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Due to the complexity and heterogeneity of solid tumors, traditional clinical treatments often only achieve limited therapeutic effects. Tumor-associated macrophages (TAMs) play a key role in the development of solid tumors, and the elimination of solid tumors based on the tumor microenvironment has proven to be an effective therapeutic strategy. Here, we successfully developed Ru-based nanoparticles, Ru@ICG-BLZ NPs, with inflammation-responsive release ability, which could repolarize TAMs into M1 macrophages (with an antitumor role) and further produce hyperthermia and ROS to eliminate cancer cells. In vitro experiments showed that Ru@ICG-BLZ NPs had superior drug (ICG and BLZ-945) loading capacity and sensitive inflammation-responsive drug release behavior, which enhanced CT26 cell uptake and penetration ability. Furthermore, in vivo experiments showed that Ru@ICG-BLZ NPs could effectively up-regulate the expression of M1 markers (iNOS, and IL-12) and exert phototherapy to ablate solid tumor, without causing obvious damage to the surrounding tissues of the tumor. The lower toxicity and excellent antitumor ability of Ru@ICG-BLZ NPs could provide new ideas for the clinical transformation of nanomedicine.

The blood-brain barrier (BBB) and low targeting are major obstacles for the treatment of gliomas. Accordingly, overcoming the BBB and enhancing the targeting of drugs to the glioma area are key to achieving a good therapeutic effect. Here, we have developed the mesoporous ruthenium nanosystem RBT@MRN-SS-Tf/Apt with dual targeting function. Transferrin (Tf) and aptamer AS1411 (Apt) are grafted on the surfaces of mesoporous ruthenium nanoparticles (MRN) with high loading capacity. This is achieved via redox-cleavable disulfide bonds, serving as both a capping agent and a targeting ligand, enabling the effective penetration of the blood-brain barrier and targeting the glioma. In addition, RBT@MRN-SS-Tf/Apt can specifically kill glioma cells in vitro and in vivo. Moreover, anti-tumor drugs [Ru(bpy) 2 (tip)] 2+ (RBT) will produce reactive oxygen species and induce apoptosis of tumor cells under laser irradiation, providing photodynamic therapy (PDT) for the treatment of gliomas, and further prolonging the median survival period. The study shows that this chemical photodynamic therapy nanosystem can be used as an efficient and powerful synergistic system for the treatment of brain tumors and other brain diseases of the central nervous system. STATEMENT OF SIGNIFICANCE: In order to overcome the blood-brain barrier and low targeting, and enhance the anti-glioma activities of nanodrugs. We have developed RBT@MRN-SS-Tf/Apt with dual targeting function. It is achieved release drug via redox-cleavable disulfide bonds, and enable the effective penetration of the blood-brain barrier and targeting the glioma. Moreover, anti-tumor drugs RBT will produce reactive oxygen species and induce apoptosis of tumor cells under laser irradiation, providing photodynamic therapy (PDT) for the treatment of gliomas, and further prolonging the median survival period. Therefore, this chemical photodynamic therapy nanosystem can be used as an efficient and powerful synergistic system for the treatment of brain tumors and other brain diseases of the central nervous system., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Human mesenchymal stem cells (MSCs) can be successively passaged and can differentiate into multiple lineages. These attributes are important in tissue engineering, which has a great deal of attention in stem cell therapy. However, the effective labelling and tracking of MSCs in vivo remain major unresolved issues. Based on the use of iron oxides to label stem cells for magnetic resonance imaging (MRI), we synthesized nanoparticle (NPs) containing ruthenium (RuNPs), γ-Fe 2 O 3 @Ru (Fe 2 O 3 @Ru), and γ-Fe 2 O 3 @selenium (Fe 2 O 3 @Se) to label MSCs and promote osteogenic differentiation. Fe 2 O 3 @Ru and Fe 2 O 3 @Se could be used as T 2 -weighted MRI contrast agents. Fe 2 O 3 @Ru more effectively diffused in the cytoplasm and localized in the nuclei of MSCs, compared with Fe 2 O 3 @Se. RuNPs, Fe 2 O 3 @Ru, and Fe 2 O 3 @Se induced MSCs to differentiate into osteoblasts. Fe 2 O 3 @Ru, in particular, was a potent osteoinductive agent. Fe 2 O 3 @Ru also inhibited adipocytic differentiation. Promotion of the osteogenic differentiation of MSCs may be regulated by a Smad-dependent bone morphogenetic protein signaling pathway with reduced expression of CD44, CD73, and CD105. MSCs treated with Fe 2 O 3 @Ru NPs expressing osteoblast surface markers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Different enantiomers exhibit large differences in their biological activity and/or toxicity, but they rarely involve the relationship of the agents for molecular and cellular imaging with the chiral structure of ruthenium complexes. Here, we report that an enantiomer of a polypyridyl ruthenium complex can selectively accumulate in the nucleus of HepG2 cells. Confocal laser scanning microscopy studies show that this phenomenon occurs via a non-endocytotic, but temperature-dependent, mechanism of cellular uptake in HepG2 cells. DNA oligonucleotides with repetitive tracts of guanine bases that can form G-quadruplex structures have aroused interest as therapeutic agents and as targets for anticancer drug design. Various biophysical techniques show that the Λ-enantiomer of ruthenium complexes can selectively stabilize human telomeric G-quadruplex DNA and has a strong preference for G-quadruplex over duplex DNA. Judged from the NMR results, we speculate that at higher 4:1 ligand/G-quadruplex stoichiometry, complex Λ-Ru is likely to bind with each groove of the tetraplex in a dimeric form or intercalate with the G-tetrad in the 3' terminal face and coexist with other modes. The molecular modeling analysis is in agreement with the NMR titrations performed in this investigation indicating that ruthenium complexes are actually characterized by a mixed binding mode. The results provide many opportunities for the development of novel agents for living cell-related studies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Studies have shown that ruthenium complexes have relatively strong anticancer activity, cell uptake of drugs have a crucial impact on the pharmacological activity, using autofluorescence of ruthenium complexes could effectively track cancer cells and drug distribution, transport accurately in real time. In this work, we present the synthesis and detailed characterization of two novel Ru(II) complexes with hydrophobic ancillary ligands, namely [Ru(bpy)2(5-idip)](2+) (RBD) and [Ru(phen)2(5-idip)](2+) (RPD) (5-idip = 2-indole-[4,5-f][1,10]phenanthroline). We have shown that RPD can enter the HeLa cells efficiently through non-endocytotic, but energy-dependent mechanism and first accumulated in lysosomes, and then escape from the lysosomes and localize within the nuclei, efficiently lead to the inhibition of DNA transcription and translation and induced cell apoptosis. Further studies on the mechanism of apoptosis in HeLa cells demonstrate that RPD is able to induce mitochondria-mediated apoptosis in HeLa cells through activation of initiator caspase-9 and down-stream effector caspase-3 and -7 and cleavage of PARP. We have also demonstrated that RPD bind to telomeric G-quadruplex DNA effectively and selectively, together with increased p21 and p16 expression. Our findings suggest that RPD induces HeLa cell apoptosis through mitochondria-mediated pathway and inhibition of telomerase activity. RPD may be a candidate for further evaluation as a chemotherapeutic agent for human cancers., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Two ruthenium(II) complexes (Ru-complexes) were synthesized and characterized in this study. The selectivity and ability of the complexes to interact with bcl-2 DNA were investigated here. It turned out that [Ru(ip)3](ClO4)2·2H2O (complex 1, ip = 1H-iminazole [4,5-f][1,10] phenanthroline) could induce and stabilize the formations of G-quadruplexes more effectively than [Ru(pip)3](ClO4)2·2H2O (complex 2, pip = 2-phenylimidazo-[4,5-f][1,10]phenanthroline) did. Considering the important role of the Ru-complex ligand in inducing and stabilizing the formations of G-quadruplex in our previous studies, we speculate that the overlarge ligand of complex 2 may block its binding affinity for G-quadruplexes. Complex 1 also induced cell apoptosis in in vitro assays. In general, this study provided potentially important information for further development of the Ru-complexes as good inducers and stabilizers of bcl-2 G-quadruplex DNA for cancer treatment., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)

Angiogenesis is crucial for tumor growth. Thus, inhibiting angiogenesis represents a promising avenue for preventing tumor growth. This study investigated the anti-angiogenesis and anti-tumor effects of 8-hydroxyquinoline ruthenium(II) complexes [Ru(bpy)2(8-HQ)](+) (BQ) and [Ru(phen)2(8-HQ)](+) (PQ). The results showed that both compounds, especially PQ, suppressed the proliferation, migration, invasion, tube formation and microvessel growth of endothelial cells in vitro. PQ also inhibited tumor growth of human hepatocellular liver carcinoma cells (HepG2) in a mouse xenograft tumor model in vivo. To understand the mechanisms of how ruthenium(II) complexes disrupt bFGF-induced angiogenesis and tumor growth, we have shown that (1) both compounds can interfere with the binding of bFGF to its cell surface receptors, thereby suppressing activation of bFGF-mediated signaling cascades; (2) PQ can induce tumor cell apoptosis. These effects might inhibit angiogenesis and tumor cell proliferation in tumor tissue. Taken together, our findings reveal that 8-hydroxyquinoline ruthenium(II) complexes are specific inhibitors of bFGF-mediated angiogenesis, and may be a viable drug candidate in anti-angiogenesis and anti-tumor therapies.

Here we reported the high tumor targeting efficacy of luminescent Ru(II)-thiols protected selenium nanoparticles (Ru-MUA@Se). We have shown that a dual-target inhibitor Ru-MUA@Se directly suppress the tumor growth but also block blood-vessel growth. We also determined that the nanoparticles entered the cells via clathrin-mediated endocytosis pathway. In a xenograft HepG2 tumor model, we found that Ru-MUA@Se effectively inhibited tumor angiogenesis and suppressed tumor growth with low side effects using metronomic chemotherapy with Ru-MUA@Se. In vivo investigation of nanoparticles on nude mice bearing HepG2 cancer xenografts confirmed that Ru-MUA@Se nanoparticles possessed high tumor-targeted fluorescence imaging, exhibited enhanced antitumor efficacy and decreased systemic toxicity. Moreover, Ru-MUA@Se not only significantly induced dose-dependent disruption of mitochondrial membrane potential in HepG2 cells after 24 h treatment, but it also enhanced reactive oxygen species (ROS) generation. Our results suggest that the potential application of these Ru-MUA@Se nanoparticles in targeting cancer imaging and chemotherapy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Two ruthenium(II) complexes [Ru(IP)2(PIP)](ClO4)2·2H2O (1) and [Ru(PIP)2(IP)](ClO4)2·2H2O (2) (IP=imidazole [4, 5-f] [1,10] phenanthroline, PIP=2-phenylimidazo-[4, 5-f][1,10] phenanthroline) have been synthesized and characterized. The quadruplex binding of the compounds was evaluated by emission spectrum, CD spectroscopy, Visual detection assay and FRET (fluorescence resonance energy transfer)-melting assay. The results show that both complexes can induce the stabilization of quadruplex DNA, while complex 1 is a better G-quadruplex binder than complex 2. Furthermore, polymerase chain reaction-stop assay, electrophoretic mobility shift assay, telomerase repeat amplification protocol and MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay demonstrate that complex 1 not only can stabilize dimer forms of the G-quadruplex at low concentrations but also exhibit better inhibitory activity for telomerase and cancer cells., (© 2013. Published by Elsevier Inc. All rights reserved.)

In the present study, the interaction between GC-rich sequence of bcl-2 gene P1 promoter (Pu39) and two ruthenium (II) polypyridyl complexes, [Ru(bpy)₂(tip)]²⁺ (1) and [Ru(phen)₂(tip)]²⁺ (2), was investigated by UV-Visible, fluorescence spectroscopy, circular dichroism, fluorescence resonance energy transfer melting assay and polymerase chain reaction stop assay. Those experimental results indicated that the two complexes can effectively stabilize the G-quadruplex of Pu39. It was found that the complex 2 exhibited greater cytotoxic activity than 1 against human Hela cells and can enter into Hela cells in a short period of time to effectively induce apoptosis of cells. Further experiments found that complexes 1 and 2 had as potent inhibitory effects on ECV-304 cell migration as suramin. Those noteworthy results provide new insights into the development of anticancer agents for targeting G-quadruplex DNA.

Two ruthenium(ii) polypyridyl complexes [Ru(phen)2(4idip)](ClO4)2 () and [Ru(bpy)2(4idip)](ClO4)2 () (phen = 1,10-phenanthroline, bpy = 2,2'-bipyridine, 4idip = 4-indoleimidazo[4,5-f][1,10]phenanthroline) designed as telomeric G-quadruplex ligands have been synthesized and characterized. The interaction of human telomeric G-quadruplex DNA (HTG21) with the designed ligands was explored by fluorescence analysis, absorption spectroscopy, continuous variation, circular dichroism spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, telomerase repeat amplification protocol (TRAP), and visual studies. The results showed that both complexes could induce and stabilize different G-quadruplex structures by using a 1 : 1 [quadruplex]/[complex] binding mode ratio. Complex exhibited higher interaction ability and better G-quadruplex selectivity than duplex DNA. Furthermore, both ruthenium complexes led to the inhibition of the enzyme telomerase, and complex was the significantly better inhibitor.

Anti-angiogenesis is an effective strategy for cancer treatment because uncontrolled tumor growth depends on tumor angiogenesis and sufficient blood supply. Thus, blocking angiogenesis could be a strategy to arrest tumor growth. The function and mechanism of luminescent ruthenium-modified selenium nanoparticles (Ru-SeNPs) in angiogenesis have not been elucidated to date. Here, we found that Ru-SeNPs significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration and tube formation. Ru-SeNPs was also tested in vivo in the chicken chorioallantoic membrane (CAM) assay and found to inhibit bFGF-treated CAMs development like suramin. Moreover, we showed that Ru-SeNPs inhibited the activations of FGFR1 and its downstream protein kinases, such ErK and AKT. Furthermore, by using fluorescence confocal microscopy and TEM imaging studies, we have demonstrated their cellular uptake and localization within the cytoplasm of HepG2 and HUVEC cells. These findings indicate that Ru-SeNPs inhibits angiogenesis and may be a viable drug candidate in anti-angiogenesis and anticancer therapies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Stem cells have generated a great deal of excitement in tissue engineering and regenerative medicine, and it is important to understand the interaction mechanisms between nanomaterials and mesenchymal stem cells (MSCs) for biomedical applications. In this study, ruthenium (II) functional selenium nanoparticles (Ru@Se) are used for stem cell research. Specifically, Ru@Se are compared with citric acid selenium nanoparticles (Cit@Se)to identify their effects on MSCs differentiation and associated molecular mechanism. These data suggest that the effective adsorbing abilities of Ru@Se and Cit@Se allow them to act as preconcentration materials for osteogenic chemical inducers, which accelerates MSCs differentiation into osteoblasts. Further results suggest that selenium nanoparticles enhance the differentiation of MSCs toward osteogenic lineage over adipocytes by promoting osteogenic transcription and attenuating adipogenic transcription. Ru@Se and Cit@Se exert these effects by activating Smad-dependent BMP signaling pathway, which regulates the expression of relevant genes to induce osteogenic differentiation. [ABSTRACT FROM AUTHOR]

Abstract: The binding properties of two Ru(II) complexes [Ru(bpy)2(ox)]2+ (RBO) and [Ru(bpy)2(suc)]2+ (RBS) (bpy=2, 2-bipyridine, ox=oxalate, and suc=succinate) to human serum albumin (HSA) have been studied by fluorescence, UV–vis absorption spectroscopy and circular dichroism (CD) spectroscopy. The fluorescence quenching mechanism was determined to be a static quenching procedure. The Stern–Volmer quenching constant K sv and corresponding thermodynamic parameters ΔH, ΔS and ΔG were calculated. The number of binding site was about 1. The result of CD showed that the secondary structure of HSA molecules was changed in the presence of the Ru(II) complexes. Furthermore, the anticancer activities of the complexes were evaluated by using the MTT assay, the results indicated that the antiproliferative activity of RBS was higher than that of RBO, and RBS showed a significant antitumor activity through induction of apoptosis in A549 cells. [Copyright &y& Elsevier]