Synthesis of Pyridin-1(2H)-ylacrylates and the Effects of Different Functional Groups on Their Fluorescence.

While fluorescent organic materials have many potential as well as proven applications and so have attracted significant attention, pyridine-olefin conjugates remain a less studied subset of such systems. Herein, therefore, we report on the development of the straightforward syntheses of pyridin-1(2H)-ylacrylates and the outcomes of a study of the effects of substituents on their fluorescent properties. Such compounds were prepared using a simple, metal-free and three-component coupling reaction involving 2-aminopyridines, sulfonyl azides and propiolates. The fluorescent properties of the ensuing products are significantly affected by the positions of substituents on the cyclic framework, with those located in central positions having the greatest impact. Electron-withdrawing groups tend to induce blue shifts while electron-donating ones cause red shifts. This work highlights the capacity that the micro-modification of fluorescent materials provides for fine-tuning their properties such that they may be usefully applied to, for example, the study of luminescent materials.

Cyclometalated Ru(II)-isoquinoline complexes overcome cisplatin resistance of A549/DDP cells by downregulation of Nrf2 via Akt/GSK-3ß/Fyn pathway.

Both ruthenium (Ru) and isoquinoline (IQ) compounds are regarded as potential anticancer drug candidates. Here, we report the synthesis and characterization of three novel cyclometalated Ru(II)-isoquinoline complexes: RuIQ-3, RuIQ-4, and RuIQ-5, and evaluation of their in vitro cytotoxicities against a panel of cell lines including A549/DDP, a cisplatin-resistant human lung cancer cell line. A549/DDP 3D multicellular tumor spheroids (MCTSs) were also used to detect the drug resistance reversal effect of Ru(II)-IQ complexes. Our results indicated that the cytotoxic activities against cancer cells of Ru(II)-IQ complexes, especially RuIQ-5, were superior compared with cisplatin. In addition, RuIQ-5 exhibited low toxicity towards both normal HBE cells in vitro and zebrafish embryos in vivo. Further investigation on cellular mechanism of action indicated that after absorption by A549/DDP cells, RuIQ-5 was mainly distributed in the nucleus, which is different from cisplatin. Besides, RuIQ-5 could induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, ROS-mediated DNA damage, and cycle arrest at both S and G2/M phases. Moreover, RuIQ-5 could inhibit the overexpression of Nrf2 through regulation of Akt/GSK-3ß/Fyn signaling pathway and hindering the nuclear translocation of Nrf2. Based on these findings, we firmly believe that the studied Ru(II)-IQ complexes hold great promise as anticancer therapeutics with high effectiveness and low toxicity.

Cyclometalated Ru(II) ß-carboline complexes induce cell cycle arrest and apoptosis in human HeLa cervical cancer cells via suppressing ERK and Akt signaling.

Two new cyclometalated Ru(II)-ß-carboline complexes, [Ru(dmb)2(Cl-Ph-ßC)](PF6) (dmb = 4,4'-dimethyl-2,2'-bipyridine; Cl-Ph-ßC = Cl-phenyl-9H-pyrido[3,4-b]indole; RußC-3) and [Ru(bpy)2(Cl-Ph-ßC)](PF6) (bpy = 2,2'-bipyridine; RußC-4) were synthesized and characterized. The Ru(II) complexes display high cytotoxicity against HeLa cells, the stabilized human cervical cancer cell, with IC50 values of 3.2 ± 0.4 µM (RußC-3) and 4.1 ± 0.6 µM (RußC-4), which were considerably lower than that of non-cyclometalated Ru(II)-ß-carboline complex [Ru(bpy)2(1-Py-ßC)] (PF6)2 (61.2 ± 3.9 µM) by 19- and 15-folds, respectively. The mechanism studies indicated that both Ru(II) complexes could significantly inhibit HeLa cell migration and invasion, and effectively induce G0/G1 cell cycle arrest. The new Ru(II) complexes could also trigger apoptosis through activating caspase-3 and poly (ADP-ribose) polymerase (PARP), increasing the Bax/Bcl-2 ratio, enhancing reactive oxygen species (ROS) generation, decreasing mitochondrial membrane potential (MMP), and inducing cytochrome c release from mitochondria. Further research revealed that RußC-3 could deactivate the ERK/Akt signaling pathway thus inhibiting HeLa cell invasion and migration, and inducing apoptosis. In addition, RußC-3-induced apoptosis in HeLa cells was closely associated with the increase of intracellular ROS levels, which may act as upstream factors to regulate ERK and Akt pathways. More importantly, RußC-3 exhibited low toxicity on both normal BEAS-2B cells in vitro and zebrafish embryos in vivo. Consequently, the developed Ru(II) complexes have great potential on developing novel low-toxic anticancer drugs.

Functionalized chitosan-modified defect-related luminescent mesoporous silica nanoparticles as new inhibitors for hIAPP aggregation.

Human islet amyloid polypeptide (hIAPP or amylin) forms the amyloid deposits that is an important factor in the induction of type II diabetes. Accordingly, it is essential to efficiently and accurately inhibit the aggregation of hIAPP for the treatment and prevention of the disease. Here, defect mesoporous silica (DLMSN), with blue fluorescence, can perfectly achieve the accurate positioning in cells or organisms. DL@CS@NF cannot only specifically bind to a hIAPP monomer, but also effectively inhibit hIAPP aggregation, reduce cytotoxicity and overcome the instability and inefficiency of NF(N-Me)GA(N-Me)IL (NF). Furthermore, DL@CS@NF nanoparticles can significantly improve the survival rate of islet cells, stabilize the mitochondrial membrane potential, reduce the content of intracellular reactive oxygen species. In summary, DL@CS@NF nanoparticles may have broader implications in inhibiting the aggregation of hIAPP and reducing cytotoxicity.

Cytotoxicity in vitro, cellular uptake, localization and apoptotic mechanism studies induced by ruthenium(II) complex.

Ruthenium-based complexes have been regarded as one of the most potential metal-based candidates for anticancer therapy. Herein, two ruthenium (II) methylimidazole complexes [Ru(MeIm)4(4npip)]2+ (complex 1) and [Ru(MeIm)4(4mopip)]2+ (complex 2) were synthesized and evaluated for their in vitro anticancer activities. The results showed that these ruthenium (II) methylimidazole complexes exhibited moderate antitumor activity comparable with cisplatin against A549, NCI-H460, MCF-7 and HepG2 human cancer cells, but with less toxicity to a human normal cell line HBE. Intracellular distribution studies suggested that complex 2 selectively localized in the mitochondria. Mechanism studies indicated that complex 2 caused cell cycle arrest at G0/G1 phase by regulating cell cycle relative proteins and induced apoptosis through intrinsic pathway, which involved mitochondrial dysfunction, reactive oxygen species (ROS) accumulation and ROS-mediated DNA damage. Further, studies by western blotting suggested that MAPK and AKT signaling pathways were involved in complex 2-induced apoptosis, and they were regulated by the level of ROS. Overall, these findings suggested that complex 2 could be a candidate for further evaluation as a chemotherapeutic agent in the treatment of cancers.

Multifunctional selenium nanoparticles: Chiral selectivity of delivering MDR-siRNA for reversal of multidrug resistance and real-time biofluorescence imaging.

Herein, chiral selenium nanoparticles (L-SeNPs/D-SeNPs) modified with a dinuclear Ruthenium (II) complex were used to effectively deliver siRNA targeting the MDR1 gene. In this co-delivery system, the luminescent dinuclear Ruthenium (II) complex was developed to act as a gene carrier and anti-tumor drug, while offering luminescent imaging to follow the intracellular trafficking. Interestingly, Ru@L-SeNPs exhibited a stronger protein and pDNA affinity than Ru@D-SeNPs, indicating that chirality may have an effect on pDNA/siRNA binding and biocompatibility. Cisplatin-resistant A549R cells treated with Ru@L-SeNPs-siRNA demonstrated significant downregulation of P-glycoprotein (P-gp) expression, resulting in unprecedented enhanced cytotoxicity through the induction of apoptosis with the involvement of phosphorylation of p53, MAPK and PI3K/Akt signaling pathways. In vivo investigation confirmed that Ru@L-SeNPs-siRNA nanoparticles exhibited high tumor-targeted fluorescence, enhanced anti-tumor efficacy, and decreased systemic toxicity. These results suggest that Ru@L-SeNPs are promising vectors for the delivery of siRNA and for real-time tracking of treatment. FROM THE CLINICAL EDITOR: In this study, the authors designed bi-functional selenium nanoparticles with specific chirality to deliver siRNA, for targeting tumor MDR1 gene. The underlying ruthenium (II) complex could also offer fluorescence for real-time imaging. This new system has been shown to have enhanced efficacy against drug resistant tumor cells in both in-vitro and in-vivo experiments.

Three Ru(II) complexes modulate the antioxidant transcription factor Nrf2 to overcome cisplatin resistance.

Here, we designed, synthesized and characterized three new cyclometalated Ru(II) complexes, [Ru(phen)2(1-(4-Ph-Ph)-IQ)]+ (phen = 1,10-phenanthroline, IQ = isoquinoline, RuIQ9), [Ru(phen)2(1-(4-Ph-Ph)-7-OCH3-IQ)]+ (RuIQ10), and [Ru(phen)2(1-(4-Ph-Ph)-6,7-(OCH3)2-IQ)]+ (RuIQ11). The cytotoxicity experiments conducted on both 2D and 3D multicellular tumor spheroids (MCTSs) indicated that complexes RuIQ9-11 exhibited notably higher cytotoxicity against A549 and A549/DDP cells when compared to the ligands and precursor compounds as well as clinical cisplatin. Moreover, the Ru(II) complexes displayed low toxicity when tested on normal HBE cells in vitro and exposed to zebrafish embryos in vivo. In addition, complexes RuIQ9-11 could inhibit A549 and A549/DDP cell migration and proliferation by causing cell cycle arrest, mitochondrial dysfunction, and elevating ROS levels to induce apoptosis in these cells. Mechanistic studies revealed that RuIQ9-11 could suppress the expression of Nrf2 and its downstream antioxidant protein HO-1 by inhibiting Nrf2 gene transcription in drug-resistant A549/DDP cells. Simultaneously, they inhibited the expression of efflux proteins MRP1 and p-gp in drug-resistant cells, ensuring the accumulation of the complexes within the cells. This led to an increase in intracellular ROS levels in drug-resistant cells, ultimately causing damage and cell death, thus overcoming cisplatin resistance. More importantly, RuIQ11 could effectively inhibit the migration and proliferation of drug-resistant cells within zebrafish, addressing the issue of cisplatin resistance. Accordingly, the prepared Ru(II) complexes possess significant potential for development as highly effective and low-toxicity lung cancer therapeutic agents to overcome cisplatin resistance.

Cyclometalated ruthenium complexes overcome cisplatin resistance through PI3K/mTOR/Nrf2 signaling pathway.

Currently, cisplatin resistance remains a primary clinical obstacle in the successful treatment of non-small cell lung cancer. Here, we designed, synthesized, and characterized two novel cyclometalated Ru(II) complexes, [Ru(bpy)2(1-Ph-7-OCH3-IQ)] (PF6) (bpy = 2,2'-bipyridine, IQ = isoquinoline, RuIQ7)and [Ru(bpy)2(1-Ph-6,7-(OCH3)2-IQ)] (PF6) (RuIQ8). As experimental controls, we prepared complex [Ru(bpy)2(1-Ph-IQ)](PF6) (RuIQ6) lacking a methoxy group in the main ligand. Significantly, complexes RuIQ6-8 displayed higher in vitro cytotoxicity when compared to ligands, precursor cis-[Ru(bpy)2Cl2], and clinical cisplatin. Mechanistic investigations revealed that RuIQ6-8 could inhibit cell proliferation by downregulating the phosphorylation levels of Akt and mTOR proteins, consequently affecting the rapid growth of human lung adenocarcinoma cisplatin-resistant cells A549/DDP. Moreover, the results from qRT-PCR demonstrated that these complexes could directly suppress the transcription of the NF-E2-related factor 2 gene, leading to the inhibition of downstream multidrug resistance-associated protein 1 expression and effectively overcoming cisplatin resistance. Furthermore, the relationship between the chemical structures of these three complexes and their anticancer activity, ability to induce cell apoptosis, and their efficacy in overcoming cisplatin resistance has been thoroughly examined and discussed. Notably, the toxicity test conducted on zebrafish embryos indicated that the three Ru-IQ complexes displayed favorable safety profiles. Consequently, the potential of these developed compounds as innovative therapeutic agents for the efficient and low-toxic treatment of NSCLC appears highly promising.

A Biomimetic Multifunctional Nanoframework for Symptom Relief and Restorative Treatment of Acute Liver Failure.

Acute liver failure (ALF) is a rare and serious condition characterized by major hepatocyte death and liver dysfunction. Owing to the limited therapeutic options, this disease generally has a poor prognosis and a high mortality rate. When ALF cannot be reversed by medications, liver transplantation is often needed. However, transplant rejection and the shortage of donor organs still remain major challenges. Most recently, stem cell therapy has emerged as a promising alternative for the treatment of liver diseases. However, the limited cell delivery routes and poor stability of live cell products have greatly hindered the feasibility and therapeutic efficacy of stem cell therapy. Inspired by the functions of mesenchymal stem cells (MSCs) primarily through the secretion of several factors, we developed an MSC-inspired biomimetic multifunctional nanoframework (MBN) that encapsulates the growth-promoting factors secreted by MSCs via combination with hydrophilic or hydrophobic drugs. The red blood cell (RBC) membrane was coated with the MBN to enhance its immunological tolerance and prolong its circulation time in blood. Importantly, the MBN can respond to the oxidative microenvironment, where it accumulates and degrades to release the payload. In this work, two biomimetic nanoparticles, namely, rhein-encapsulated MBN (RMBN) and N-acetylcysteine (NAC)-encapsulated MBN (NMBN), were designed and synthesized. In lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced and acetaminophen (APAP)-induced ALF mouse models, RMBN and NMBN could effectively target liver lesions, relieve the acute symptoms of ALF, and promote liver cell regeneration by virtue of their strong antioxidative, anti-inflammatory, and regenerative activities. This study demonstrated the feasibility of the use of an MSC-inspired biomimetic nanoframework for treating ALF.

Mild and efficient synthesis of benzothiazolopyrimidine derivatives via CuAAC/ring cleavage/cyclization reaction.

An operationally mild and efficient synthesis of benzothiazolopyrimidine is achieved by a three-component reaction of 2-aminebenzo[d]thiazoles, sulfonyl azides and terminal ynones. This cascade process involved a CuAAC/ring cleavage/cyclization reaction. Particularly, most of the benzothiazolopyrimidine derivatives could be isolated by filtration without further purification.

Imaging of nerve injury in neonatal acute bilirubin encephalopathy using 1H-MRS and Glu-CEST techniques.

Objectives: To investigate the significance of proton magnetic resonance spectroscopy (1H-MRS) and glutamate chemical exchange saturation transfer (Glu-CEST) techniques in assessing the condition and prognosis of acute bilirubin encephalopathy patients and to understand the mechanism of nerve injury in this disease. Materials and methods: From September 2019 to February 2021, 31 neonates with acute bilirubin encephalopathy and 16 healthy neonates were enrolled in this study. All the quantitative results of 1H-MRS, Glu-CEST, and conventional magnetic resonance imaging (MRI) of all neonates were analyzed. The associations between statistically significant indicators of imaging and developmental quotients (DQ) were analyzed. Results: The 31 cases were assigned to the mild subgroup (n = 21) and moderate and severe subgroup (n = 10) according to the bilirubin-induced neurologic dysfunction (BIND) scores. The case group had elevated Cho and GABA absolute concentrations compared to the normal control group (all p < 0.05). Compared with the normal control group, the absolute concentration of GABA of the moderate and severe subgroup was significantly larger (p < 0.05). Compared with the normal control group, the Glu-CEST% values in the left basal ganglia, right thalamus, left frontal cortex and bilateral medial geniculate body of the case group was significantly larger (all p < 0.05). The moderate and severe subgroup had higher Glu-CEST% values in the left basal ganglia, right thalamus, and bilateral medial geniculate body than the normal control group (all p < 0.05). A negative association was revealed between the DQ scores and the Glu-CEST% values in the left basal ganglia (r = -0.888, p < 0.05). Conclusion: The combination of 1H-MRS and Glu-CEST techniques can monitor the intracerebral metabolite level of acute bilirubin encephalopathy and evaluate the illness severity.

Cyclometalated ruthenium (II) complexes induced HeLa cell apoptosis through intracellular reductive injury.

The main challenge of cancer chemotherapy is the resistance of tumor cells to oxidative damage. Herein, we proposed a novel antitumor strategy: cyclic metal­ruthenium (Ru) complexes mediate reductive damage to kill tumor cells. We designed and synthesized Ru(II) complexes with ß-carboline as ligands: [Ru (phen)2(NO2-Ph-ßC)](PF6) (RußC-7) and [Ru(phen)2(1-Ph-ßC)](PF6) (RußC-8). In vitro experimental results showed that RußC-7 and RußC-8 can inhibit cell proliferation, promote mitochondrial abnormalities, and induce DNA damage. Interestingly, RußC-7 with SOD activity could reduce intracellular reactive oxygen species (ROS) levels, while RußC-8 has the opposite effect. Accordingly, this study identified the reductive damage mechanism of tumor apoptosis, and may provide a new ideas for the design of novel metal complexes.

Nanozyme-based guanidinium peptides mediate surface reactive oxygen species for multidrug resistant bacterial infection management.

Nanozymes are effective novel antibacterial agents. However, they still have some shortcomings such as low catalytic efficiency, poor specificity, and non-negligible toxic side effects. Here, we synthesized iridium oxide nanozymes (IrOx NPs) by a one-pot hydrothermal method and used guanidinium peptide-betaine (SNLP/BS-12) to modify the surface of IrOx NPs (SBI NPs) to obtain a high-efficiency and low-toxicity antibacterial agent. In vitro experiments showed that SBI NPs with SNLP/BS12 could enhance IrOx NPs to target bacteria, mediate bacterial surface catalysis and reduce the cytotoxicity of IrOx NPs to mammalian cells. Importantly, SBI NPs were able to effectively alleviate MRSA acute lung infection and effectively promote diabetic wound healing. Accordingly, iridium oxide nanozymes functionalized with guanidinium peptides are expected to be an effective antibiotic candidate in the postantibiotic era.

Mitochondria-targeted cyclometalated iridium-ß-carboline complexes as potent non-small cell lung cancer therapeutic agents.

Natural products and metals play a crucial role in cancer research and the development of antitumor drugs. We designed and synthesized three new carboline-based cyclometalated iridium complexes [Ir(C-N)2(PPßC)](PF6), where PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide, C-N = 2-phenylpyridine (ppy, Ir1), 2-(2,4-difluorophenyl) pyridine (dfppy, Ir2), 7,8-benzoquinoline (bzq, Ir3), by combining iridium with ß-carboline derivative. These iridium complexes exhibited high potential antitumor effects after being promptly taken up by A549 cells. Accumulating in mitochondria rapidly and preferentially, Ir1-3 caused a series of changes in mitochondrial events, including the loss of mitochondrial membrane potential, the depletion of cellular ATP, and the elevation of reactive oxygen species, leading to significant death of A549 cells. Moreover, the activation of intracellular caspase pathway and apoptosis was further validated to contribute to iridium complexes-induced cytotoxicity. These novel iridium complexes exerted a prominent inhibitory effect on tumor growth in a three-dimensional multicellular tumor spheroid model.

Ruthenium(II) complexes as mitochondrial inhibitors of topoisomerase induced A549 cell apoptosis.

Two new ruthenium(II) complexes [Ru(dip)2(PPßC)]PF6 (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline, PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide) and [Ru(phen)2(PPßC)]PF6 (Ru2, phen = 1, 10-phenanthroline) with ß-carboline derivative PPßC as the primary ligand, were designed and synthesized. Ru1 and Ru2 displayed higher antiproliferative activity than cisplatin against the test cancer cells, with IC50 values ranging from 0.5 to 3.6 µM. Moreover, Ru1 and Ru2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events, including the depolarization of mitochondrial membrane potential, the damage of mitochondrial DNA, the depletion of cellular ATP, and the elevation of intracellular reactive oxygen species levels. Then, it induced caspase-3/7-mediated A549 cell apoptosis. More importantly, both complexes could act as topoisomerase I catalytic inhibitors to inhibit mitochondrial DNA synthesis. Accordingly, the developed Ru(II) complexes hold great potential to be developed as novel therapeutics for cancer treatment.

Mitochondria-targeted cyclometalated iridium (III) complexes: Dual induction of A549 cells apoptosis and autophagy.

In this study, we synthesized 4 cyclometalated iridium complexes using N-(1,10-phenanthrolin-5-yl)picolinamide (PPA) as the main ligand, denoted as [Ir(ppy)2PPA]PF6 (ppy = 2-phenylpyridine, Ir1), [Ir(bzq)2PPA]PF6 (bzq = benzo[h]quinoline, Ir2), [Ir(dfppy)2PPA]PF6 (dfppy = 2-(3,5-difluorophenyl)pyridine, Ir3), and [Ir(thpy)2PPA]PF6 (thpy = 2-(thiophene-2-yl)pyridine, Ir4). Compared to cisplatin and oxaliplatin, all four complexes exhibited significant anti-tumor activity. Among them, Ir2 demonstrated higher cytotoxicity against A549 cells, with an IC50 value of 1.6 ± 0.2 µM. The experimental results indicated that Ir2 primarily localized in the mitochondria, inducing a large amount of reactive oxygen species (ROS) generation, that decreased in mitochondrial membrane potential (MMP), reduced ATP production, and further impaired mitochondrial function, leading to cytochrome c release. Additionally, Ir2 caused cell cycle arrest at the S phase and induced apoptosis through the AKT-mediated signaling pathway. Further investigations revealed that Ir2 could simultaneously induce both apoptosis and autophagy in A549 cells, with the latter acting as a non-protective mechanism that promoted cell death. More importantly, Ir2 exhibited low toxicity to both normal LO2 cells in vitro and zebrafish embryos in vivo. Consequently, these newly developed Ir(III) complexes show great potential in the development of novel and low-toxicity anticancer agents.

Design and synthesis of aptamer-cyclometalated iridium(III) complex conjugate targeting cancer cells.

Targeted therapy showed broad application prospects in the treatment of various types of cancer. Through carriers such as aptamers, antibodies, proteins and peptides, targeted therapy can selectively deliver drugs into tumor cells. Compared with traditional treatment methods such as chemo- and radiotherapy, targeted drug delivery systems can reduce the toxic effects of drugs on normal cells and avoid adverse reactions. Herein, an aptamer-cyclometalated iridium(III) complex conjugate (ApIrC) has been designed and developed as a targeted anticancer agent. Owing to the targeting ability of aptamers, ApIrC specifically bound to nucleolin over-expressed on the surface of cancer cells and showed strong fluorescence signal for tumor imaging and diagnosis. ApIrC had more substantial cellular uptake in cancer cells than the iridium complex alone and exhibited favorable low toxicity to normal cells. After uptake by cells through endocytosis, ApIrC can selectively accumulated in mitochondria and induced caspase-3/7-dependent cell death. Remarkably, ApIrC can also specifically target 3D multicellular spheroids (MCSs) and show excellent tumor permeability. So, it can effectively reach the interior of MCSs and cause cell damage. To our knowledge, this is the first report of the aptamer-cyclometalated iridium(III) complex conjugate which studied for cancer targeted therapy. The developed conjugate has great potential to be developed as novel therapeutics for effective and low-toxic cancer treatment.

Development of nucleic acid aptamer-based lateral flow assays: A robust platform for cost-effective point-of-care diagnosis.

Lateral flow assay (LFA) has made a paradigm shift in the in vitro diagnosis field due to its rapid turnaround time, ease of operation and exceptional affordability. Currently used LFAs predominantly use antibodies. However, the high inter-batch variations, error margin and storage requirements of the conventional antibody-based LFAs significantly impede its applications. The recent progress in aptamer technology provides an opportunity to combine the potential of aptamer and LFA towards building a promising platform for highly efficient point-of-care device development. Over the past decades, different forms of aptamer-based LFAs have been introduced for broad applications ranging from disease diagnosis, agricultural industry to environmental sciences, especially for the detection of antibody-inaccessible small molecules such as toxins and heavy metals. But commercial aptamer-based LFAs are still not used widely compared with antibodies. In this work, by analysing the key issues of aptamer-based LFA design, including immobilization strategies, signalling methods, and target capturing approaches, we provide a comprehensive overview about aptamer-based LFA design strategies to facilitate researchers to develop optimised aptamer-based LFAs.

Novel cyclometalated Ru(II) complexes containing isoquinoline ligands: Synthesis, characterization, cellular uptake and in vitro cytotoxicity.

Two novel cyclometalated Ru(II) complexes containing isoquinoline ligand, [Ru(bpy)2(1-Ph-IQ)](PF6), (bpy = 2,2'-bipyridine; 1-Ph-IQ = 1-phenylisoquinoline; RuIQ-1) and [Ru(phen)2(1-Ph-IQ)](PF6) (phen = 1,10-phenanthroline; RuIQ-2) were found to show high cytotoxic activity against NCI-H460, A549, HeLa and MCF-7 cell lines. Notably, both of them exhibited IC50 values that were an order of magnitude lower than those of clinical cisplatin and two structurally similar Ru(II)-isoquinoline complexes [Ru(bpy)2(1-Py-IQ)](PF6)2 (Ru3) and [Ru(phen)2(1-Py-IQ)](PF6)2 (Ru4) (1-Py-IQ = 1-pyridine-2-yl). The cellular uptake and intracellular localization displayed that the two cyclometalated Ru(II) complexes entered NCI-H460 cancer cells dominantly via endocytosis pathway, and preferentially distributed in the nucleus. Further investigations on the apoptosis-inducing mechanisms of RuIQ-1 and RuIQ-2 revealed that the two complexes could cause S, G2/M double-cycle arrest by regulating cell cycle related proteins. The two complexes also could reduce the mitochondrial membrane potential (MMP), promote the generation of intracellular ROS and trigger DNA damage, and then lead to apoptosis-mediated cell death. More importantly, RuIQ-2 exhibits low toxicity both towards normal HBE cells in vitro and zebrafish embryos in vivo. Accordingly, the developed complexes hold great potential to be developed as novel therapeutics for effective and low-toxic cancer treatment.

Ru(II) Complexes Bearing O, O-Chelated Ligands Induced Apoptosis in A549 Cells through the Mitochondrial Apoptotic Pathway.

Two new Ru(II) complexes containing O, O-chelated ligands, Ru(dip)2(SA) (Ru-1) and Ru(dmp)2(SA) (Ru-2) (dip = 4,7-diphenyl-1,10-phenanthroline; dmp = 2,9-dimethyl-1,10-phenanthroline; SA = salicylate) were synthesized to evaluate their cytotoxicity in vitro. These complexes were found to exhibit moderate antitumor activity to different types of human cancers, including A549 (human lung carcinoma), MCF-7 (breast cancer), HeLa (human cervical cancer), and HepG2 (human hepatocellular carcinoma) cell lines, but displayed low toxicity to human normal cell lines BEAS-2B (immortalized human bronchial epithelial cells) when compared with that of cisplatin. Further studies revealed that these complexes could induce apoptosis in A549 cells, including activating caspase family proteins and poly (ADP-ribose) polymerase (PARP), reducing Bcl-2/Bax and Bcl-xl/Bad ratio, enhancing cellular reactive oxygen species (ROS) accumulation, triggering DNA damage, decreasing mitochondrial membrane potential (MMP), and leading cytochrome c release from mitochondria. Notably, complex Ru-1 showed low toxicity to developing zebrafish embryos. The obtained results suggest that these new synthetic complexes have the potential to be developed as low-toxicity agents for lung cancer treatment.