Qiu-Yun Chen

Anticancer activity, attenuation on the absorption of calcium in mitochondria, and catalase activity for manganese complexes of N-substituted di(picolyl)amine.

In order to find multifunction anticancer complexes, three Mn(II) complexes of N-substituted di(2-pyridylmethyl)amine were characterized and used as agents to interfere with the functions of mitochondria and the metabolite of O(2) in cancer cells. It was found that carboxylate-bridged dimanganese(II) systems are good models of catalase and exhibit good inhibition of the proliferation of U251 and HeLa cells. The inhibiting activity of these manganese(II) complexes on the tumor cells in vitro was related to their disproportionating H(2)O(2) activity. The reaction of carboxylate-bridged dimanganese Mn(II) complex with H(2)O(2) forms a stable Mn(III)-(μ-O)(2)-Mn(IV) complex. Extensive experimental results show that chloride-bridged dimanganese(II) complexes could inhibit the swelling of calcium(II) overloaded mitochondria, and carboxylate-bridged manganese(II) complexes enhance the swelling of calcium(II) overloaded mitochondria. These results indicate that the interactions between Mn(II) complexes of N-substituted di(picolyl)amine and mitochondria are influenced by the structure and conformation of the complexes. Mn(II) complexes of N-substituted di(picolyl)amine could be developed as multifunctional anticancer complexes to interfere with the absorption of calcium(II) in mitochondria and the metabolite of O(2) through the H(2)O(2) or ROS involved signaling induced apoptosis of cancer cells.

ROS-mediated autophagy was involved in cancer cell death induced by novel copper(II) complex.

In this study, we investigated autophagy induced in HeLa cells by copper(II) complex of ethyl 2-[bis(2-pyridylmethyl)amino] propionate ligand (ETDPA) (formula: [(ETDPA)Cu(phen)](ClO4)2 (abbreviated as LCu),a novel synthetic copper(II) complex whose DNA binding activity has been proved. Cell viability, autophagic levels and generation of ROS were evaluated following the exposure to LCu. LCu-induced cell death in a dose- and time-dependent manner, which was demonstrated by enhanced fluorescence intensity of monodansylcadervarine (MDC), as well as elevated expression of autophagy-related protein MAP-LC3. These phenomena were all attenuated after pretreatment with autophagy inhibitors 3-MA or NH(4)Cl. Furthermore, our data indicated that LCu-triggered autophagy through ROS: cellular ROS levels were increased after LCu treatment, which was reversed by ROS scavenger NAC (N-acetylcysteine). As a consequence, Lcu-mediated autophagy was partly blocked by NAC. In summary, we synthesized a novel copper(II) complex and showed that this compound was effective in killing HeLa cells via ROS-triggered autophagic pathway.

Tumor-targeting novel manganese complex induces ROS-mediated apoptotic and autophagic cancer cell death

In this study, the antitumor activity of the novel manganese (II) compound, Adpa-Mn {[(Adpa)Mn(Cl)(H2O)] (Adpa=bis(2-pyridylmethyl)amino-2-propionic acid)}, and its possible mechanisms of action were investigated. In vitro, the growth inhibitory effects of Adpa-Mn (with IC50 values lower than 15 μM) on tumor cell lines were examined by MTT assay. We found that this compound was more selective against cancer cells than the popular chemotherapeutic reagent, cisplatin. We then found that Adpa-Mn achieved its selectivity against cancer cells through the transferrin (Tf)-transferrin receptor (TfR) system, which is highly expressed in tumor cells. Furthermore, Adpa-Mn induced both apoptosis and autophagy, as indicated by chromatin condensation, the activation of poly(ADP-ribose) polymerase (PARP), Annexin V/prop-idium iodide staining, an enhanced fluorescence intensity of monodansylcadaverine (MDC), as well as the elevated expression of the autophagy-related protein, microtubule-associated protein 1 light chain 3 (LC3). In addition, Adpa-Mn induced the generation of intracellular reactive oxygen species (ROS) and its anticancer effects were significantly reduced following pre-treatment with the antioxidant, N-acetyl cysteine, indicating that ROS triggered cell death. In vivo, the induction of apoptosis and autophagy in tumor tissue was confirmed following treatment with Adpa-Mn, which contributed to its significant antitumor activity against hepatocellular carcinoma (Hep-A cell) xenografts at 10 mg/kg. Taken together, these data suggest the possible use of Adpa-Mn as a novel anticancer drug.

The interaction between ionic liquids modified magnetic nanoparticles and bovine serum albumin and the cytotoxicity to HepG-2 cells.

The interaction between ionic liquids modified magnetic Fe3O4 (Fe2) and bovine serum albumin (BSA) is reported and is compared with NH2 functionalized magnetic nanoparticles Fe3O4 (Fe1) based on the UV-visible spectrum, steady-state fluorescence measurements, synchronous fluorescence and DSC methods. The results indicate a static quenching mechanism operating in both nanoparticles. The binding constant of the Fe2-BSA complex calculated from fluorescence data shows that BSA has a low binding affinity for Fe2 than Fe1. DSC data reveal that the thermal stability process of BSA in the Fe2-BSA complex is semi-reversible. This demonstrates that the ionic liquid modified magnetic nanoparticles (Fe2) enhance the thermostability of BSA in the range of 20-40°C, and protein attached Fe2 has higher thermal stability than free BSA. Moreover, the in vitro assay results show that Fe2 shows low cytotoxicity to HepG-2 cells.

Targeting cancer cells through iron(III) complexes of di(picolyl)amine modified silica core-shell nanospheres.

In this report, we aim at optimizing the approach of delivering and imaging cancer cell targeting using anti-proliferative nanoparticle complex. Rhodamine B isothiocyanate doped silica-coated (RBITC-SiO₂) were prepared by microemulsion method. Fe(III) complex of di(picolyl)amine was conjugated on to the surface RBITC-SiO₂ to produce final nanosphere (RBITC-SiO₂ @dpa-Fe) with an average hydrodynamic diameter of 74 nm. The Fe(III)-di(picolyl)amine complex modified nanospheres displayed enhanced HeLa cells uptake in vitro suggesting selective cancer cell payload delivery. RBITC-SiO₂ @dpa-Fe also showed reduced off-target cytotoxicity. The conjugate of dpa-Fe(III) complex and fluorescence core-shell nanoparticles RBITC-SiO₂ represents a class of novel multi-functional nanoparticles that combines the advantages of active cancer-targeting through Fe(III) complex mediated intracellular drug delivery and compatibility with fluorescence imaging.

Functional ionic liquids induced the formation of mitochondria targeted fluorescent core-shell ellipsoidal nanoparticles with anticancer properties.

A functional ionic liquid (IL) (IL=4-acetyl-N-butyl pyridinium hexafluorophosphate) was synthesized and conjugated with low toxicity of nanospheres (RBITC@SiO(2)), forming a new kind of fluorescent core-shell ellipsoidal RBITC@SiO(2)-IL nanoparticle. In vitro assay results indicate that particle shape plays an important role in cellular interactions with NPs. Furthermore, the positively charged ellipsoidal RBITC@SiO(2)-IL nanoparticles can enter into HeLa cells and induce the cells to condense, split and decrease on the oxygen consumption. The enhanced cell image and decrease of mitochondria potential indicate that the ellipsoidal RBITC@SiO(2)-IL nanoparticles could be uptaken by HeLa cells through mitochondria involved path. Experimental results give us a new path to design nano-medicines through ionic liquid modified silica nanoparticles to target mitochondria.

A novel manganese complex LMnAc selectively kills cancer cells by induction of ROS-triggered and mitochondrial-mediated cell death

We previously identified a novel synthesized metal compound, LMnAc ([L2Mn2(Ac)(H2O)2](Ac) (L=bis(2-pyridylmethyl) amino-2-propionic acid)). This compound exhibited significant inhibition on cancer cell proliferation and was more selective against cancer cells than was the popular chemotherapeutic reagent cisplatin. In this study, we further investigated the underlying molecular mechanisms of LMnAc-induced cancer cell death. We found that LMnAc achieved its selectivity against cancer cells through the transferrin-transferrin receptor system, which is highly expressed in tumor cells. LMnAc triggered cancer cells to commit autophagy and apoptosis, which was mediated by the mitochondrial pathway. Moreover, LMnAc disrupted mitochondrial function, resulting in mitochondrial membrane potential collapse and ATP reduction. In addition, LMnAc induced intracellular Ca2+ overload and reactive oxygen species generation. Interestingly, its anticancer effect was significantly reduced following pretreatment with the antioxidant N-acetyl cysteine, indicating that reactive oxygen species triggered cell death. Altogether, our data suggest that LMnAc appears to be a selectively promising anticancer drug candidate.

BODIPY-Mn nanoassemblies for accurate MRI and phototherapy of hypoxic cancer

Hypoxia promotes not only the metastasis of tumors but also therapeutic resistance. Photosensitizer-mediated consumption of O2 during photodynamic therapy (PDT) reinforces tumor hypoxia. Herein, a light-dependent attenuator of a hypoxic environment is reported for accurate MRI and phototherapy of hypoxic cancer. First, a photoresponsive Mn(ii) nanoassembly was constructed, then it was assembled with bovine serum albumin (BSA) and modified with polyethylene glycol-folic acid (PEG-FA), forming cancer targeting Mn-DBA@BSA-FA nanoassemblies, which offer T1 signals and can catalyze the water oxidation reaction under irradiation of red light emitting diode (LED) light with the generation of O2 and heat. Moreover, they could selectively penetrate through and accumulate in the tumor tissues with clear T1 magnetic resonance imaging (MRI) signals, and have remarkably eliminated the tumors in vivo, while they are of low toxicity to the healthy organs. The release of the Mn(ii) complex from the nanoparticles in an acidic environment and the in vivo biodistribution results confirm the selective cancer targeting. Our work demonstrates the potential of nanoparticles as excellent theranostic agents for MR imaging combined with phototherapy triggered by near-infrared light.

A Mn(II) complex of boradiazaindacene (BODIPY) loaded graphene oxide as both LED light and H2O2 enhanced anticancer agent

Cancer cells are more susceptible to H2O2 induced cell death than normal cells. H2O2-activatable and O2-evolving nanoparticles could be used as photodynamic therapy agents in hypoxic environments. In this report, a photo-active Mn(II) complex of boradiazaindacene derivatives (Mn1) was used as a dioxygen generator under irradiation with LED light in water. Moreover, the in vitro biological evaluation for Mn1 and its loaded graphene oxide (herein called Mn1@GO) on HepG-2 cells in normal and hypoxic conditions has been performed. In particular, Mn1@GO can react with H2O2 resulting active anticancer species, which show high inhibition on both HepG-2 cells and CoCl2-treated HepG-2 cells (hypoxic cancer cells). The mechanism of LED light enhanced anticancer activity for Mn1@GO on HepG-2 cells was discussed. Our results show that Mn(II) complexes of boradiazaindacene (BODIPY) derivatives loaded GO can be both LED light and H2O2-activated anticancer agents in hypoxic environments.

Interaction of manganese(II) complex with apotransferrin and the apotransferrin enhanced anticancer activities

Apotransferrin could bind a number of metal ions besides Fe, which makes it an attractive delivery vehicle for metal-based medicines. In order to evaluate whether anticancer Mn(II) complex of [(Adpa)Mn(Cl)(H(2)O)] Adpa=bis(2-pyridylmethyl)amino-2-propionic acid) (AdpaMn) could be transported by apotransferrin, we investigated its interaction with human apotransferrin by fluorescence and circular dichroism spectroscopy (CD). The association dynamics show that AdpaMn could bind to apotransferrin spontaneously in Hepes buffer. Synchronous fluorescence spectroscopy and CD spectroscopy show that the conjugation of AdpaMn and apotransferrin by hydrophobic interactions induces the change of the microenvironment and conformation of apotransferrin. The reversible binding and release of AdpaMn was studied with fluorescence titration method. The AdpaMn complex can be released from the AdpaMn-apotransferrin entity in weak acid environments. MTT assay in vitro confirms that apotransferrin can enhance the inhibition rate of AdpaMn on the proliferation of HepG-2 cells, so we deduce that AdpaMn could be transported by apotransferrin in vivo.