Arene-Arene Coupled Disulfamethazines (or Sulfadiazine)-Phenanthroline-Metal(II) Complexes were Synthesized by In Situ Reactions and Inhibited the Growth and Development of Triple-Negative Breast Cancer through the Synergistic Effect of Antiangiogenesis, Anti-Inflammation, Pro-Apoptosis, and Cuproptosis.

The novel metal(II)-based complexes HA-Cu, HA-Co, and HA-Ni with phenanthroline, sulfamethazine, and aromatic-aromatic coupled disulfamethazines as ligands were synthesized and characterized. HA-Cu, HA-Co, and HA-Ni all showed a broad spectrum of cytotoxicity and antiangiogenesis. HA-Cu was superior to HA-Co and HA-Ni, and even superior to DDP, showing significant inhibitory effect on the growth and development of tripe-negative breast cancer in vivo and in vitro. HA-Cu exhibited observable synergistic effects of antiproliferation, antiangiogenesis, anti-inflammatory, pro-apoptosis, and cuproptosis to effectively inhibited tumor survival and development. The molecular mechanism was confirmed that HA-Cu could downregulate the expression of key proteins in the VEGF/VEGFR2 signaling pathway and the expression of inflammatory cytokines, enhance the advantage of pro-apoptotic protein Bax, and enforce cuproptosis by weakening the expression of FDX1 and enhancing the expression of HSP70. Our research will provide a theoretical and practical reference for the development of metal-sulfamethazine and its derivatives as chemotherapy drugs for cancer treatment.

A novel chiral oxazoline copper(II)-based complex inhibits ovarian cancer growth in vitro and in vivo by regulating VEGF/VEGFR2 downstream signaling pathways and apoptosis factors.

A novel chiral oxazoline copper(II)-based complex {[Cu(C13H14NO3S)2]}2 (Cu-A) was synthesized by an in situ reaction using L-methioninol, 4-hydroxyisophthalaldehyde, sodium hydroxide and copper(II) nitrate trihydrate as reactants. Its crystal structure was characterized. In vitro, Cu-A was superior to cis-dichlorodiammineplatinum (DDP) in cytotoxicity and angiogenesis inhibition. Cu-A significantly induced apoptosis of ovarian cancer cells (SKOV3) and human umbilical vein endothelial cells (HUVECs), showing significant anti-ovarian cancer and anti-angiogenesis effects. Notably, Cu-A significantly inhibits the growth of ovarian cancer in nude mice xenografted with SKOV3 cells, and it is less renal toxic than DDP. The molecular mechanism of anti-ovarian cancer and anti-angiogenesis is possibly that it down-regulates the expression of the proteins ERK1/2, AKT, FAK, and VEGFR2 and their phosphorylated proteins p-ERK1/2, p-AKT, p-FAK, and p-VEGFR2 in the VEGF/VEGFR2 signal transduction pathway to inhibit SKOV3 cell and HUVEC proliferation, induce apoptosis, suppress migration and metastasis, and inhibit angiogenesis. What's more, Cu-A significantly inhibits ovarian tumor growth in vivo by inhibiting tumor cells from inducing vascular endothelial cells to form their own vasculature and by inhibiting the expression of the anti-apoptotic protein Bcl-2 and up-regulating the expression of the pro-apoptotic proteins Caspase-9 and Bax to induce apoptosis of tumor cells.

Two novel chiral tetranucleate copper-based complexes: syntheses, crystal structures, inhibition of angiogenesis and the growth of human breast cancer in vitro and in vivo.

The single crystals of two novel chiral tetranucleate copper(II)-based complexes (TNCu-A and TNCu-B) containing L-methioninol-derived Schiff-bases were obtained. Their single structures were characterized by X-ray single crystal diffraction, infrared (IR) rays, elemental analysis, and liquid chromatography-mass spectrometry analysis. TNCu-A can effectively inhibit human umbilical vein endothelial cells (HUVECs) to form a tubular structure and it induces apoptosis of human triple-negative breast cancer MDA-MB-231 cells and HUVECs in vitro in a mitochondria dependent manner. Moreover, in vivo TNCu-A can remarkably inhibit the growth of triple-negative breast cancer from which MDA-MB-231 cells were xenografted into severely immunodeficient nude mice by inhibiting proliferation, inducing apoptosis of MDA-MB-231 cells by dramatically inhibiting the expression of the anti-apoptotic protein Bcl-2 and up-regulating the expressions of proapoptotic proteins caspase-9 and Bax, and simultaneously inhibiting tumor angiogenesis by decreasing the density of vascular endothelial cells and suppressing migration and even partially inducing apoptosis.

Two novel chiral tetranucleate copper-based complexes: crystal structures, nanoparticles, and inhibiting angiogenesis and the growth of human breast cancer by regulating the VEGF/VEGFR2 signal pathway in vitro.

The single crystals of two novel copper(ii)-based complexes containing l-methioninol-derived Schiff bases were obtained and characterized. The nanoparticles of these complexes were prepared and their cellular uptake was measured in MDA-MB-231 cells and HUVECs. It was found that these complexes could remarkably induce apoptosis, inhibit proliferation, suppress migration and metastasis, and inhibit angiogenesis and the growth of triple-negative breast cancer derived from MDA-MB-231 cells in vitro. Meanwhile, these complexes exhibit anticancer and antiangiogenic functions by activating the important protein molecules VEGFR2, FAK, AKT and Erk1/2 or their phosphorylated molecules p-VEGFR2, p-FAK, p-AKT, and p-Erk1/2 in the VEGF/VEGFR2 signaling pathway, collapsing the mitochondrial membrane potential, and damaging the level of reactive oxygen species.

Microbubbles in combination with focused ultrasound for the delivery of quercetin-modified sulfur nanoparticles through the blood brain barrier into the brain parenchyma and relief of endoplasmic reticulum stress to treat Alzheimer's disease.

The delivery of drugs across the blood-brain barrier (BBB) effectively and safely is one of the major challenges in the treatment of neurodegenerative diseases. In this work, we constructed a nano-system using microbubbles to promote the crossing of drugs across the BBB, where microbubbles in combination with focused ultrasound were used to mediate the transient opening of the BBB and delivery of nanomedicines. This system (Qc@SNPs-MB) was formed by embedding quercetin-modified sulfur nanoparticles (Qc@SNPs) in microbubbles (MB). Qc@SNPs-MB was destroyed instantly when exposed to ultrasonic pulses, and it enhanced the permeability of the blood vessels, resulting in the brief opening of the BBB owing to the "sonoporation" effect. Also, Qc@SNPs were released from the outer shell of the microbubbles and entered the brain across the open BBB, accumulating in the brain parenchyma. Due to the rapid accumulation of Qc@SNPs in the brain, it effectively reduced neuronal apoptosis, inflammatory response, calcium homeostasis imbalance, and oxidative stress, which are all mediated by endoplasmic reticulum stress, and protected nerve cells, thus treating Alzheimer's disease (AD) effectively. The Morris water maze experiment showed that the learning ability and memory ability of the AD mice treated with Qc@SNPs were significantly improved, and no obvious side effects were found. Therefore, Qc@SNPs-MB combined with ultrasound can provide an effective and safe drug delivery method for the treatment of neurodegenerative diseases and a promising strategy for endoplasmic reticulum stress therapy.

Ru@CeO2 yolk shell nanozymes: Oxygen supply in situ enhanced dual chemotherapy combined with photothermal therapy for orthotopic/subcutaneous colorectal cancer.

Hypoxia is an important factor in forming multidrug resistance, recurrence and metastasis in solid tumors. Nanozymes respond to tumor microenvironment for tumor-specific treatment is a new and effective strategy. In this study, one-pot method was used to synthesize hollow Ru@CeO2 yolk shell nanozymes (Ru@CeO2 YSNs), which possess excellent light-to-heat conversion efficiency and catalytic performance. Antitumor drug ruthenium complex (RBT) and resveratrol (Res) were dual-loaded in Ru@CeO2 YSNs, and a double outer layer structure using polyethylene glycol was constructed to form dual-drug delivery system (Ru@CeO2-RBT/Res-DPEG) that was released on demand. The double outer layer structure increased the biocompatibility of Ru@CeO2 YSNs and effectively prolong the circulation time in blood. Ru@CeO2-RBT/Res-DPEG catalyzes endogenous H2O2 to produce oxygen, which achieve in situ oxygen supply and enhanced dual-chemotherapy and photothermal therapy (PTT) for colorectal cancer. In vitro studies found that Ru@CeO2-RBT/Res-DPEG has good tumor penetration depth and antitumor effect. In addition, Ru@CeO2-RBT/Res-DPEG can alleviate tumor hypoxia, and inhibit metastasis and recurrence of orthotopic and subcutaneous colorectal cancer. Accordingly, the study shows that yolk shell nanozymes can be used as an efficient synergistic system for dual-chemotherapy and PTT to kill tumor and inhibit orthotopic colorectal cancer metastasis and recurrence.

Anti-cancer activities of metal-based complexes by regulating the VEGF/VEGFR2 signaling pathway and apoptosis-related factors Bcl-2, Bax, and caspase-9 to inhibit angiogenesis and induce apoptosis.

Three novel single crystals of the metal-based complexes Cu-1, Cu-2, and Co-1 were obtained and characterized. Compared with Cu-2 and Co-1, Cu-1 showed remarkable activities of anti-cervical cancer, anti-cisplatin-resistant non-small cell lung cancer and anti-angiogenesis by downregulating the expressions of important proteins in the VEGF/VEGFR2 signaling pathway to inhibit angiogenesis and cancer cell proliferation, induce apoptosis, and suppress migration and metastasis. Moreover, Cu-1 dramatically inhibited the expression of the anti-apoptotic protein Bcl-2 and up-regulated the expressions of the proapoptotic proteins caspase-9 and Bax to induce the apoptosis of tumor cells, simultaneously decreasing the density of endothelial cells to inhibit tumor angiogenesis in cisplatin-resistant tumors.

Photothermal-Chemotherapy Integrated Nanoparticles with Tumor Microenvironment Response Enhanced the Induction of Immunogenic Cell Death for Colorectal Cancer Efficient Treatment.

Inducing immunogenic cell death (ICD) that enhances the immunogenicity of dead cancer cells is a new strategy for tumor immunotherapy, but efficiently triggering ICD is the biggest obstacle to achieving this strategy, especially for distant and deep-seated tumors. Here, a new therapeutic system (Pd-Dox@TGMs NPs) that can effectively trigger ICD by combining chemotherapy and photothermal therapy was designed. The nanosystem was fabricated by integrating doxorubicin (Dox) and a photothermal reagent palladium nanoparticles (Pd NPs) into amphiphile triglycerol monostearates (TGMs), which showed specific accumulation, deep penetration, and activation in response to the tumoral enzymatic microenvironment. It was proved that codelivery of Dox and Pd NPs not only effectively killed CT26 cells through chemotherapy and photothermal therapy but also promoted the release of dangerous signaling molecules, such as high mobility group box 1, calreticulin, and adenosine triphosphate, improving the immunogenicity of dead tumor cells. The effective ICD induction mediated by Pd-Dox@TGMs NPs boosted the PD-L1 checkpoint blockade effect, which efficiently improved the infiltration of toxic T lymphocytes at the tumor site and showed excellent tumor treatment effects to both primary and abscopal tumors. Therefore, this work provides a simple and effective immunotherapeutic strategy by combining chemical-photothermal therapy to enhance immune response.

Bacteria-Responsive Biomimetic Selenium Nanosystem for Multidrug-Resistant Bacterial Infection Detection and Inhibition.

Multidrug-resistant (MDR) bacterial infections are a severe threat to public health owing to their high risk of fatality. Noticeably, the premature degradation and undeveloped imaging ability of antibiotics still remain challenging. Herein, a selenium nanosystem in response to a bacteria-infected microenvironment is proposed as an antibiotic substitute to detect and inhibit methicillin-resistant Staphylococcus aureus (MRSA) with a combined strategy. Using natural red blood cell membrane (RBCM) and bacteria-responsive gelatin nanoparticles (GNPs), the Ru-Se@GNP-RBCM nanosystem was constructed for effective delivery of Ru-complex-modified selenium nanoparticles (Ru-Se NPs). Taking advantage of natural RBCM, the immune system clearance was reduced and exotoxins were neutralized efficiently. GNPs could be degraded by gelatinase in pathogen-infected areas in situ; therefore, Ru-Se NPs were released to destroy the bacteria cells. Ru-Se NPs with intense fluorescence imaging capability could accurately monitor the infection treatment process. Moreover, excellent in vivo bacteria elimination and a facilitated wound healing process were confirmed by two kinds of MRSA-infected mice models. Overall, the above advantages proved that the prepared nanosystem is a promising antibiotic alternative to combat the ever-threatening multidrug-resistant bacteria.

Inflammation-responsive functional Ru nanoparticles combining a tumor-associated macrophage repolarization strategy with phototherapy for colorectal cancer therapy.

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.

Targeted hexagonal Pd nanosheet combination therapy for rheumatoid arthritis via the photothermal controlled release of MTX.

Methotrexate (MTX) is a drug that is used for the clinical treatment of rheumatoid arthritis (RA), a stubborn disease caused by over-immunization. However, the toxicity that arises as a result of poor selectivity to inflammatory cells severely limits the application of MTX. Therefore, new therapeutic strategies are needed for treating RA. Here, we describe the design and synthesis of a nanotherapy agent, Pd-Cys@MTX@RGD, which can target inflammatory cells and control MTX release. The novel hexagonal palladium (Pd) nanosheets were used as a near-infrared (NIR) photothermal agent modified with arginine-glycineaspartic acid (RGD) peptides on the surface to enhance the ability of the nanosheet targeting of inflammatory cells. In subsequent experiments, the Pd-Cys@MTX@RGD nanosheets were observed to greatly reduce the toxicity of MTX, showing controlled MTX release under irradiation of 808 nm (0.3 W cm-2). Moreover, taking advantage of the fact that MTX can be combined with multiple therapeutic methods, the photothermal therapy (PTT) of Pd nanosheets provided a compensatory effect to enhance the therapeutic efficacy of MTX. Under combination therapy, Pd-Cys@MTX@RGD was shown to effectively inhibit the inflammatory response induced by vascular endothelial growth factor (VEGF) and IL-1ß. And, in vivo, multifunctional Pd-Cys@MTX@RGD effectively inhibited the symptoms of RA by inhibiting the expression of pro-inflammatory cytokines (TNF-α,COX-2). We hope that the construction of nanomaterials can add potential value to the design of chemical drugs and therapeutic strategies for RA.

Correction: Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response.

Correction for 'Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response' by Yanan Liu et al., J. Mater. Chem. B, 2019, 7, 586-597.

Flower-like gold nanoparticles for enhanced photothermal anticancer therapy by the delivery of pooled siRNA to inhibit heat shock stress response.

Due to the anti-apoptotic effect employed by cells to protect themselves, recent research shows that photothermal therapy (PTT) can lead to heat shock response, thus reducing the effect of treatment on cancer cells. Small interfering RNA (siRNA), as an effective carrier of RNA interference, can silence the expression of heat shock protein, HSPs or BAG3 genes by inhibiting the expression of specific genes, and thereby inhibiting heat shock response and making cancer cells more sensitive to PTT. In this study, flower-like gold nanoparticles were used as a core for a layer-by-layer strategy to produce a safe and biodegradable nanoparticle platform for gene silencing and photothermal therapy. The results showed that when the mass ratio of the GNFs and siRNA was 20 : 1, the loading efficiency was above 90%, which can effectively silence the expression of BAG3 siRNA. We demonstrated that the GNFs-siRNA still had a good photothermal effect after siRNA modification. In vitro, the GNFs-siRNA showed good biocompatibility and effectively tumor killing properties after laser irradiation. Furthermore, the GNFs-siRNA with laser treatment significantly decreased the expression of BAG3 and remarkably inhibited tumor growth in vivo. This nanosystem establishes an optimized platform for future gene delivery and photothermal therapy.

Synthesis, characterization, and anticancer activity of two mixed ligand copper(ii) complexes by regulating the VEGF/VEGFR2 signaling pathway.

The single crystals of two novel mixed-ligand copper(ii)-based complexes were obtained and characterized. These complexes can remarkably induce apoptosis, inhibit proliferation, suppress migration and metastasis, and inhibit angiogenesis to inhibit the growth of cervical cancer by down-regulating the expressions of the important proteins FAK, Akt and Erk1/2 or their phosphorylated proteins p-FAK, p-Akt, and p-Erk1/2 downstream of the VEGF/VEGFR2 signaling pathway.

Dinuclear ruthenium complexes display loop isomer selectivity to c-MYC DNA G-quadriplex and exhibit anti-tumour activity.

G-quadruplex DNA, especially the cellular-myelocytomatosis viral oncogene (c-MYC) is closely associated with cell-cycle regulation, proliferation of tumour cells. In this work, the interaction between the c-MYC and two dinuclear Ru(II) complexes [(bpy)2Ru(bpibp)Ru(bpy)2](ClO4)4 (compound 1) and [(phen)2Ru(bpibp)Ru(phen)2](ClO4)4 (compound 2) have been studied. The data from UV-Visible, PCR-stop and Fluorescence resonance energy transfer (FRET) showed that two complexes can stabilize the structure of G-quadruplex in the c-MYC promoter and targeting the G-quadruplex loop isomers. Interestingly, the complex 2 has a greater effect on the 1:2:1 and 2:1:1 loop isomers while the 1 prefers to the 1:2:1 isomers. The mechanism studies revealed that complexes can induce apoptosis in HepG2 cells by generating ROS metabolites, triggering mitochondrial membrane potential loss and down-regulation of P-Akt (Akt also known as protein kinase B), P-p44/42 MAP kinase protein (P-p44/42), and c-MYC. Taken together, these results suggested that the two dinuclear complexes may both be candidates as anti-tumour agents as they may reduce the c-MYC gene expression. {bpibp: 4, 4'-bis (1, 10-phenanthroline-[5, 6-d] imidazole-2-yl)-biphenyl, bpy: 2,2-bipyridine, phen: 1,10-phenanthroline}.

Co-delivery of Se nanoparticles and pooled SiRNAs for overcoming drug resistance mediated by P-glycoprotein and class III ß-tubulin in drug-resistant breast cancers.

Drug resistance mediated by P-glycoprotein (P-gp) and class III ß-tubulin (ß-tubulin III) is a major barrier in microtubule-targeting cancer chemotherapy. In this study, layered double hydroxide nanoparticles (LDHs) were employed to simultaneously deliver selenium (Se) and pooled small interfering RNAs (siRNAs) to achieve therapeutic efficacy. LDH-supported Se nanoparticles (Se@LDH) were compacted with siRNAs (anti-P-gp and anti-ß-tubulin III) via electrostatic interactions, which could protect siRNA from degradation. Se@LDH showed excellent abilities to deliver siRNA into cells, including enhancing siRNA internalization, and promoting siRNA escape from endosomes. siRNA transfection experiments further confirmed a higher gene silencing efficiency of Se@LDH than LDH. Interestingly, we found Se@LDH may be a microtubule (MT) stabilizing agent which could inhibit cell proliferation by blocking cell cycle at G2/M phase, disrupting normal mitotic spindle formation and inducing cell apoptosis. When complexed with different specific siRNAs, Se@LDH/siRNA nanoparticles, especially the Se@LDH-pooled siRNAs, exhibit an efficient gene-silencing effect that significantly downregulate the expression of P-gp and ß-tubulin III. Moreover, Se@LDH-pooled siRNAs could induce cell apoptosis, change cell morphology and increase cellular ROS levels through change the expression of Bcl-2/Bax, activation of caspase-3, PI3K/AKT/mTOR and MAPK/ERK pathways. These results suggested that co-delivery of Se and pooled siRNAs may be a promising strategy for overcoming the drug resistance mediated by P-gp and ß-tubulin III in drug-resistant breast cancers.

Improving the Anticancer Efficacy of Laminin Receptor-Specific Therapeutic Ruthenium Nanoparticles (RuBB-Loaded EGCG-RuNPs) via ROS-Dependent Apoptosis in SMMC-7721 Cells.

Functionalization can promote the uptake of nanoparticles into cancer cells via receptor-mediated endocytosis, enabling them to exert their therapeutic effects. In this paper, epigallocatechin gallate (EGCG), which has a high binding affinity to 67 kDa laminin receptor (67LR) overexpressed in HCC cells, was employed in the present study to functionalized ruthenium nanoparticles (RuNPs) loaded with luminescent ruthenium complexes to achieve antiliver cancer efficacy. [Ru(bpy)2(4-B)] (ClO4)2·2H2O (RuBB)-loaded EGCG-RuNPs (bpy = 2,2'-bipyridine) showed small particle size with narrow distribution, better stability, and high selectivity between liver cancer and normal cells. The internalization of RuBB-loaded EGCG-RuNPs was inhibited by 67LR-blocking antibody or laminin, suggesting that 67LR-mediated endocytosis played an important role in the uptake into HCC cells. Moreover, transmission electron microscopy and confocal microscopic images showed that RuBB-loaded EGCG-RuNPs accumulated in the cytoplasm of SMMC-7721 cells. Furthermore, our results indicated that the EGCG-functionalized nanoparticles displayed enhanced anticancer effects in a target-specific manner. Concentrations of RuBB-loaded EGCG-RuNPs, nontoxic in normal L-02 cells, showed direct reactive oxygen species-dependent cytotoxic, pro-apoptotic, and anti-invasive effects in SMMC-7721 cells. Furthermore, in vivo animal study demonstrated that RuBB-loaded EGCG-RuNPs possessed high antitumor efficacy on tumor-bearing nude mice. It is encouraging to conclude that the multifunctional RuNPs may form the basis of new strategies on the treatment of liver cancer and other malignancies.

The use of pH-sensitive functional selenium nanoparticles shows enhanced in vivo VEGF-siRNA silencing and fluorescence imaging.

The utility of small interfering RNAs (siRNAs) has shown great promise in treating a variety of diseases including many types of cancer. While their ability to silence a wide range of target genes underlies their effectiveness, the application of therapies remains hindered by a lack of an effective delivery system. In this study, we sought to develop an siRNA-delivery system for VEGF, a known signaling molecule involved in cancer, that consists of two selenium nanoparticles SeNPs and G2/PAH-Cit/SeNPs. A G2/PAH-Cit/SeNP is a pH-sensitive delivery system that is capable of enhancing siRNA loading, thus increasing siRNA release efficiency and subsequent target gene silencing both in vitro and in vivo. In vivo experiments using G2/PAH-Cit/SeNPs@siRNA led to significantly higher accumulation of siRNA within the tumor itself, VEGF gene silencing, and reduced angiogenesis in the tumor. Furthermore, the G2/PAH-Cit/SeNP delivery system not only enhanced anti-tumor effects on tumor-bearing nude mice as compared to SeNPs@siRNA, but also resulted in weak occurrence of lesions in major target organs. In sum, this study provides a new class of siRNA delivery system, thereby providing an alternative therapeutic route for cancer treatment.

Ruthenium(II) polypyridyl complexes: cellular uptake, cell image and apoptosis of HeLa cancer cells induced by double targets.

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.

Mixed-ligand mononuclear copper(II) complex: crystal structure and anticancer activity.

A novel copper(II) complex with mixed ligands including ß-[(3-formyl-5-methyl-2-hydroxy-benzylidene)amino]propionic acid anion and 1,10'-phenanthroline was synthesized, and its crystal structure was thoroughly characterized. It exerted excellent inducing apoptosis, anti-angiogenesis and antiproliferative properties in vitro. The complex can bind human serum albumin (HSA) at physiological pH conditions. Remarkably, it can induce formation of the mixed parallel/antiparallel G-quadruplex structures in the G-rich sequence of the proximal vascular endothelial growth factor (VEGF) promoter, and stabilize these G-quadruplex structures, which provide an opportunity for anti-angiogenesis chemotherapeutics. Furthermore, the complex showed a strong uptake, and exhibited multiple anticancer functions by inhibiting the expression of p-Akt and p-Erk1/2 proteins and by upregulating the levels of reactive oxygen species (ROS). Because of the reported results, this new copper(II) complex qualifies itself as a potential anticancer drug candidate.