RESUMEN
Hydrogels are a popular class of biomaterial that are used in a number of commercial applications (e.g.; contact lenses, drug delivery, and prophylactics). Alginate-based tough hydrogel systems, interpenetrated with acrylamide, reportedly form both ionic and covalent cross-links, giving rise to their remarkable mechanical properties. In this work, we explore the nature, onset and extent of such hybrid bonding interactions between the complementary networks in a model double-network alginate-acrylamide system, using a host of characterisation techniques (e.g.; FTIR, Raman, UV-vis, and fluorescence spectroscopies), in a time-resolved manner. Further, due to the similarity of bonding effects across many such complementary, interpenetrating hydrogel networks, the broad bonding interactions and mechanisms observed during gelation in this model system, are thought to be commonly replicated across alginate-based and broader double-network hydrogels, where both physical and chemical bonding effects are present. Analytical techniques followed real-time bond formation, environmental changes and re-organisational processes that occurred. Experiments broadly identified two phases of reaction; phase I where covalent interaction and physical entanglements predominate, and; phase II where ionic cross-linking effects are dominant. Contrary to past reports, ionic cross-linking occurred more favourably via mannuronate blocks of the alginate chain, initially. Evolution of such bonding interactions was also correlated with the developing tensile and compressive properties. These structure-property findings provide mechanistic insights and future synthetic intervention routes to manipulate the chemo-physico-mechanical properties of dynamically-forming tough hydrogel structures according to need (i.e.; durability, biocompatibility, adhesion, etc.), allowing expansion to a broader range of more physically and/or environmentally demanding biomaterials applications.
RESUMEN
Novel demethylcantharidin-platinum (DMC-Pt) complexes have been found to have superior in vitro anticancer activity against a number of human colon cancer cell lines when compared with oxaliplatin. One complex where the DMC-Pt moiety was integrated with trans-R,R-diamino-cyclohexane (DACH), exhibited the most pronounced cytotoxicity. To ascertain the mechanistic contribution of the DMC component, microarray analysis was conducted to compare the effect of the novel (R,R-DACH)-Pt-(DMC) complex and oxaliplatin, on the gene expression of human colorectal cancer (HCT116) cells. The Affymetrix HG-U133A oligonucleotide microarray was used, and the data allowed for the discrimination of genes that were specifically affected by the DMC ligand. One hundred and forty-one genes were found to be up-regulated. Of these, 48 can be classified according to different cellular responses including DNA repair, DNA synthesis, cell adhesion, cell cycle regulation, mitotic spindle checkpoint and apoptosis/antiapoptosis. The DMC ligand is likely to have caused damage to DNA bases and/or strands, and nucleotide mismatch, as highlighted by the recruitment of the repairing genes from the BER, HR and MMR. Antiapoptotic genes such as survivin, BRCA1 and ITGB3BP were up-regulated, and it is proposed that the inherent defense mechanism of the cell may have been triggered, creating potential resistance to apoptosis. This study is the first to demonstrate the impact of the DMC ligand on the gene expression profile of HCT116 colon cancer cells and further substantiates its inclusion in the design of novel platinum-based anticancer complexes.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias del Colon/genética , Expresión Génica/efectos de los fármacos , Compuestos Organoplatinos/farmacología , Cantaridina/administración & dosificación , Cantaridina/análogos & derivados , Línea Celular Tumoral , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Compuestos de Platino/administración & dosificaciónRESUMEN
BACKGROUND: Quantum chemical methods and molecular mechanics approaches face a lot of challenges in drug metabolism study because of either insufficient accuracy, huge computational cost, or lack of clear molecular level pictures for building computational models. Low-cost QSAR methods can often be carried out, even though molecular level pictures are not well defined; however, they show difficulty in identifying the mechanisms of drug metabolism and delineating the effects of chemical structures on drug toxicity because a certain amount of molecular descriptors are difficult to be interpreted. OBJECTIVE: In order to make a breakthrough of QSAR, mechanistically interpretable molecular descriptors were used to correlate with biological activity to establish structure-activity plots. The biological activity is the lethality of anthracycline anticancer antibiotics denoted as log LD50. The mechanistically interpretable molecular descriptors include electrophilicity and the mathematical function in the London formula for dispersion interaction. METHOD: The descriptors were calculated using quantum chemical methods. RESULTS: The plots for electrophilicity, which is interpreted as redox reactivity of anthracyclines, can describe oxidative degradation for detoxification and reductive bioactivation for toxicity induction. The plots for the dispersion interaction function, which represents the attraction between anthracyclines and biomolecules, can describe efflux from and influx into the target cells of toxicity. The plots can also identify three structural scaffolds of anthracyclines that have different metabolic pathways, resulting in their different toxicity behavior. CONCLUSION: This structure-dependent toxicity behavior revealed in the plots can provide perspectives on drug design and drug metabolism study.
Asunto(s)
Antraciclinas/química , Antraciclinas/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Biotransformación , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Diseño de Fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Dosificación Letal Mediana , Oxidación-Reducción , Relación Estructura-Actividad Cuantitativa , Transducción de SeñalRESUMEN
The use of microorganisms in biosorption is one of the most promising ways to remove trace amounts of heavy metal ions. Nevertheless, the enhancement of the successful removal of heavy metal ions by using different combinations of biosorbents is not generally guaranteed which leaves room to explore the application of the technique. In this study, the performance of free and immobilized forms of a yeast strain, Candida krusei (C. krusei), and calcium alginate (CaAlg) are evaluated for their ability to remove copper(II). Infrared spectroscopy, studies on the effects of pH and temperature, and kinetics and isotherm modelling are carried out to evaluate the biosorption. The infrared spectroscopy shows that the primary biosorption sites on the biosorbents are carboxylate groups. In addition, a higher pH and higher temperatures promote biosorption while a decline in biosorption ability is observed for C. krusei at 50 °C. The kinetics study shows that C. krusei, CaAlg and immobilized C. krusei (MCaAlg) conform with good correlation to pseudo-second order kinetics. MCaAlg and CaAlg fit well to the Langmuir isotherm while C. krusei fits well to the Temkin isotherm. From the experimental data, encapsulating C. krusei showed improved biosoprtion and address clogging in practical applications.
Asunto(s)
Candida/química , Cobre/química , Metales Pesados/química , Adsorción , Alginatos/química , Concentración de Iones de Hidrógeno , Microesferas , Modelos Teóricos , Soluciones , Espectroscopía Infrarroja por Transformada de Fourier , TemperaturaRESUMEN
The different types of cell death occurring in HCT116 colorectal cancer cell after the treatment of cisplatin, carboplatin, oxaliplatin, DMC, Pt(NH3)2(demethylcantharidin:DMC) and Pt(R,R-1,2-diaminocyclohexane: DACH)(DMC) were examined. Pt(NH3)2(DMC) and Pt(R,R-DACH)(DMC) are the two DMC-integrated platinum complexes:Pt(R,R-DACH)(DMC) with the same Pt moiety as oxaliplatin and Pt(NH3)2(DMC) akin to carboplatin. Using the light scattering properties of cells combined with propidium iodide (PI) red fluorescence to distinguish between early apoptotic and necrotic cells, the results confirmed that apoptosis, which triggered by cisplatin, carboplatin and oxaliplatin, was the major type of cell death, while the major DMC-induced cell death type was necrosis. The increase in the necrotic cell population was observed after Pt((NH3)2(DMC) treatment when compared with carboplatin; therefore, the DMC ligand in Pt(NH3)2(DMC) contributing to cell death was demonstrated. However, the DMC ligand in Pt(R,RDACH)( DMC) failed to elevate the necrotic cell population significantly in contrast to oxaliplatin, thus Pt(R,R-DACH) in Pt(R,RDACH)( DMC) dominantly contributed to cell death. The IC50 value (antiproliferative activity) reflects the net effect of drugs on cell proliferation resulting from inhibition of cell growth and division, and induction of cell death. The sub-G1 populations representing the sum of the amounts of late apoptotic cells and necrotic cells after the treatment of cispatin, carboplatin, oxaliplatin, DMC, Pt(NH3)2(DMC) and Pt(R,R-DACH)(DMC) were found to be not correlated with the corresponding IC50 values;therefore, the rate of cell growth and division inhibition rather than the rate of induction of cell death dictated to the IC50 values. This combined analysis of IC50 values and the sub-G1 population data also reveals that the platinum compounds containing R,R-DACH are most efficient in inhibiting cell growth and division, while carboplatin induces cell death most rapidly. When the Pt-DNA adducts are believed to be major cytotoxic species, the combined analysis of the IC50 values and the sub-G1 population data infers that the R,R-DACH-Pt-1,2-d(GpG) intrastrand cross-links caused by oxaliplatin treatment are more effective in inducing cell growth and division inhibition, while the (NH3)2Pt-1,3- d(GpXpG) intrastrand cross-links caused by carboplatin treatment can trigger cell death more rapidly. The rate of cell growth and division inhibition and the cell death rate induced by the main cisplatin-DNA adducts:(NH3)2Pt-1,2-d(GpG) intrastrand cross-links lie in between.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Cantaridina/análogos & derivados , Complejos de Coordinación/farmacología , Compuestos Organoplatinos/farmacología , Platino (Metal) , Antineoplásicos/química , Cantaridina/química , Cantaridina/farmacología , Carboplatino/farmacología , Cisplatino/farmacología , Complejos de Coordinación/química , Aductos de ADN/metabolismo , Células HCT116 , Humanos , Concentración 50 Inhibidora , Luz , Necrosis/metabolismo , Imagen Óptica , Compuestos Organoplatinos/química , Piridinas/farmacología , Dispersión de RadiaciónRESUMEN
A statistically significant and interpretable relationship between electrophilicity as a redox reactivity indicator and LD50 as a lethality indicator of drugs was discovered, and this relationship could be interpreted by the action of the cytochrome P450. The drugs chosen in this study were Topoisomerase II inhibitor anticancer drugs, and the electrophilicity of drugs was obtained by quantum chemical calculation. Since the P450 detoxification mechanism is the catalytic oxidation of drug molecules, it may infer that the drug molecules being easily oxidized (low electrophilicity) will be weak in lethality in general. In addition, this relationship revealed two structural scaffolds for the anthracycline-based topoisomerase II inhibitors, and their lethality mechanisms are not totally the same. Such relationship can assist in designing new drugs that candidates possessing low electrophilicity are recommended for lowering of lethality, and moieties providing a large inductive effect can reduce the electrophilicity of the anthracycline-based topoisomerase II inhibitors.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/toxicidad , Animales , Interpretación Estadística de Datos , Dosificación Letal Mediana , Ratones , Oxidación-ReducciónRESUMEN
Oxaliplatin is a third generation platinum (Pt) drug with a diaminocyclohexane (DACH) entity, which has recently obtained worldwide approval for the clinical treatment of colon cancer, and apparently operates by a different mechanism of action to the classical cisplatin or carboplatin. Introducing a novel dual mechanism of action is one approach in designing a new platinum-based anticancer agent, whereby an appropriate ligand, such as demethylcantharidin (DMC), is released from the parent compound to exert a cytotoxic effect, in addition to that of the DNA-alkylating function of the platinum moiety. To investigate the likelihood of a novel dual mechanism of anticancer action, demethylcantharidin-integrated Pt complexes: Pt(R,R-DACH)(DMC) with the same Pt-DACH moiety as oxaliplatin, and Pt(NH(3))(2)(DMC) akin to carboplatin; were studied for their ability to induce DNA damage in HCT116 colorectal cancer cells by an alkaline comet assay. The results showed that the DMC ligand released from the novel complexes caused additional DNA lesions when compared with oxaliplatin and carboplatin. The comet assay also revealed that the DNA-damaging behavior of cisplatin is characteristically different; and this study is the first to demonstrate the ability of DMC to induce DNA lesions, thus providing sufficient evidence to explain the superior antiproliferative effect of the novel DMC-integrated complexes.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cantaridina/análogos & derivados , Neoplasias Colorrectales/genética , Daño del ADN/genética , ADN de Neoplasias/efectos de los fármacos , ADN de Neoplasias/genética , Platino (Metal)/administración & dosificación , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/química , Cantaridina/administración & dosificación , Cantaridina/química , Línea Celular Tumoral , Humanos , Platino (Metal)/químicaRESUMEN
A series of platinum complexes derived from integrating demethylcantharidin (DMC) with different isomers of 1,2-diaminocyclohexane (DACH) has been synthesized and found to exhibit superior in vitro anticancer activity against colorectal and human hepatocellular cancer cell lines when compared with oxaliplatin, cisplatin, and carboplatin. Flow cytometric analysis revealed that the trans-DACH-Pt-DMC analogues showed similar behavior to oxaliplatin on affecting the cell cycle of the HCT116 colorectal cancer cell line, but distinct from that of cisplatin or carboplatin. The DACH component apparently dictates the trans-DACH-Pt-DMC complexes to behave mechanistically similar to oxaliplatin, whereas the DMC ligand appears to enhance the compounds' overall anticancer activity, probably by accelerating the cell cycle from G1 to S-phase with subsequent onset of G2/M arrest and accompanying apoptosis.