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 bis-amine-substituted styrylquinolinium dye (BSAQ) was designed and synthesized.•BSAQ could be used as a colorimetric and red-emitting fluorescent probe for G-quadruplex DNAs.•The limits of detection of BASQ with various G-quadruplex DNAs were found to below 1 nM.•The binding properties were demonstrated.Searching for specific G-quadruplex DNA probes is important for study of the function of G-rich gene sequence, as well as design of novel effective anticancer drugs. In this paper, a novel bis-amine-substituted styrylquinolinium dye (BSAQ) was designed and synthesized to enhance the performance for the application as a G-quadruplex DNA probe. The studies on BSAQ with different DNA forms showed that it could be used as a colorimetric and red-emitting fluorescent probe for G-quadruplex DNA. The limits of detection of BASQ with various G-quadruplex DNAs were found to below 1 nM. CD spectroscopy analysis revealed that BSAQ did not induce the G-rich sequence folding into G-quadruplex structure. These results of this study gave some crucial factors on developing of effective probes for G-quadrupex DNA applications.Download high-res image (158KB)Download full-size image

A novel Eu metal–organic framework graphene oxide composite noted as MOF@GO has been synthesized and successfully employed as a photocatalyst for the oxidation of benzyl alcohol using water as an oxygen source. The results show that graphene oxide (GO) not only acts as a structure-directing agent in controlling the morphology of MIL@GO composites but also minimizes the recombination of photogenerated electron–hole pairs to enhance photocatalytic activity. A possible photocatalytic reaction mechanism shows that water is essential for the photocatalytic oxidation, reacting with photo-generated holes to produce molecular oxygen or other active species intermediate in the oxidation of benzyl alcohol.

Targeting cellular metabolism is becoming a hallmark to overcome drug resistance in breast cancer treatment. Activation of fatty acid synthase (FASN) has been shown to promote breast cancer cell growth. However, there is no concrete report underlying the mechanism associated with mitochondrial dysfunction in relation to fatty acid synthase inhibition-induced apoptosis in breast cancer cells. The current study is aimed at exploring the effect of the novel manganese (Mn) complex, labeled as PdpaMn, on lipid metabolism and mitochondrial function in breast cancer cells. Herein, we observed that PdpaMn displayed strong cytotoxicity on breast cancer cell lines and selectively targeted the tumor without affecting the normal organs or cells in vivo. We also observed that PdpaMn could bind to TE domain of FASN and decrease the activity and the level of expression of FASN, which is an indication that FASN could serve as a target of PdpaMn. In addition, we demonstrated that PdpaMn increased intrinsic apoptosis in breast cancer cells relayed by a suppressed the level of expression of FASN, followed by the release of mitochondrial cytochrome c and the activation of caspases-9. Instigated by the above observations, we hypothesized that PdpaMn-induced apoptosis events are dependent on mitochondrial dysfunction. Indeed, we found that mitochondrial membrane potential (MMP) collapse, mitochondrial oxygen consumption reduction and adenosine triphosphate (ATP) release were deeply repressed. Furthermore, our results showed that PdpaMn significantly increased the reactive oxygen species (ROS) production, and the protection conferred by the free radical scavenger N-acetyl-cysteine (NAC) indicates that PdpaMn-induced apoptosis through an oxidative stress-associated mechanism. More so, the above results have demonstrated that mitochondrial dysfunction participated in FASN inhibition-induce apoptosis in breast cancer cells by PdpaMn. Therefore, PdpaMn may be considered as a good candidate for anti-breast cancer therapeutic option.

•A NIR-fluorescence MnIII/IV nanopolymer (PMnD) was reported.•The PMnD-water system can be a dioxygen generator.•It can image the mitochondria.•It attenuates the expression of HIF-1α in hypoxic cancer cells.To obtain near-IR absorbing biomaterials as fluorescence cellular imaging and anticancer agents for hypoxic cancer cell, a nano NIR fluorescence Mn(III/IV) polymer (PMnD) was spectroscopically characterized. The PMnD shows strong emission at 661 nm when excited with 643 nm. Furthermore, PMnD can catalyze water oxidation to generate dioxygen when irradiated by red LED light (10 W). In particular, the PMnD can enter into HepG-2 cells and mitochondria. Both anticancer activity and the inhibition of the expression of HIF-1α for PMnD were concentration dependent. Our results demonstrate that PMnD can be developed as mitochondria targeted imaging agents and new inhibitors for HIF-1 in hypoxic cancer cells.Download high-res image (110KB)Download full-size image

•A manganese complex (Mn1)/water system as a dioxygen generator•Electrochemical properties of Mn1 and its loaded graphene oxide (Mn1@GO) were reported.•Mn1@GO can react with H2O2 resulting active anticancer species.•Mn1@GO was used as materials for hypoxic cancer phototherapy.•The mechanism of LED light enhanced anticancer activity was discussed.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.Photoactive Mn(II) complex loaded GO (Mn1@GO) shows both LED light and H2O2-activated enhanced inhibition on the proliferation of HepG-2 cells in hypoxic conditions.

The design and preparation of highly active, environmentally friendly photo-catalysts with low cytotoxicity for the oxidation of water are important in achieving the efficient splitting of water. We present a novel supramolecular nanocomplex BODIPY@Fe1 obtained by assembling a flower-like nano-Fe(III) complex (PPM@Fe) with 8-(4-methoxyphenyl)boron-dipyrromethane (BODIPY) through a hydrogen bond. This complex catalysed the oxidative conversion of water to dioxygen. The hydrogen bond CO⋯H(N)–F– facilitated the charge transfer interaction between the ligand and the metal centre in BODIPY@Fe. The TOF value of BODIPY@Fe/H2O (7.76 h−1) was much higher than that of the PPM@Fe/Ru(bpy)3Cl2/Na2S2O8 system (3.06 h−1). Electron paramagnetic resonance spectrometry and water oxidation activity data indicated that the high-spin Fe(III) species in the BODIPY@Fe complex was involved during the catalysed oxidation of water. The formation of the Fe–O and O–O bonds were confirmed. BODIPY@Fe can also catalyse the oxidative degradation of methylene blue using water as the oxygen source. Hence the assembly of a photosensitizer with an Fe(III) complex of pyrrole-conjugated carbonyl group derivatives provides a promising green generator of dioxygen via photoirradiation.

Design and synthesis of highly efficient and cost-effective catalysts for water oxidation is one of the biggest challenges that chemists are facing today. The low-cost salophen cobalt complex represents a promising water oxidation visible-light-photocatalyst under neutral conditions. To avoid degradation and improve the photocatalytic activity of cobalt salophen, we have synthesized a cobalt salophen-based organic–inorganic hybrid mesoporous material (MC) via grafting cobalt salophen into mesoporous SBA-15 for water oxidation under mild conditions. MC is found to be more active and stable than the neat salophen cobalt. Under similar conditions, MC shows a significantly higher activities (turnover frequency: 59.64 mol of O2 h−1 mol Co−1) than the corresponding cobalt complex (turnover frequency: 2.520 mol of O2 h−1 mol Co−1). After being used four times, the reactivity and the yield of oxygen for MC is still 10 times higher than pure salophen cobalt. MC could be considered as a promising catalyst for water oxidation.

New types of fluorescence DNA-based silver nanoclusters (DNAn-AgNCs, n = 1, 2, 3c, 4c, 5c) were synthesized by C3T-rich nucleotides as templates. It is found that the assembly of DNAn-AgNCs with nucleotides containing GAG sequences produce silver clusters with an enhanced red emission. Results indicate that GAG is the good enhancer of DNAn-AgNCs constructed by C3T-rich nucleotides. The fluorescence titration reveals that enhanced red emission is sensitive to Fe(III/II) ions with the formation of non-emission nanoclusters. Thus, the GAG-containing nucleotide can be an enhancer for the emission of silver clusters with C3T-rich nucleotide and a mediator of the iron-cluster interplay.GAG-containing nucleotides were found to be enhancers for the emission of silver clusters with C3T-rich nucleotides and mediators of the Fe(III)-cluster interplay.

•A nanoassembly (PEG-Mn-BDA) was successfully constructed.•A mitochondria targeting bimode image agent was reported.•PEG-Mn-BDA can be an inhibitor of both LDH-A and glycolysis.•In vivo inhibition was studied.HIF-1α and LDH-A are important targets for hypoxia-driven drug resistance. Mitochondria targeted fluorescent manganese(II)-complexes can be used as potential fluorescence imaging agents, MRI contrast agents and HIF-1α and LDH-A involved anticancer complexes. In this study, a fluorescent manganese(II) nanoparticle, labeled as (PEG-Mn-BDA), was synthesized and used as both fluorescent and MRI imaging agents in cancer cells. In vitro bioassay results indicate that PEG-Mn-BDA was able to inhibit LDH-A activity and depolarize mitochondrial membrane potential with the generation of intracellular ROS, which contributed to the induction of apoptosis. Moreover, the pro-apoptotic protein, caspase 3 was highly expressed. In vivo, PEG-Mn-BDA could also exert inhibition on a mouse hepatocellular carcinoma xenograft. These results suggest that mitochondria targeted PEG-Mn-BDA was able to simultaneously induce selective inhibition on cancer cells and a mouse carcinoma xenograft, label cancer cells with fluorescence and enhance MRI contrast. Therefore, PEG-Mn-BDA is a good candidate for cancer treatment and imaging.A Mn nanoassembly of BODIPY is constructed for LDH-A, mitochondria modulated therapy and bimodal imaging of cancer.

•LDH-A inhibitor were assayed by spectroscopic analysis.•The fluorescence titration revealed the affinity interaction for compounds to LDH-A•The change of conformation of LDHA- was investigated by CD spectra.•A bifunctional anticancer compound was reported.Lactate dehydrogenase A (LDH-A) is a potentially important metabolic target for the inhibition of the highly activated glycolysis pathway in cancer cells. In order to develop bifunctional compounds as inhibitor of LDH-A and anticancer agents, two pyrrol-2-yl methanone (or ethanone) derivatives (PM1 and PM2) were synthesized and evaluated as inhibitors of LDH-A based on the enzyme assay and cell assay by spectroscopy analysis. Fluorescence and CD spectra results demonstrated that both the change of second structure of LDH-A and the affinity interaction for compounds to LDH-A gave great effect on the activity of LDH-A. In particular, low concentration of compounds (1 μμ–25 μμ) could change the level of pyruvate in cancer cells. Moreover, the in vitro assay results demonstrated that pyrrol-2-yl ethanone derivatives can inhibit the proliferation of cancer cells. Therefore, pyrrol-2-yl ethanone derivatives (PM2) can be both LDH-A inhibitor and anticancer agents.

•A new kind of fluorescent DNA-AgNCs were reported.•The fluorescence response and reassembly mechanism were revealed.•The loading and releasing of Dox in DNA-AgNCs can be monitored.•It has special sensitive to HepG-2 cells.DNA silver nanoclusters (DNA-AgNCs) with a fluorescence emission at 610 nm were synthesized using a special hairpin DNA sequence (5′-AGCACGTAG-C3AC3AC3GC3A-CTACGTGCT-3′). Spectroscopic data demonstrate that the DNA changed from an i-motif structure containing C-quadruplexes to anti-parallel four strands structure during the formation of DNA-AgNCs. Importantly, the loose and compact four strand structure caused by the melting and hybridization of stem duplex was confirmed by the reversible fluorescence change of DNA-AgNCs in the range of 25–66 °C. Herein, DNA-AgNCs were used as temperature sensitive vehicles of drug loading. The drug loading capacity is 1 Doxorubicin (Dox) molecules per CG pairs on stem-duplexes. The loaded Dox can be released by raising temperature with the melt of stem duplex. Moreover, the special DNA sequence makes it sensitive to the HepG-2 cells.

•The interaction of iron(III) complex with water was reported.•The LED light driven water oxidation reaction was found.•The iron(III) complex shows the light accelerated anticancer property.•The cell uptake and cytotoxicity of the complex was assayed.The iron complex [(m-BDA)FeCl3] (Fe1) (m-BDA = 8-[di(2-picolyl)amine-3-benzyl]-4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene) was characterized by spectroscopic methods. The emission intensity of Fe1 is weaker than that of m-BDA due to the electrostatic interaction between the Fe(III) ion and m-BDA. However, the coordination of water with the central Fe(III) ion in Fe1 changed metal–ligand charge transfer, thus the quenched emission at 509 nm was recovered. Furthermore, Fe1 can catalyze water oxidation to generate dioxygen when irradiated by green LED light (10 W). In particular, the Fe1 can enter into HepG-2 cells and show different inhibition rates in black and under irradiation. The anticancer activity of Fe1 was greatly enhanced under irradiation. Our results demonstrate that Fe(III) complexes of BODIPY can be developed as new kinds of photodynamic agents.

•The interaction of bifunctional chelators with Aβ42 was reported.•The compound with hydrophobic group (BDA) shows high affinity to Aβ42.•The chelator–Cu(II)–Aβ42 neurotoxic nanospheres were revealed.•The change of Aβ42 secondary structure induced by chelators was reported.•The toxicity of chelators was reported.In order to confirm the neurotoxicity of bifunctional chelators containing hydrophobic groups and metal chelating moiety, the interaction of di(picolyl)amine (dpa) derivatives toward Aβ42 peptide was investigated. Fluorescence titration reveals that a hydrophobic chelator (such as BODIPY) shows high binding affinity to amyloid Aβ42. Circular dichroism (CD) spectra confirm that the hydrophobic bifunctional chelator can decrease α-helix fraction and increase the β-sheet fraction of amyloid Aβ42. In particular, experimental results indicate that a bifunctional chelator can assemble with Cu(II)–Aβ42 forming chelator–Cu(II)–Aβ42 nanospheres, which are toxic to SH-S5Y5 cells. The hydrophobic interaction between the chelator and the amyloid peptide (Aβ42) has great contribution to the formation of neurotoxic chelator–Cu(II)–Aβ42 nanospheres. This work gives a general guide to the development of low cytotoxic inhibitors of Aβ42 aggregation.Graphical abstract

To develop molecular catalysts for the generation of dioxygen, the photophysical properties of cobalt complexes of boradiazaindacene (BODIPY) derivatives were studied. It is found that the intramolecular energy transfer due to d–π interaction between boradiazaindacene (BODIPY) and the cobalt central in aqua-cobalt complexes, which was confirmed by DFT calculation, leads to the quenched fluorescence emission being recovered completely. The effect of link spacers (benzyl groups) on the intramolecular d–π interaction was discussed. Results show that cobalt complexes of BODIPY derivatives can be photo-sensitizers and a good blue LED light driven precatalyst for the oxidation of water. The dioxygen generation was further confirmed by the photooxidization of 1,5-dihydroxylnaphthalene (DHN) catalyzed by cobalt complexes using water as the oxygen source. This will give a new path to design photo-active complexes to be used as PDT in hypoxic environments.

•The complex [(PPMdpa)CoCl2] (Co1) is characterized.•A blue LED light driven pre-catalyst for water oxidation•Electrochemical catalyst for water oxidation•Co1 as photo-sensitizers and electron acceptorsThe cobalt complex [(PPMdpa)CoCl2] (Co1) (PPMdpa = 4-((bis(pyridin-2-ylmethyl)amino)methyl)phenyl-3,5-dimethyl-1H-pyrrol-2-yl-methanone) was characterized by X-ray crystal structure and spectroscopic methods. The electrochemical analysis confirms the reduction of dioxygen formed at the working electrode in the Co1–H2O system. A catalytic current increases with increasing pH, evidencing the involvement of a proton in the initial stage of electrochemical catalysis. The light driven catalytic water oxidation was supported by the presence of the shifted cathodic wave at − 0.62 V, (pH 8.5) and obvious oxygen evolution when irradiated with LED light. Thus, Co1 can be a pre-catalyst to the oxidation of water without using ruthenium complexes as the photo-sensitizer and Na2S2O8 as the electron acceptor. [(PPMdpa)CoCl2]–H2O system is a blue LED light driven dioxygen evolving system.Cobalt complex works as blue LED light driven pre-catalyst for water oxidation.

•Indole conjugated nanosilica and magnetic nanoparticles were constructed.•Indole conjugated magnetic nanoparticles are found to be good mimics of catalase.•The time dependent cytoxicity of magnetic nanoparticles is reported.•The two nanoparticles can inhibit the expression of HIF and GLUT1 in vitro.•A new way to construct inhibitor of glycolysis is reported.Multifunctional silica nano-vehicles (SiO2@indol-IL) and magnetic nanoparticles (Fe3O4@indol-IL) were constructed through the Schiff bases condensation of indole-3-carboxaldehyde and 4-acetyl-N-allyl pyridinium chloride (ILs) with the amine groups of silica and magnetic nanoparticles. SiO2@indol-IL can inhibit the proliferation of HepG-2 cells in 48 h. Fe3O4@indol-IL can mimic the function of catalase to disproportionate H2O2 to O2, and has obvious effect on the proliferation of HepG-2 cells in 72 h. Moreover, the two nanoparticles show some inhibition on the expression of hypoxia inducible factor (HIF-1α), glucose transporter (GLUT1) and the production of lactate in HepG-2 cells. Therefore, we deduced that indole conjugated silica and magnetic nanparticles could be used as inhibitors of HIF-1α or GLUT1.

In order to find mitochondria-targeted mimics of catalase that can attenuate the metabolism of oxygen for cancer chemotherapy, two complexes [Mn(QA)Cl2] and [Mn(QA)(OAc)(H2O)2](OAc) (QA = 2-di(picolyl)amine-N-(quinoline-8-yl)acetamide) were synthesized and characterized by spectroscopic methods. In addition, the crystal structure of [Mn(QA)Cl2] shows that the Mn(II) atom is coordinated by three N atoms (N1, N2,and N3), and one oxygen atom (O1) of the ligand QA, plus two chloride atoms (Cl1 and Cl2), forming a distorted octahedral geometry. The complex [Mn(QA)(OAc)(H2O)2](OAc) could disproportionate H2O2 in Tris–HCl solution at 37 °C, with Kcat/KM = 9,226. Furthermore, both Mn(II) complexes were found to be active against the proliferation of HepG-2 cells and could attenuate the swelling of calcium-overloaded mitochondria. These results demonstrate that Mn(II) complexes of quinoline derivatives have potential as attenuators of the absorption of Ca2+ in mitochondria and can interfere with the metabolism of O2 for cancer chemotherapy.

A new type of fluorescent silver nanoclusters consisting of one silver bound to several strands of DNA, called multi-DNA–AgNCs, have been constructed using a bifunctional oligonucleotide with the recognition sequence 5′-CTACT-3′ as a stabilizing agent. The target oligonucleotide causes the multi-DNA–AgNCs to reassemble into smaller sized Ag clusters with quenched emission properties, while BSA induces the reassembly of the multi-DNA–AgNCs to give large particles with an enhanced emission. This demonstrates that the multi-DNA–AgNCs can specifically detect this recognition sequence. Furthermore, the multi-DNA–AgNCs show different fluorescence responses toward the total protein of normal cells (WRL-68), HepG-2 cells and HepG-2 cells incubated with 5-fluorourcil (5-Fu). The results show that the total protein of the HepG-2 cells, in which HIF is highly expressed, significantly decreases the fluorescence emission. Consequently, the multi-DNA–AgNCs can be used as a fluorescence probe for the detection of cancer cells, which have a high expression of HIF.

Two multifunctional colorimetric and fluorescent chemosensors were synthesized by the conjugation of BODIPY (4,4-difluoro-1, 3, 5, 7-tetramethyl-4-bora-3a, 4a-diaza-s-indacene) and di(2-picolyl)amine with benzyl groups (para-substituted, L1; meta-substituted, L2) as spacers, for selectively sensing copper(II) ions in preference to a variety of other common metal ions in aqueous media. The two analogous compounds exhibit different cytotoxic behaviour and attenuate mitochondrial membrane potentials in HepG-2 cells. In vitro bioassay results demonstrate that only L2 causes the decrease of mitochondrial membrane potentials in HepG-2 cells with low toxicity. Furthermore, fluorescence imaging in vitro confirms that L2 is a low toxicity chemosensor for copper(II) ions in living cells.

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)(H2O)] 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.Graphical abstractHighlights► The interaction of [(Adpa)Mn(Cl)(H2O)] to human transferrin (apoTf) was reported. ► The affinity of [(Adpa)Mn(Cl)(H2O)] to apoTf is a pH controlled reversible process. ► The apoTf enhanced inhibition rate on HepG-2 cells indicates apoTf is a carrier of this complex.

A new functional ionic liquid (IL) (IL = 4-acetyl-N-propenylpyridinium hexafluorophosphate) and methoxy poly(ethylene glycol) (PEG)-modified central hollow nano-vehicle (SiO2@IL–PEG) was synthesized and assembled with Mn(II) complexes, leading to two new kinds of nano-mimics of catalase. In vitro assay results show that the synthesized nano-mimics of catalase can decrease the oxygen consumption and mitochondria potential, which leads to effective inhibition of the proliferation of HepG-2 cells. Taken together, this study demonstrates that the ionic liquid and PEG-modified nano-vehicle is a good carrier of nano-models of catalase to target mitochondria, which would give a new path to develop mediators of cancer progression and the metabolite of oxygen.

Most anticancer complexes are unable to differentiate between diseased and healthy cells, systemic toxicity and undesired side effects can result. In the current study, a PEG and RGD peptides functionalized fluorescent dye Rhodamine B isothiocyanate (RBITC) doped magnetic silica nanoparticle (MnFe3O4@SiO2-PEG-RGD), carrying a anticancer superparamagnetic Mn(II) complex, was synthesized and characterized using spectroscopic methods. The multifunctional nanoparticles (MnFe3O4@SiO2-PEG-RGD) can image HepG-2 cells and differentiate between HepG-2 and WRL-68 cells based on T1 MR imaging technology. The in vitro fluorescence image and inhibition assay on the proliferation of HeLa cells indicate that MnFe3O4@SiO2-PEG-RGD nanoparticles can effectively reach the tumor site, be internalized by endocytosis and then retain in cancer cells due to the retention effect of nanoparticles. This study demonstrated that a PEG and RGD peptides functionalized silica nanoparticle was a good carrier for the anticancer complexes, and the anticancer complexes loaded multifunctional nanoparticles could be developed as special agents in monitoring therapy of cancer.Graphical abstractHighlights► A fluorescent superparamagnetic silica nanoparticle was synthesized. ► The nanoparticles can image HepG-2 cells. ► The nanoparticles could differentiate HepG-2 from WRL-68 cells. ► It can be internalized by endocytosis.

A functional ionic liquid (IL) (IL = 4-acetyl-N-butyl pyridinium hexafluorophosphate) was synthesized and conjugated with low toxicity of nanospheres (RBITC@SiO2), forming a new kind of fluorescent core–shell ellipsoidal RBITC@SiO2-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@SiO2-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@SiO2-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.Graphical abstractA new functional ionic liquid (IL) (IL = 4-acetyl-N-butyl pyridinium hexafluorophosphate) was conjugated with nanosphere RBITC@SiO2 forming a fluorescent core–shell epplisoidal RBITC@SiO2-IL nanoparticle with anticancer activities through mitochondria involved path.Highlights► A new functional ionic liquid (IL) was synthesized and conjugated with a nanosphere. ► A fluorescent core–shell ellipsoidal RBITC@SiO2-IL nanoparticle was obtained. ► Ellipsoidal RBITC@SiO2-IL is more active against the proliferation of HeLa cells. ► Target mitochondria and image cancer cell.

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 O2 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 H2O2 activity. The reaction of carboxylate-bridged dimanganese Mn(II) complex with H2O2 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 O2 through the H2O2 or ROS involved signaling induced apoptosis of cancer cells.

Three new copper(II) complexes of N-benzyl di(pyridylmethyl)amine (phdpa) were synthesized and characterized by spectroscopic methods. The interaction between CT–DNA and the complexes was studied by UV and fluorescence titration methods. It was found that the complex [(phdpa)Cu(H2O)Ac)](Ac), with the non-planar aromatic heterocyclic ring ligand (phdpa), showed good anticancer properties and could cause the fragmentation of the nucleus, although its interaction with CT–DNA was weaker than that of 1,10-phenanthroline (phen) -based copper(II) complexes. The anticancer activities of copper(II) complexes with phdpa and phen based ligands are correlated to their binding constants with DNA, but phen-based copper(II) complexes did not cause the nucleus fragmentation of HeLa cells. [(phdpa)Cu(H2O)Ac)](Ac) can noticeably decrease the oxygen content of a culture solution and of HeLa cells, which make it a new nucleus and oxygen related anticancer copper(II) complex. Information obtained here would be helpful in the design of new antitumor complexes in oxidative therapy.

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.Graphical abstract. Fe(III)-di(picolyl)amine complex modified nanospheres displayed a enhanced fluorescent imaging of HeLa cells in vitro and cause morphological change of HeLa cell under UV irradiation.Highlights► The Fe(III)-di(picolyl)amine complex modified nanospheres displayed enhanced HeLa cells uptake in vitro. ► This is the first report of a multifunctional nanosphere that combines the advantage of a target of cancer environment and fluorescence imaging. ► The conjugate of dpa-Fe(III) complex and fluorescence core–shell nanoparticles RBITC-SiO2 represents a class of novel multi-functional nanoparticles.

The dinuclear Mn(II) complexes of bis(2-pyridylmethyl)amine (dpa) reacted with H2O2 producing a fluorescent dioxodimanganese(III,IV) intermediate [(dpa)Mn2Cl2(μ-O2)(OHdpa)]3+, which was characterized by IR, UV, ESR, ES-MS and fluorescence spectra. ES-MS data show that this intermediate could bind an acetone molecule forming dioxodimanganese(III,IV)–acetone adduct [(dpa)Mn2Cl2(μ-O)(CH3COCH3)(OHdpa)]3+. The emission of dioxodimanganese(III,IV)–acetone at 378 nm was stronger than that of dioxodimanganese(III,IV) complex. Excess acetone molecules promoted the intramolecular C–H oxidation and the formation of one dimensional chain Mn(II) complex [(2-picolinic-acid)Mn(H2O)2Cl(O)]n through possible intramolecular oxygen transfer reaction.Graphical abstractHighlights► A first fluorescent dioxodimanganese(III,IV) intermediate was characterized by spectrometric methods. ► This intermediate could bind an acetone molecule forming a new fluorescence dioxodimanganese(III,IV)–acetone adduct. ► Excess acetone molecules promote the intramolecular C–H oxidation of dioxodimanganese(III,IV) complexes through possible intramolecular oxygen transfer reaction.

Two new complexes [(Etdpa)MnCl2] and [(Adpa)Mn(Cl)(H2O)] (Etdpa = ethyl bis(2-pyridylmethyl)amino-2-propionate; Adpa = bis(2-pyridylmethyl)amino-2-propionic acid) were synthesized and characterized by spectral methods. The crystal structure of [(Etdpa)MnCl2] shows that the Mn(II) atom is coordinated by three N atoms (N1, N2, N3), one oxygen atom (O1) of the ligand (Etdpa) and two chloride atoms (Cl1, Cl2), forming a distorted octahedral geometry. The binding interaction between ct-DNA and the synthesized complexes was relatively weak, but they can inhibit the induced swelling of Ca2+-loaded mitochondria in a dose-dependent manner. The [(Adpa)Mn(Cl)(H2O)] can cause the obvious decrease of mitochondria membrane potential. The MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenpyltetra-zolium bromide) assay shows that the two Mn(II) complexes are more active against cancer cells. Especially [(Adpa)Mn(Cl)(H2O)] can inhibit the proliferation of glioma cells with IC50 9.5 μM. Experimental results indicate that the [(Adpa)Mn(Cl)(H2O)] could be a new potential antitumor complex to target the mitochondria.The manganese (II) complexes of bis(2-pyridylmethyl)amino-2-propionic acid) were synthesized and characterized by spectral methods. The complex can cause the obvious decrease of mitochondria membrane potential and can inhibit the proliferation of glioma cells with IC50 9.5 μM. Experimental results indicate that the [(Adpa)Mn(Cl)(H2O)] could be a new potential antitumor complex to target the mitochondria.

Four copper(II) complexes with N-allyl di(picolyl)amine were synthesized and characterized by physico-chemical and spectroscopic methods. The spectrophotometric and fluorescence titration data indicate that the [(Aldpa)Cu(L)](ClO4)2 (L = dppz, dione, phen) with conjugated aromatic rings as coordinated ligands can be inserted into the base stacks of DNA more deeply than the [(Aldpa)CuCl2]. The copper(II) complexes [(Aldpa)Cu(L)](ClO4)2 (L = dppz, dione, phen) can inhibit the proliferation of the four cancer cells (Mcf-7, Eca-109, A549 and HeLa) with IC50 0.5–19.2 μM, which is larger than that (23.2–84.3 μM) of [(Aldpa)CuCl2], suggesting their inhibiting activities on the four cancer cells are correlated with their DNA-binding properties. However, the selectivity of [(Aldpa)CuCl2] to cancer cells is better than that of the other three complexes [(Aldpa)Cu(L)](ClO4)2, which indicates the substituents introduced on the secondary amino nitrogen atom of dpa have great contribution to the antitumor activities of these copper(II) complexes.

The unique properties of paramagnetic nanoscale metal-organic frameworks provide them with high potential as key probes and vectors in the next generation of biomedical applications. To increase the nanoparticle targeting at the tumor site, the grafting of Mn(II)-dpa (dpa =di(picolyl)amines) on oxide nanoparticles (SiO2) is proposed. The new Mn(II)-dpa-grafted silica nanoparticles can enhance the MR imaging area in cancer tissues and perturb the Ca2+-loaded mitochondria swelling. Experimental results indicate the cancer cells may be targeted through possible intracellular Ca2+ signaling mitochondria accumulating in vivo.

Three complexes with 2-[bis(2-pyridylmethyl)amino] propanic acid (Adpa) were synthesized and characterized. The crystal structure of [(Adpa)CoCl] (1) shows that the cobalt(II) atom is coordinated by three N atoms, one oxygen atom from the Adpa ligand and one chloride, forming a distorted trigonal bipyramidal geometry. The fluorescence titration data indicate the interactions of ct-DNA with complexes [(Adpa)FeCl2] (2) and [(Adpa)Fe(H2O)2] (3) are exothermic, but binding of complex (1) with ct-DNA is endothermic. The inhibiting activities of the three complexes on the cancer cells (Mcf-7, Eca-109, A549 and Hela) follow the order: (3) > (2) ≫ (1), which is in correlation with their DNA-binding properties.

Three new Cu(II) complexes with ethyl bis(2-pyridylmethyl)amino-2-propionate (Etdpa), or bis(2-pyridylmethyl)amino-2-propionate (Adpa), were synthesized and characterized by physico-chemical and spectroscopic methods. The X-ray crystal structure of [(Adpa)CuCl] shows that the copper(II) atom is coordinated by three N atoms, one oxygen atom from the ligand (Adpa) and one chloride anion, forming a trigonal bipyramidal geometry. The spectrophotometric and fluorescence titration data indicate that the interaction of square pyramidal [(Etdpa)CuCl2] with ct-DNA is weak, but the trigonal bipyramidal complexes [(Adpa)Cu(H2O)](ClO4) and [(Adpa)CuCl] interact with ct-DNA with the mode of intercalation. The inhibition activities of the three new copper(II) complexes on the four cancer cells (Mcf-7, Eca-109, A549, and Hela) are in the order: [(Adpa)Cu(H2O)](ClO4) > [(Adpa)CuCl] > [(Etdpa)CuCl2], which correlates with their DNA-binding properties. The results show that the substituents introduced on the secondary amino nitrogen atom of dpa have great contribution to the antitumor activities of these copper(II) complexes. It is also found that the coordination of copper(II) ions with AdpaH can decrease the toxicity of AdpaH.

Copper(II) complexes of ethyl 2-[bis(2-pyridylmethyl)amino]propionate ligand (ETDPA) have been synthesized and characterized by elemental analyses, IR spectra, UV spectra and ES-MS. These complexes are stable in air with the formula of [(ETDPA)CuCl2] and [(ETDPA)Cu(phen)](ClO4)2. The DNA-binding properties of the Cu(II) complexes have been investigated by ultraviolet spectroscopy and fluorescence spectroscopy, which showed that the binding mode of the two complexes with DNA was different. The binding mode of [(ETDPA)CuCl2] is not the classical intercalation binding, and the binding mode of [(ETDPA)Cu(phen)](ClO4)2 with DNA is intercalation. The cytotoxic assay shows that the [(ETDPA)Cu(phen)](ClO4)2 is more active on the proliferation of cancer cells than the [(ETDPA)CuCl2].

Two new Mn(II) complexes of bis(2-pyridylmethyl)benzylamine (bpa) were synthesized and characterized by elemental analyses, IR and UV–visible spectroscopies, thermal analyses and ES-MS. These complexes are stable in air with the formula of [(pba)2Mn2Cl2(μ-Cl)2] (1) and [(pba)2Mn2(H2O)2(μ-Ac)2] (Ac)2 (2). The spectroscopic titration results show that the complexes could react with H2O2 resulting active oxidants, which could cause the intramolecular aromatic hydroxylation. The hydroxylated ligand (pba-OH) was confirmed by ES-MS and HPLC.

Fourteen novel compounds were synthesized and characterized by using NMR and ESI-MS methods. The bioactivities of the four novel 4-Ar-2-oxo-glutaric acids were studied by using the LC-MS method. The experimental results show that 3-nitrobenzyl-2-oxo-glutaric acid is a mild inhibitor for the hydroxylation reaction catalyzed by PHD2. The decarboxylated peak for 3-fluorobenzyl-2-oxo-glutaric acid was observed by using the negative LC-MS method, indicating that it can be used as a mild cosubstrate to replace 2-OG, but this is possible only in the presence of the prime peptide CODD 19 mer.

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 new type of fluorescent silver nanoclusters consisting of one silver bound to several strands of DNA, called multi-DNA–AgNCs, have been constructed using a bifunctional oligonucleotide with the recognition sequence 5′-CTACT-3′ as a stabilizing agent. The target oligonucleotide causes the multi-DNA–AgNCs to reassemble into smaller sized Ag clusters with quenched emission properties, while BSA induces the reassembly of the multi-DNA–AgNCs to give large particles with an enhanced emission. This demonstrates that the multi-DNA–AgNCs can specifically detect this recognition sequence. Furthermore, the multi-DNA–AgNCs show different fluorescence responses toward the total protein of normal cells (WRL-68), HepG-2 cells and HepG-2 cells incubated with 5-fluorourcil (5-Fu). The results show that the total protein of the HepG-2 cells, in which HIF is highly expressed, significantly decreases the fluorescence emission. Consequently, the multi-DNA–AgNCs can be used as a fluorescence probe for the detection of cancer cells, which have a high expression of HIF.

A new functional ionic liquid (IL) (IL = 4-acetyl-N-propenylpyridinium hexafluorophosphate) and methoxy poly(ethylene glycol) (PEG)-modified central hollow nano-vehicle (SiO2@IL–PEG) was synthesized and assembled with Mn(II) complexes, leading to two new kinds of nano-mimics of catalase. In vitro assay results show that the synthesized nano-mimics of catalase can decrease the oxygen consumption and mitochondria potential, which leads to effective inhibition of the proliferation of HepG-2 cells. Taken together, this study demonstrates that the ionic liquid and PEG-modified nano-vehicle is a good carrier of nano-models of catalase to target mitochondria, which would give a new path to develop mediators of cancer progression and the metabolite of oxygen.

Three new copper(II) complexes of N-benzyl di(pyridylmethyl)amine (phdpa) were synthesized and characterized by spectroscopic methods. The interaction between CT–DNA and the complexes was studied by UV and fluorescence titration methods. It was found that the complex [(phdpa)Cu(H2O)Ac)](Ac), with the non-planar aromatic heterocyclic ring ligand (phdpa), showed good anticancer properties and could cause the fragmentation of the nucleus, although its interaction with CT–DNA was weaker than that of 1,10-phenanthroline (phen) -based copper(II) complexes. The anticancer activities of copper(II) complexes with phdpa and phen based ligands are correlated to their binding constants with DNA, but phen-based copper(II) complexes did not cause the nucleus fragmentation of HeLa cells. [(phdpa)Cu(H2O)Ac)](Ac) can noticeably decrease the oxygen content of a culture solution and of HeLa cells, which make it a new nucleus and oxygen related anticancer copper(II) complex. Information obtained here would be helpful in the design of new antitumor complexes in oxidative therapy.