cytotoxicity was evaluated by the MTT assay in three human cancer cell lines (A549, non-small-cell lung carcinoma; CH1/PA-1, ovarian teratocarcinoma; SW480, colon adenocarcinoma). All conjugates displayed a high increase in their cytotoxic activity by factors of up to 286 times compared to their corresponding platinum(IV) complexes and mostly outperformed the respective platinum(II) counterparts by factors of up to 20 times, also taking into account the respective loading of platinum(IV) units per GCPQ polymer. Finally, a biodistribution experiment was performed with an oxaliplatin-based GCPQ conjugate in non-tumour-bearing BALB/c mice revealing an increased accumulation in lung tissue. These findings open promising opportunities for further tumouricidal activity studies especially focusing on lung tissue.
ABSTRACT
The synthesis, characterization and biological activity of tungstenocenes with varying biologically active (O,O-), (S,O-) and (N,O-) chelates are described. Complexes were characterized by 1H and 13C NMR, elemental analysis, ESI-mass spectrometry, FT-IR spectroscopy and X-ray diffraction analysis. The aqueous stability was studied by UV/Vis spectroscopy and the WIV to WV process by cyclic voltammetry. The cytotoxicity was determined by the MTT assay in A549, CH1/PA-1 and SW480 cancer cells as well as in IMR-90 human fibroblasts. Extensive biological evaluation was performed in three other human cancer cell lines (HCT116, HT29 and MCF-7) in monolayer and multicellular tumor spheroid cultures to better understand the mode of action. Lead compounds showed promising in vitro anticancer activity in all cancer cell lines. Further studies yielded important insights into apoptosis induction, ROS generation, different patterns in metal distribution (detected by LA-ICP-TOF-MS), changes in KI67 (proliferation marker) expression and DNA interactions. The results based on qualitative and quantitative research designs show that complexes containing (S,O-) chelates are more active than their (O,O-) and (N,O-) counterparts. The most striking results in spheroid models are the high antiproliferative capacity and the different distribution pattern of two complexes differing only in a W-S or W-O bond.
ABSTRACT
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.
ABSTRACT
In the last decades, inflammation has been recognized as being closely connected to cancer, and joint strategies encompassing chemotherapeutic and anti-inflammatory agents have been extensively studied. In this work, a series of novel cisplatin and oxaliplatin-based Pt(IV) complexes comprising non-steroidal anti-inflammatory drugs (NSAIDs) and their carboxyl ester analogues as axial moieties were synthesized. Several of the cisplatin-based Pt(IV) complexes 22-30 showed increased cytotoxicity in the human cancer cell lines CH1/PA-1, SW480 and A549 compared to the Pt(II) drug. For the most potent complex 26, comprising two aceclofenac (AFC) moieties, the formation of Pt(II)-9-methylguanine (9-MeG) adducts after activation with ascorbic acid (AsA) was proven. Additionally, a significant inhibition of cyclooxygenase (COX) activity and prostaglandin E2 (PGE2) production was observed, as well as increased cellular accumulation, depolarization of mitochondrial membranes, and strong proapoptotic potencies in SW480 cells. Overall, these systematic effects shown in vitro confer 26 as a potential anticancer agent combined with anti-inflammatory properties.
Subject(s)
Cisplatin , Prodrugs , Humans , Cisplatin/pharmacology , Prodrugs/pharmacology , Platinum/pharmacology , Prostaglandin-Endoperoxide Synthases , Cell Line, Tumor , Anti-Inflammatory Agents, Non-Steroidal/pharmacologyABSTRACT
An article was published in the journal "Current Medicinal Chemistry," Volume 12, No. 18, 2005, pp: 2075-2094 [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: http://www.benthamscience.com/article/5874.
ABSTRACT
Based on their drug delivery properties and activity against tumors, we combined PAMAM dendrimers with various platinum(IV) complexes in order to provide an improved approach of anticancer treatment. Platinum(IV) complexes were linked to terminal NH2 moieties of PAMAM dendrimers of generation 2 (G2) and 4 (G4) via amide bonds. Conjugates were characterized by 1H and 195Pt NMR spectroscopy, ICP-MS and in representative cases by pseudo-2D diffusion-ordered NMR spectroscopy. Additionally, the reduction behavior of conjugates in comparison to corresponding platinum(IV) complexes was investigated, showing a faster reduction of conjugates. Cytotoxicity was evaluated via the MTT assay in human cell lines (A549, CH1/PA-1, SW480), revealing IC50 values in the low micromolar to high picomolar range. The synergistic combination of PAMAM dendrimers and platinum(IV) complexes resulted in up to 200 times increased cytotoxic activity of conjugates in consideration of the loaded platinum(IV) units compared to their platinum(IV) counterparts. The lowest IC50 value of 780 ± 260 pM in the CH1/PA-1 cancer cell line was detected for an oxaliplatin-based G4 PAMAM dendrimer conjugate. Finally, in vivo experiments of a cisplatin-based G4 PAMAM dendrimer conjugate were performed based on the best toxicological profile. A maximum tumor growth inhibition effect of 65.6% compared to 47.6% for cisplatin was observed as well as a trend of prolonged animal survival.
ABSTRACT
BACKGROUND: Nanotechnology offers many benefits in the globally important field of food production and human nutrition, particularly by implementing agricultural nanoproducts. Of these, edible plant fertilizers enriched with nanosized forms of essential metals, Mn and Fe, are growing in importance with the advantages of enhanced action on plant roots. SCOPE AND APPROACH: This review focuses on the importance of tracking the bioaccumulation and biodistribution of these pertinent nanofertilizers. An emphasis is given to the critical analysis of the state-of-the-art analytical strategies to examine the Mn and Fe nanoparticles in edible plant systems as well as to shedding light on the vast gap in the methodologies dedicated to the speciation, in vitro simulation, and safety testing of these promising nanomaterials. Also provided are guidances for the food chemists and technologists on the lights and shadows of particular analytical approaches as a matter of authors' expertise as analytical chemists. KEY FINDINGS AND CONCLUSIONS: While the use of nanotechnology in agriculture seems to be growing increasingly, there is still a lack of analytical methodologies capable of investigating novel Mn- and Fe-based nanomaterials as potential fertilizers. Only the advent of reliable analytical tools in the field could bridge the gaps in our knowledge about processes in which those materials participate in the plant systems and their effects on crop production and quality of the produced food.