High Cytotoxic Properties Research Articles

An alternative hybrid lipid nanosystem combining cytotoxic and magnetic properties as a tool to potentiate antitumor effect of 5-fluorouracil

AimsColorectal cancer is the third most frequent type of cancer and the second leading cause of cancer-related deaths worldwide. The majority of cases are diagnosed at a later stage, leading to the need for more aggressive treatments such as chemotherapy. 5-Fluorouracil (5-FU), known for its high cytotoxic properties has emerged as a chemotherapeutic agent. However, it presents several drawbacks such as lack of specificity and short half-life. To reduce these drawbacks, several strategies have been designed namely chemical modification or association to drug delivery systems. Materials and methodsCurrent research was focused on the design, physicochemical characterization and in vitro evaluation of a lipid-based system loaded with 5-FU. Furthermore, aiming to maximize preferential targeting and release at tumour sites, a hybrid lipid-based system, combining both therapeutic and magnetic properties was developed and validated. For this purpose, liposomes co-loaded with 5-FU and iron oxide (II, III) nanoparticles were accomplished. Key findingsThe characterization of the developed nanoformulation was performed in terms of incorporation parameters, mean size and surface charge. In vitro studies assessed in a murine colon cancer cell line confirmed that 5-FU antiproliferative activity was preserved after incorporation in liposomes. In same model, iron oxide (II, III) nanoparticles did not exhibit cytotoxic properties. Additionally, the presence of these nanoparticles was shown to confer magnetic properties to the liposomes, allowing them to respond to external magnetic fields. SignificanceOverall, a lipid nanosystem loading a chemotherapeutic agent displaying magnetic characteristics was successfully designed and physicochemically characterized, for further in vivo applications.

Fluorometric carbon-dots nanosensor for the detection of hexavalent chromium in water

The detection of trace residues of hexavalent chromium (Cr(VI)) in water is crucial for assessing ecological hazards due to its high cytotoxicity and carcinogenic properties. In this study, we have developed a selective and sensitive fluorescent sensor utilizing carbon dots (CDs) with an average size of 2 nm. The CDs is synthesized via a low-cost and facile one-step method without the need for additional heteroatoms. The CDs-based sensor exhibits superior selectivity, even in the presence of environmentally relevant cations, and can detect Cr(VI) over a concentration range of 1–1000 μM (with a linear range of 1 – 125 μM and R2≥ 0.998). The detection limit of the sensor is found to be 0.6 μM (equivalent to 31 μg L−1), which is below the value of 50 μg L−1 for drinking water guide-lined by the World Health Organization. This performance can be attributed to the combination of inner filter effect with the static quenching effect between the as-synthesized CDs and Cr(VI). Furthermore, we demonstrate the applicability of the CDs-based sensor for Cr(VI) detection in real samples of drinking water and tap water.

Dual receptor specific nanoparticles targeting EGFR and PD-L1 for enhanced delivery of docetaxel in cancer therapy

Dual-receptor targeted (DRT) nanoparticles which contain two distinct targeting agents may exhibit higher cell selectivity, cellular uptake, and cytotoxicity toward cancer cells than single-ligand targeted nanoparticle systems without additional functionality. The purpose of this study is to prepare DRT poly(lactic-co-glycolic acid) (PLGA) nanoparticles for targeting the delivery of docetaxel (DTX) to the EGFR and PD-L1 receptor positive cancer cells such as human glioblastoma multiform (U87-MG) and human non-small cell lung cancer (A549) cell lines. Anti-EGFR and anti-PD-L1 antibody were decorated on DTX loaded PLGA nanoparticles to prepare DRT-DTX-PLGA via. single emulsion solvent evaporation method. Physicochemical characterizations of DRT-DTX-PLGA, such as particle size, zeta-potential, morphology, and in vitro DTX release were also evaluated. The average particle size of DRT-DTX-PLGA was 124.2 ± 1.1 nm with spherical and smooth morphology. In the cellular uptake study, the DRT-DTX-PLGA endocytosed by the U87-MG and A549 cells was single ligand targeting nanoparticle. From the in vitro cell cytotoxicity, and apoptosis studies, we reported that DRT-DTX-PLGA exhibited high cytotoxicity and enhanced the apoptotic cell compared to the single ligand-targeted nanoparticle. The dual receptor mediated endocytosis of DRT-DTX-PLGA showed a high binding affinity effect that leads to high intracellular DTX concentration and exhibited high cytotoxic properties. Thus, DRT nanoparticles have the potential to improve cancer therapy by providing selectivity over single-ligand-targeted nanoparticles.

A PET Fluorescent Probe for Dynamic Pd2+ Tracking with Imaging Applications in the Nanofiber and Living Cells.

Constructed on the moiety of a lactam screw ring, a near-infrared fluorescent probe RCya for Pd2+ was designed under the PET mechanism and synthesized by incorporating 2,4-dihydroxybenzaldehyde as the recognition group. Dynamic detection of aqueous Pd2+ by the probe RCya could be accomplished through ion competition, linear response, fluorescence-pH/time stabilities, and other optical tests. Moreover, the high selectivity, low cytotoxicity, cell permeability, and lysosome accumulation properties of RCya enabled the imaging applications on solid-state RCya-PAN composite nanofibers and in living cells. The recognition mechanism of probe RCya toward Pd2+ was further studied through simulation calculation and MS analysis.

A circulating subset of iNKT cells mediates antitumor and antiviral immunity.

Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244-CXCR6-), C1 (CD244-CXCR6+), or C2 (CD244+CXCR6+) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell-like features, whereas C1 iNKT cells showed more T cell-like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244+CXCR6+ iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell-like properties distinct from conventional tissue-resident iNKT cells.

Thrombin receptor protease-activated receptor 1 (PAR1) related cytotoxic CD8+ T cell activity is associated with atrial myopathy and pro-inflammatory immune response in early atrial fibrillation

Abstract Background and aims Cytotoxic CD8+ T cells mediate myocardial damage in patients with virus induced myocarditis, plaque erosion during acute coronary syndrome, and promote adverse post-ischemic cardiac remodeling. There is emerging evidence to support a link between inflammation and atrial fibrillation (AF). Protease-activated receptor 1 (PAR1) is the thrombin receptor expressed on platelets, but it is also expressed in endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and CD8+ T cells. The role of CD8+ T cells and PAR1 in atrial myopathy and early AF have not been studied. Methods In 80 non-anticoagulated patients with a first documented episode of AF, and 20 control subjects without AF but with a comparable cardiovascular risk profile (e.g. SCORE2, CHA2DS2-VASc, p>0.05), we studied PAR1-related cytotoxic T cell activity in the first hours (up to 24 h) of AF clinical manifestation. The Apolipoprotein E–knock out (ApoEko) mouse is a commonly used model of metabolic syndrome that develops atrial myopathy (structural correlate of AF). ApoEko male mice (Apoetm1Unc with a C57BL/6 genetic background) were fed for six weeks with a standard chew, western-type diet (high fat and high sucrose = WD) ± the specific PAR1 inhibitor vorapaxar. Results High levels of circulating, activated CD8+ T cells (CD8+CD57+ T cells with pro-inflammatory and high cytotoxic properties) were present in patients with early AF (flow cytometry). Stimulation of cytotoxic T cells, that expressed the thrombin receptor PAR1, that were isolated from patients with new onset of AF, released pro-inflammatory cytokines (e.g. IFN-γ, TNF-α). Enhanced cytotoxic activity of CD8+ T cells was suggested by elevated plasma levels of effector molecules (e.g. granulysin and granzyme). In ApoEko mice fed a WD, atrial myopathy as the structural correlate for AF, was paralleled by increased expression of effector molecules that were associated with CD8+ T cell activity (like perforin, granzyme A, granzyme B, IFN-γ). Cytotoxic T cell activity disrupted the release of the potective atrial natriuretic peptide, ANP, and increased signaling pathways associated with atrial fibrosis (e.g. TGF-β, cTGF, TGF-β receptor). The specific PAR1 inhibitor, vorapaxar, reduced inflammatory T cell activity, transcription of fibrotic mediators, and reconstituted ANP secretion in atria of ApoEko mice. Conclusions Targeting the FXa/FIIa-PAR1-CD8+ axis might be a promising approach to reduce atrial fibrosis and inflammation. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BIH Charité Clinician Scientist Program

The Medicinal Halophyte Frankenia laevis L. (Sea Heath) Has In Vitro Antioxidant Activity, α-Glucosidase Inhibition, and Cytotoxicity towards Hepatocarcinoma Cells.

This work explored the medicinal halophyte Frankenia laevis L. (sea heath) as a potential source of bioactive natural products. In this sense, methanol and dichloromethane extracts were prepared from aerial organs containing flowers, leaves and stems, and were profiled for their chemical composition using high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS/MS). The extracts were evaluated for their in vitro antioxidant capacity using five complementary methods: enzyme inhibitory effects on enzymes related with neurodegeneration (acetyl (AChE) and butyrylcholinesterase (BuChE)), Type 2 diabetes (α-glucosidase and α-amylase), hyperpigmentation/food oxidation (tyrosinase), and cytotoxicity towards human hepatocarcinoma (HepG2) cells. Fifty-one molecules were identified in the extracts, including several derivatives of phenolic acids, lignans and flavonoids, monoterpenes, and hydroxylated derivatives of linoleic acid. The methanol extract was effective in DPPH and ABTS radical scavenging (EC50 = 0.25 and 0.65 mg/mL, respectively), copper chelation (EC50 = 0.78 mg/mL), and iron reduction (EC50 = 0.51 mg/mL) activities, whereas the dichloromethane extract had high iron chelating ability (EC50 = 0.76 mg/mL). Both extracts showed the capacity to inhibit α-glucosidase, especially the dichloromethane (EC50 = 0.52 mg/mL). This extract also exerted a significant selective cytotoxicity towards HepG2 cells (EC50 = 52.1 μg/mL, SI > 1.9). In conclusion, extracts from the aerial parts of sea heath were shown to be a promising source of natural products for pharmaceutical and/or food additive applications due to their high antioxidant, anti-diabetic, and cytotoxic properties.

Carbon-Based Quantum Dots for Electrochemical Detection of Monoamine Neurotransmitters-Review.

Imbalance in the levels of monoamine neurotransmitters have manifested in severe health issues. Electrochemical sensors have been designed for their determination, with good sensitivity recorded. Carbon-based quantum dots have proven to be an important component of electrochemical sensors due to their high conductivity, low cytotoxicity and opto-electronic properties. The quest for more sensitive electrodes with cheaper materials led to the development of electrochemical sensors based on carbon-based quantum dots for the detection of neurotransmitters. The importance of monoamine neurotransmitters (NTs) and the good electrocatalytic activity of carbon and graphene quantum dots (CQDs and GQDs) make the review of the efforts made in the design of such sensors for monoamine NTs of huge necessity. The differences and the similarities between these two quantum dots are highlighted prior to a discussion of their application in electrochemical sensors over the last ten years. Compared to other monoamine NTs, dopamine (DA) was the most studied with GQDs and CQD-based electrochemical sensors.

Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX‐2 and PD‐L1

AbstractBreast cancer (BC) is one of the most common malignancies in women and often accompanied by inflammatory processes. Cyclooxygenase‐2 (COX‐2) plays a vital role in the progression of BC, correlating with the expression of programmed death‐ligand 1 (PD‐L1). Overexpression of PD‐L1 contributes to the immune escape of cancer cells, and its blockade would stimulate anticancer immunity. Two multispecific platinum(IV) complexes DNP and NP were prepared using non‐steroidal antiinflammatory drug naproxen (NPX) as axial ligand(s) to inhibit the BC cells. DNP exhibited high cytotoxicity and antiinflammatory properties superior over NP, cisplatin and NPX; moreover, it displayed potent antitumor activity and almost no general toxicity in mice bearing triple‐negative breast cancer (TNBC). Mechanistic studies revealed that DNP could downregulate the expression of COX‐2 and PD‐L1 in vitro and vivo, inhibit the secretion of prostaglandin, reduce the expression of BC‐associated protein BRD4 and phosphorylation of extracellular signal‐regulated kinases 1/2 (Erk1/2), and block the oncogene c‐Myc in BC cells. These findings demonstrate that DNP is capable of intervening in inflammatory, immune, and metastatic processes of BC, thus presenting a new mechanism of action for anticancer platinum(IV) complexes. The multispecificity offers a special superiority for DNP to treat TNBC by combining chemotherapy and immunotherapy in one molecule.

Multispecific Platinum(IV) Complex Deters Breast Cancer via Interposing Inflammation and Immunosuppression as an Inhibitor of COX-2 and PD-L1.

Breast cancer (BC) is one of the most common malignancies in women and often accompanied by inflammatory processes. Cyclooxygenase-2 (COX-2) plays a vital role in the progression of BC, correlating with the expression of programmed death-ligand 1 (PD-L1). Overexpression of PD-L1 contributes to the immune escape of cancer cells, and its blockade would stimulate anticancer immunity. Two multispecific platinum(IV) complexes DNP and NP were prepared using non-steroidal antiinflammatory drug naproxen (NPX) as axial ligand(s) to inhibit the BC cells. DNP exhibited high cytotoxicity and antiinflammatory properties superior over NP, cisplatin and NPX; moreover, it displayed potent antitumor activity and almost no general toxicity in mice bearing triple-negative breast cancer (TNBC). Mechanistic studies revealed that DNP could downregulate the expression of COX-2 and PD-L1 in vitro and vivo, inhibit the secretion of prostaglandin, reduce the expression of BC-associated protein BRD4 and phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2), and block the oncogene c-Myc in BC cells. These findings demonstrate that DNP is capable of intervening in inflammatory, immune, and metastatic processes of BC, thus presenting a new mechanism of action for anticancer platinum(IV) complexes. The multispecificity offers a special superiority for DNP to treat TNBC by combining chemotherapy and immunotherapy in one molecule.

Cytotoxic effects, microbiological analysis and inhibitory properties on carbonic anhydrase isozyme activities of 2-hydroxy-5-methoxyacetophenone thiosemicarbazone and its Cu(II), Co(II), Zn(II) and Mn(II) complexes

Metal complexes of thiosemicarbazones have been receiving considerable attention in biological applications such as antimicrobial and anticancer therapies. In this work, Co(II), Zn(II) and Mn(II) complexes of 2-hydroxy-5-methoxyacetophenone thiosemicarbazone (HMAT) were synthesized for the first time and characterized by EPR, FT-IR, NMR, UV–Vis spectroscopies, TG/DSC and elemental analysis. X-ray powder diffraction analysis was carried out for Zn(II) complex. HMAT and its Cu(II), Co(II), Zn(II) and Mn(II) complexes were tested as enzyme inhibitory agents. All compounds are effective inhibitor of cytosolic carbonic anhydrase I and II isoforms (hCA I and II) enzymes. IC50 values of HMAT and its Cu(II), Co(II), Zn(II) and Mn(II) complexes were determined as 93.35, 324.46, 25.67, 1.06 and 22.36 μM for CA I isozyme and 99.02, 86.64, 57.76, 10.34 and 36.48 μM for CA II isozyme, respectively. The evaluation of potential cytotoxic effects of the compounds was performed against normal epithelial breast mammary gland CRL-4010, estrogen-positive low metastatic MCF-7 and triple negative highly metastatic MDA-MB-231 breast adenocarcinoma cell lines by MTT assay. The results showed that the tested metal complexes have high cytotoxic effects than their ligand molecule. In particular, the Cu(II) complex displayed preciously high cytotoxic properties different from the others. Given these facts, the Cu(II) complex could be debated as potential chemotherapeutic molecule against drug-resistant breast cancer cells. Minimum inhibitory concentrations of the compounds against the test organisms were also detected for the microbiological analysis.

Fluorescence Imaging of Mitochondria with Three Different Sets of Signals Based on Fluorene Cation Fluorescent Probe.

Herein, we develop a novel mitochondria-targetable fluorescence probe (FVPI) based on fluorene cation derivative. This mitochondria-targetable fluorescence probe exhibits large Stokes shift in various solutions. In addition, FVPI displays numerous advantages, including high photostability, low cytotoxicity, and two-photon properties. View of the above features, FVPI is successfully capable of imaging mitochondria in biological systems with three different sets of signals. This finding will provide a new platform for the constructing mitochondria-targetable fluorescent probes with excellent optical properties.

Disaccharides obtained from carrageenans as potential antitumor agents

Carrageenans are sulfated galactans found in certain red seaweeds with proven biological activities. In this work, we have prepared purified native and degraded κ-, ι-; and λ-carrageenans, including the disaccharides (carrabioses) and disaccharide-alditols (carrabiitols) from seaweed extracts as potential antitumor compounds and identified the active principle of the cytotoxic and potential antitumor properties of these compounds. Both κ and ι-carrageenan, as well as carrageenan oligosaccharides showed cytotoxic effect over LM2 tumor cells. Characterized disaccharides (carrabioses) and the reduced product carrabiitols, were also tested. Only carrabioses were cytotoxic, and among them, κ-carrabiose was the most effective, showing high cytotoxic properties, killing the cells through an apoptotic pathway. In addition, the cells surviving treatment with κ-carrabiose, showed a decreased metastatic ability in vitro, together with a decreased cell-cell and cell-matrix interactions, thus suggesting possible antitumor potential. Overall, our results indicate that most cytotoxic compounds derived from carrageenans have lower molecular weights and sulfate content. Potential applications of the results emerging from the present work include the use of disaccharide units such as carrabioses coupled to antineoplasics in order to improve its cytotoxicity and antimetastatic properties, and the use of ι-carrageenan as adjuvant or carrier in anticancer treatments.

Crystal Structures and Cytotoxicity of Four Silver(I)carboxylate Complexes with 1,2-Ethylenediamine Analogues

Four silver(I) compounds, [Ag(dapn)(dnbc)]n·1.5nH2O (1), [Ag(en)]n[Ag(dnbc)2]n·2nH2O (2), [Ag(en)]n[Ag(nbc)2]n·2nH2O (3) and [Ag(dapn)]n -(nbc)n·2nH2O (4), where dapn = 1,2-diaminopropane, dnbc = 3,5-dinitrobenzoate, en = 1,2-diaminoethane and nbc = 4-nitrobenzoate, have been synthesized and characterized by X-ray diffraction. The Ag(I) ions show T-shaped coordination geometry in compound 1 but linear coordination geometry in compounds 2, 3 and 4. There are ligand-unsupported Ag…Ag interaction in compounds 2 and 3 with Ag…Ag distance of 3.177 ~3.267 Å. All the four complexes showed high cytotoxicity properties.

Total Synthesis in Search of Potent Antibody-Drug Conjugate Payloads. From the Fundamentals to the Translational.

The emergence and evolution of antibody-drug conjugates (ADCs) as targeted cancer therapies in recent years is a living example of the "magic bullet" concept of Paul Ehrlich, introduced by him more than a century ago. Consisting of three components, the antibody serving as the delivery system, the payload drug that kills the cancer cell, and the chemical linker through which the payload is attached to the antibody, ADCs represent a currently hotly pursued paradigm of targeted cancer therapies. While the needed monoclonal antibody falls in the domains of biology and biochemistry, the potent payload and the linker belong to the realm of chemistry. Naturally occurring molecules and their derivatives endowed with high cytotoxic properties have proven to be useful payloads for the first approved ADCs (i.e., Mylotarg, Adcetris, Kadcyla, and Besponsa). The latest approaches and intensifying activities in this new paradigm of cancer therapy demands a variety of payloads with different mechanisms of action in order to address the medical needs for the various types of cancers, challenging synthetic organic chemists to enrich the library of potential payloads. Total synthesis of natural and designed molecules not only provides a powerful avenue to replicate rare naturally occurring compounds in the laboratory but also offers a unique opportunity to rationally design and synthesize analogues thereof for biological evaluation and optimization of ADC payloads. In this Account, we describe our efforts in this area highlighting a number of total synthesis endeavors through which we rendered scarce naturally occurring molecules readily available for biological evaluations and, most importantly, employed the developed synthetic strategies and methods to construct, otherwise unavailable or difficult to reach, designed analogues of these molecules. Specifically, we summarize the total syntheses of natural and designed molecules of the calicheamicin, uncialamycin, tubulysin, trioxacarcin, epothilone, shishijimicin, namenamicin, thailanstatin, and disorazole families of compounds and demonstrate how these studies led to the discovery of analogues of higher potencies, yet some of them possessing lower complexities than their parent compounds as potential ADC payloads. The highlighted examples showcase the continuing impact of total synthesis of natural products and their analogues on modern medicine, including the so-called biologics and should prove useful and inspirational in advancing both the fields of total synthesis and biomedical research and the drug discovery and development process.

Amantagula Fruit (Carissa macrocarpa (Eckl.) A.DC.): Nutritional and Phytochemical Characterization.

Fruits are one of the most promising food matrices and they have been explored in the discovery of new natural and safer bioactive compounds. Carissa macrocarpa (Eckl.) A. DC. fruits are widely consumed in African countries for the preparation of traditional foodstuff, but also for their beneficially health effects. Thus, as the authors' best knowledge there are no studies on the chemical and bioactive characterization of these fruits. Therefore, fruits of C. macrocarpa from Tunisia were chemically characterized regarding their nutritional value and bioactive compounds. Furthermore, the hydroethanolic extract of these fruits was evaluated regarding its bioactive properties. The fruit powder sample showed high amounts of sugars and polyunsaturated fatty acids (PUFA). The organic acids and tocopherols' profiles revealed the presence of five organic acids and two tocopherol isoforms, being quinic acid and α-tocopherol the most abundant. The hydroethanolic extract of the fruits presented high antioxidant, cytotoxic, anti-inflammatory, and antibacterial properties, showing activity against all the bacterial strains studied, also inhibiting the cell growth of all the tested tumor cell lines, with the exception of HepG2, and did not reveal toxicity for the non-tumor cells PLP2. Therefore, the fruits of C. macrocarpa could be included in a daily basis diet as a source of high nutritional quality compounds with high bioactive potential.

Electrodeposition of amorphous Fe-Cr-Ni stainless steel alloy with high corrosion resistance, low cytotoxicity and soft magnetic properties

Electrodeposition of Fe-Cr-Ni alloy thin films with high corrosion resistance, low cytotoxicity and soft-magnetic properties is reported. Fe-Cr-Ni films with Cr contents from 5 wt% to 40 wt% were prepared by adjusting the current density during electrodeposition and the film properties were investigated. An excellent corrosion resistance was found in films with high Cr contents (≥30 wt%), where anodic polarization performance similar to those of AISI 304 and 316L stainless steels was observed in both acidic and biological media. Cell compatibility, measured by lactate dehydrogenase assay, demonstrated that electrodeposited Fe-Cr-Ni films exhibit low cytotoxicity, comparable to AISI 304 and 316L stainless steels. Unlike AISI 304 and AISI 316L, which are conventional austenite stainless steels, the electrodeposited Fe-Cr-Ni films were found to be amorphous. This leads to soft ferromagnetic characteristics, which are dependent on the alloy composition. The unique combination of excellent corrosion resistance, low cytotoxicity and tunable magnetic properties makes this material interesting for functional coatings and components in advanced biological and medical microsystems.

Methotrexate and epirubicin conjugates as potential antitumor drugs.

The use of hybrid molecules has become one of the most significant approaches in new cytotoxic drug design. This study describes synthesis and characterization of conjugates consisting of two well-known and characterized chemotherapeutic agents: methotrexate (MTX) and epirubicin (EPR). The synthesized conjugates combine two significant anticancer strategies: combinatory therapy and targeted therapy. These two drugs were chosen because they have different mechanisms of action, which can increase the anticancer effect of the obtained conjugates. MTX, which is a folic acid analog, has high cytotoxic properties and can serve as a targeting moiety that can reach folate receptors (FRs) overexpresing tumor cells. Combination of nonselective drugs such as EPR with MTX can increase the selectivity of the obtained conjugates, while maintaining the high cytotoxic properties. Conjugates were purified by RP-HPLC and the structure was investigated by MS and MS/MS methods. The effect of the conjugates on proliferation of LoVo, LoVo/Dx, MCF-7 and MV-4-11 human cancer cell lines was determined by SRB or MTT assay. The conjugation reaction results in the formation of monosubstituted (α, γ) and disubstituted MTX derivatives. In vitro proliferation data demonstrate that the conjugates synthesized in our study show lower cytotoxic properties than both chemotherapeutics used alone. Epirubicin cytotoxicity was not observed in obtained conjugates. Effective drugs release after internalization needs further investigation.

Primary and secondary metabolites of an European edible mushroom and its nutraceutical value: Suillus bellinii (Inzenga) Kuntze

In this work, we report the study on the composition in primary and secondary metabolites of the polar and less-polar fractions obtained from the fruiting bodies of Suillus bellinii (Inzenga) Kuntze collected from Central Italy. Thirteen compounds were identified through a series of classical chromatographic methods and through spectroscopic techniques (nuclear magnetic resonance (NMR) and mass spectrometry (MS)), namely suillin (1), ergosterol (2), glutamic acid (3), isoleucine (4), leucine (5), threonine (6), tyrosine (7), valine (8), D-mannitol (9), sucrose (10), D-sorbitol (11), fumaric acid (12) and alanine (13). These results allowed us to make specific considerations about the possible applications of this mushroom, which vary from medicine, due to the high cytotoxic and antitumor properties of suillin (1), to nutritional values, due to the presence of essential nutrients as amino acids and pre-vitamin D2 (ergosterol), together with low-calories sweeteners, confirming the close association between the identified components and the health-promoting properties of this species.

Antiproliferative properties and biomolecular interactions of three Pd(II) and Pt(II) complexes

Three Pd(II) and Pt(II) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands i.e. [Pd(DMEAImiPr)Cl2] (1) (DMEAImiPr, 2-(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine)ethan-1-dimethylamine), [Pd(DACH(ImiPr)2)Cl2] (2) (DACH(ImiPr)2, N,N′-(cyclohexane-1,2-diyl)bis(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine)) and [Pt(DMEAImiPr)Cl2] (3), are evaluated here as potential cytotoxic and anticancer agents. An acceptable solution behaviour was found for the three study compounds in terms of solubility and stability. Notably, the three metal complexes demonstrated moderate to high cytotoxic properties in selected cancer cell lines (liquid and solid tumor). To gain deeper mechanistic insight, the reactivity of the study complexes with model DNA oligos and protein molecules was investigated through spectrometric and spectroscopic methods; in both cases adduct formation was clearly documented by ESI-MS measurements. The binding of these metal complexes to calf thymus DNA (CT-DNA) was further examined by absorption (UV–Vis) and emission spectral studies (Ethidium bromide displacement studies, EtBr). Overall, the studied complexes 1–3 exhibited a remarkable DNA binding ability that might be linked to the observed cytotoxic effects. Interestingly our results revealed that DNA binding, as well as anticancer activity of 1–3 follows the order 2>3>1. The implications of these findings are discussed.