RESUMEN
Cisplatin (CDDP) and arsenic trioxide (ATO), two representative inorganic anticancer drugs, have been successful in the treatment against several kinds of malignancies. However, combination therapy with these two drugs in clinical application suffers from poor pharmacokinetics, serious side effects, and drug resistance of the tumor. Herein, we report a carrier-free aquo-cisplatin arsenite multidrug nanocomposite loaded with cisplatin and arsenic trioxide prodrugs simultaneously. This nanocomposite achieves a high loading capacity and pH-dependent controlled release of the drugs. Because of these features, this nanocomposite shows better in vitro toxicity against various carcinoma cell lines than either the single drug or free drug combination, promotes the synergistic effect of cisplatin and arsenic trioxide, and significantly inhibits the growth of tumors in vivo. Furthermore, cisplatin and arsenic trioxide in this nanocomposite can realize a coordination of both enhanced DNA damage and DNA repair interference within cisplatin-resistant cells, which results in overcoming the drug resistance effectively. Gene expression profiles demonstrate the reduced expression of proto-oncogenes and DNA damage repair related genes MYC, MET, and MSH2, along with the increase of tumor suppressor genes PTEN, VHL, and FAS after the nanocomposite treatment. This type of multidrug nanocomposite offers an alternative and promising strategy for combination therapy and overcoming drug resistance.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Trióxido de Arsénico/análogos & derivados , Trióxido de Arsénico/farmacología , Cisplatino/análogos & derivados , Cisplatino/farmacología , Nanocompuestos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Trióxido de Arsénico/síntesis química , Trióxido de Arsénico/uso terapéutico , Arsenitos/síntesis química , Arsenitos/química , Arsenitos/farmacología , Línea Celular Tumoral , Cisplatino/síntesis química , Cisplatino/uso terapéutico , Daño del ADN/efectos de los fármacos , Resistencia a Antineoplásicos , Humanos , Masculino , Ratones Endogámicos BALB C , Nanocompuestos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Transcriptoma/efectos de los fármacosRESUMEN
Surface complexation between arsenious acid anions (As(III)) and ferric (hydr)oxides in water is important for the transformation and transfer of inorganic arsenic species. The mechanisms of formation and the photochemistry of dissolved Fe(III)-As(III) complexes in acidic aqueous solution are still unclear. Here, the photooxidation of As(III) in the presence of Fe(III) ions in acidic media has been investigated by laser flash and steady-state photolysis. At low arsenite concentrations (<1 mM), As(III) is oxidized by the ËOH radical generated by photolysis of the FeOH(2+) complex. At higher arsenite concentrations (>10 mM), photoactive Fe(III)-As(III) complexes are formed (Ï≈ 0.012). At all arsenite concentrations, a white FeAsO4 colloid is formed during As(III) photolysis in the presence of Fe(III) ions. Solid Fe(III)-As(III) complexes have been prepared and characterized, and the photochemical transformation of As(III) into As(V) in solid Fe(III)-As(III) complexes has been confirmed. These findings are important for a better understanding of the evolution of As(III) species under environmental conditions and should provide guidance for detoxification of As(III)-polluted water systems.
Asunto(s)
Arsenitos/química , Arsenitos/efectos de la radiación , Compuestos Férricos/química , Compuestos Férricos/efectos de la radiación , Fotólisis , Agua/química , Arsenitos/síntesis química , Compuestos Férricos/síntesis química , Concentración de Iones de Hidrógeno , SolucionesRESUMEN
The entropy-driven affinity of trivalent (in)organic arsenicals for closely spaced dithiols has been exploited to develop a novel route to peptide/protein-polymer conjugation. A trivalent arsenous acid (As(III)) derivative (1) obtained from p-arsanilic acid (As(V)) was shown to readily undergo conjugation to the therapeutic peptide salmon calcitonin (sCT) via bridging of the Cys(1)-Cys(7) disulfide, which was verified by RP-HPLC and MALDI-ToF-MS. Conjugation was shown to proceed rapidly (t < 2 min) in situ and stoichiometrically through sequential reduction-conjugation protocols, therefore exhibiting conjugation efficiencies equivalent to those reported for the current leading disulfide-bond targeting strategies. Furthermore, using bovine serum albumin as a model protein, the trivalent organic arsenical 1 was found to demonstrate enhanced specificity for disulfide-bond bridging in the presence of free cysteine residues relative to established maleimide functional reagents. This specificity represents a shift toward potential orthogonality, by clearly distinguishing between the reactivity of mono- and disulfide-derived (vicinal or neighbors-through-space) dithiols. Finally, p-arsanilic acid was transformed into an initiator for aqueous single electron-transfer living radical polymerization, allowing the synthesis of hydrophilic arsenic-functional polymers which were shown to exhibit negligible cytotoxicity relative to a small molecule organic arsenical, and an unfunctionalized polymer control. Poly(poly[ethylene glycol] methyl ether acrylate) (PPEGA480, DPn = 10, Mn,NMR = 4900 g·mol(-1), D = 1.07) possessing a pentavalent arsenic acid (As(V)) α-chain end was transformed into trivalent As(III) post-polymerization via initial reduction by biological reducing agent glutathione (GSH), followed by binding of GSH. Conjugation of the resulting As(III)-functional polymer to sCT was realized within 35 min as indicated by RP-HPLC and verified later by thermodynamically driven release of sCT, from the conjugate, in the presence of strong chelating reagent ethanedithiol.
Asunto(s)
Arsenicales/química , Calcitonina/química , Cisteína/química , Acrilatos/química , Animales , Arsenicales/síntesis química , Arsenitos/síntesis química , Arsenitos/química , Línea Celular , Ratones , Modelos Moleculares , Polietilenglicoles/química , Polimerizacion , Salmón , Compuestos de Sulfhidrilo/químicaRESUMEN
In this study, a new strategy was proposed for the preparation of As (III)-imprinted polymer by using arsenic (methacrylate)3 as template. Precipitation polymerization was utilized to synthesize nano-sized As (III)-imprinted polymer. Methacrylic acid and ethylene glycol dimethacrylate were used as the functional monomer and cross-linking agent, respectively. In order to assembly functional monomers around As (III) ion, sodium arsenite and methacrylic acid were heated in the presence of hydroquinone, leading to arsenic (methacrylate)3. The nano-sized As (III) selective polymer was characterized by FT-IR and scanning electron microscopy techniques (SEM). It was demonstrated that arsenic was recognized as As(3+) by the selective cavities of the synthesized IIP. Based on the prepared polymer, the first arsenic cation selective membrane electrode was introduced. Membrane electrode was constructed by dispersion of As (III)-imprinted polymer nanoparticles in poly(vinyl chloride), plasticized with di-nonylphthalate. The IIP-modified electrode exhibited a Nernstian response (20.4±0.5 mV decade(-1)) to arsenic ion over a wide concentration range (7.0×10(-7) to 1.0×10(-1) mol L(-1)) with a lower detection limit of 5.0×10(-7) mol L(-1). Unlike this, the non-imprinted polymer (NIP)-based membrane electrode was not sensitive to arsenic in aqueous solution. The selectivity of the developed sensor to As (III) was shown to be satisfactory. The sensor was used for arsenic determination in some real samples.
Asunto(s)
Arsenitos/síntesis química , Técnicas Electroquímicas/métodos , Ionóforos/síntesis química , Nanopartículas del Metal/química , Polímeros/síntesis química , Compuestos de Sodio/síntesis química , Técnicas Electroquímicas/instrumentación , Electrodos , Potenciometría/instrumentación , Potenciometría/métodosRESUMEN
Seafood frequently contains high concentrations of arsenic (approximately 10-100 mg/kg dry weight). In marine algae (seaweed), this arsenic occurs predominantly as ribose derivatives known collectively as arsenosugars. Although it is clear that arsenosugars are not acutely toxic, there is a possibility of arsenosugars having slight chronic toxicity. In general, trivalent arsenicals are more toxic than their pentavalent counterparts, so in this work we examine the hypothesis that trivalent arsenosugars might be significantly more toxic than pentavalent arsenosugars in vitro. We compared the in vitro toxicity of (R)-2,3-dihydroxypropyl-5-deoxy-5-dimethylarsinoyl-beta-D-riboside, a pentavalent arsenosugar, to that of its trivalent counterpart, (R)-2,3-dihydroxypropyl-5-deoxy-5-dimethylarsino-beta-D-riboside. The trivalent arsenosugar nicked plasmid DNA, whereas the pentavalent arsenosugar did not. The trivalent arsenosugar was more cytotoxic (IC50 = 200 microM, 48 h exposure) than its pentavalent counterpart (IC50 > 6000 microM, 48 h exposure) in normal human epidermal keratinocytes in vitro as determined via the neutral red uptake assay. However, both the trivalent and the pentavalent arsenosugars were significantly less toxic than MMA(III), DMA(III), and arsenate. Neither the pentavalent arsenosugar nor the trivalent arsenosugar were mutagenic in Salmonella TA104. The trivalent arsenosugar was readily formed by reaction of the pentavalent arsenosugar with thiol compounds, including, cysteine, glutathione, and dithioerythritol. This work suggests that the reduction of pentavalent arsenosugars to trivalent arsenosugars in biology might have environmental consequences, especially because seaweed consumption is a significant environmental source for human exposure to arsenicals.