New methods of top-to-down mixture toxicity prediction: A case study of eliminating of the effects of cosolvent from binary mixtures.

At present, the toxicity prediction of mixtures mainly focuses on the concentration addition (CA) and independent action (IA) based on individual toxicants to predict the toxicity of multicomponent mixtures. This process of predicting the toxicity of multicomponent mixtures based on single substances or low component mixtures is called down-to-top method in this study. However, due to the particularity of some toxicants, we have to use the top-to-down idea to obtain or eliminate the toxicity of some components from mixtures. For example, the toxicity of toxicants is obtained from the toxicity of a mixture with, especially toxic, cosolvent added. In the study, two top-to-down methods, the inverse CA (ICA) and inverse IA (IIA) models, were proposed to eliminate the effects of a certain component from multicomponent mixtures. Furthermore, taking the eight binary mixtures consisting of different shapes of cosolvents (isopropyl alcohol (IPA) having hormesis and dimethyl sulfoxide (DMSO)) and toxicants (two ionic liquids and two pesticides) as an example, combined with the interaction evaluated by CA and IA model, the influence of different shapes of components on top-to-down toxicity prediction was explored. The results showed that cosolvent IPA having hormesis may cause unpredictable effects, even at low concentrations, and should be used with caution. For DMSO, most of the toxicant's toxicity obtained by ICA and IIA models were almost in accordance with those observed experimentally, which showed that ICA and IIA could effectively eliminate the effects of cosolvent, even if toxic cosolvent, from the mixture. Ultimately, a frame of cosolvent use and toxicity correction for the hydrophobic toxicant were suggested based on the top-to-down toxicity prediction method. The proposed methods improve the existing framework of mixture toxicity prediction and provide a new idea for mixture toxicity evaluation and risk assessment.

Synthesis and photodynamic activities of integrin-targeting silicon(IV) phthalocyanine-cRGD conjugates.

A series of novel symmetric or unsymmetric silicon (IV) phthalocyanines axially substituted with cyclic Arg-Gly-Asp (cRGD) ligands through different ethylene glycol chains have been synthesized by a facile and mild "click" reaction. All the compounds show efficient photosensitizing activities in N,N-dimethylformamide, and are essentially non-aggregated in RPMI 1640 medium with 0.05% Cremophor EL. Owing to the presence of two cRGD ligands, the conjugate 6b exhibits highest selectivity toward αvß3+ HT-29 cells in photocytotoxicities. It shows higher cellular uptake and ROS generation efficiency toward the αvß3+ HT-29 cells compared with that of αvß3- MCF-7 cells. The competitive cellular uptake and subcellular localization indicate that 6b is internalized mainly through integrin-mediated endocytosis. In addition, the in vivo studies showed that 6b can mainly accumulate in tumor sites and show a significant PDT effect resulting in 75% tumor growth inhibition. The results indicate that 6b is a highly promising photosensitizer for targeted photodynamic therapy.

Oxidation of the ß-blocker propranolol by UV/persulfate: Effect, mechanism and toxicity investigation.

In this study, the degradation of propranolol (PRO) by UV/persulfate process was systematically investigated. Direct photolysis of PRO was limited due to its low quantum yield, while the PRO degradation efficiency can be greatly promoted by the combination of persulfate and UV irradiation. Radical scavenging tests showed that both SO4- and OH contributed to the removal of PRO, with SO4- playing a more important role. The degradation rate of PRO was improved by increasing the persulfate dose and initial solution pH consistent with pseudo-first-order reaction kinetics. The effects of common water constituents were species dependent. HCO3- and Cl- promoted PRO degradation. By contrast, NO3- and HA were found to inhibit PRO degradation. A total of nine degradation products were identified by LC/MS/MS, which mainly derived from the ring-opening attack on the naphthalene group or oxidation of the amino moiety by SO4- and OH. Finally, the toxicity of the reaction mixtures was also assessed using luminescent bacteria Vibrio fischeri, and the results indicated that UV/persulfate is capable of controlling the toxicity of PRO degradation.

Using Delaunay triangulation and Voronoi tessellation to predict the toxicities of binary mixtures containing hormetic compound.

Concentration addition (CA) was proposed as a reasonable default approach for the ecological risk assessment of chemical mixtures. However, CA cannot predict the toxicity of mixture at some effect zones if not all components have definite effective concentrations at the given effect, such as some compounds induce hormesis. In this paper, we developed a new method for the toxicity prediction of various types of binary mixtures, an interpolation method based on the Delaunay triangulation (DT) and Voronoi tessellation (VT) as well as the training set of direct equipartition ray design (EquRay) mixtures, simply IDVequ. At first, the EquRay was employed to design the basic concentration compositions of five binary mixture rays. The toxic effects of single components and mixture rays at different times and various concentrations were determined by the time-dependent microplate toxicity analysis. Secondly, the concentration-toxicity data of the pure components and various mixture rays were acted as a training set. The DT triangles and VT polygons were constructed by various vertices of concentrations in the training set. The toxicities of unknown mixtures were predicted by the linear interpolation and natural neighbor interpolation of vertices. The IDVequ successfully predicted the toxicities of various types of binary mixtures.

A tumor-targeted activatable phthalocyanine-tetrapeptide-doxorubicin conjugate for synergistic chemo-photodynamic therapy.

Chemo-photodynamic therapy is a promising strategy for cancer treatments. However, it remains a challenge to develop a chemo-photodynamic therapeutic agent with little side effect, high tumor-targeting, and efficient synergistic effect simultaneously. Herein, we report a zinc(II) phthalocyanine (ZnPc)-doxorubicin (DOX) prodrug linked with a fibroblast activation protein (FAP)-responsive short peptide with the sequence of Thr-Ser-Gly-Pro for chemo-photodynamic therapy. In the conjugate, both photosensitizing activity of ZnPc and cytotoxicity of DOX are inhibited obviously. However, FAP-triggered separation of the photosensitizer and DOX can enhance fluorescence emission, singlet oxygen generation, dark- and photo-cytotoxicity significantly, and lead to a synergistic anticancer efficacy against HepG2 cells. The prodrug can also be specifically and efficiently activated in tumor tissue of mice. Thus, this prodrug shows great potential for clinical application in chemo-photodynamic therapy.