Effect of size and morphology of functionalized upconversion nanoparticle labeled probe on stem cell absorption.

In order to improve the application of stem cell therapy, it is important to monitor the proliferation and differentiation of transplanted stem cells in real time, high sensitivity and high precision. Upconversion nanoparticles (UCNPs) have been employed as bioimaging agents and delivery vehicles for gene therapeutics in several types of cells. Herein, we fabricated multiple functional upconversion nanoparticles (FUC-NPs) as exogenous contrast agents to investigate the effect of FUC-NPs size on the efficiency of tracking human umbilical cord mesenchymal stem cells (HUCMSCs). We used TEM, DLS, MTT, etc. systematically detected the effects of nanoparticle dose and exposure time on HUCMSCs cytotoxicity. Our data showed that incubation of FUC-NPs, HUCMSCs are able to maintain their viability and differentiation ability. Interestingly, the small size FUC-NPs examined, S-FUCs, had a much higher uptake capability than the other FUC-NPs (B-FUCs, H-FUCs and R-FUCs).The study will aid in UCNPs for the engineering of stem cell application in the future.

The cellular immunotherapy of integrated photothermal anti-oxidation Pd-Se nanoparticles in inhibition of the macrophage inflammatory response in rheumatoid arthritis.

Reducing the inflammatory response is a major goal in the therapy of rheumatoid arthritis (RA). Herein, we integrated palladium nanoparticles (Pd NPs) with selenium nanoparticles (Se NPs) and obtained a multiple nanosystem (Pd@Se-HA NPs) that could simultaneously scavenge hydroxyl radicals (⋅OH) and provide a photothermal effect. The Pd@Se-HA NPs were constructed by a simple self-assembly method in which Se NPs were electrostatically bonded to Pd NPs; hyaluronic acid (HA) was linked to the NPs by ester bonding to provide macrophage targeting ability. The experiments show that the combined therapy of eliminating ⋅OH with Se NPs and utilizing PTT with Pd NPs could effectively reduce the inflammatory response in macrophages more effectively than either individual NP treatment. In addition, the outer layer of HA could specifically target the CD44 receptor to enhance the accumulation of Pd@Se NPs at the lesion, further enhancing the therapeutic effect. After treatment for 15 days, the Pd@Se-HA NPs nearly eliminated the inflammatory response in the joints of mice in an induced RA model, and prevented joint damage and degradation.

Clay-based nanocomposite hydrogel with attractive mechanical properties and sustained bioactive ion release for bone defect repair.

Although clay-based nanocomposite hydrogels have been widely explored, their instability in hot water and saline solution inhibits their applications in biomedical engineering, and the exploration of clay-based nanocomposite hydrogels in bone defect repair is even less. In this work, we developed a stable clay-based nanocomposite hydrogel using 4-acryloylmorpholine as the monomer. After UV light illumination, the obtained poly(4-acryloylmorpholine) clay-based nanocomposite hydrogel (poly(4-acry)-clay nanocomposite hydrogel) exhibits excellent mechanical properties due to the hydrogen bond interactions between the poly(4-acryloylmorpholine) chains and the physical crosslinking effect of the nanoclay. Besides good biocompatibility, the sustainable release of intrinsic Mg2+ and Si4+ from the poly(4-acry)-clay nanocomposite hydrogel endows the system with excellent ability to promote the osteogenic differentiation of primary rat osteoblasts (ROBs) and can promote new bone formation effectively after implantation. We anticipate that these kinds of clay-based nanocomposite hydrogels with sustained release of bioactive ions will open a new avenue for the development of novel biomaterials for bone regeneration.

Ru nanoparticles coated with γ-Fe2O3 promoting and monitoring the differentiation of human mesenchymal stem cells via MRI tracking.

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-Fe2O3@Ru (Fe2O3@Ru), and γ-Fe2O3@selenium (Fe2O3@Se) to label MSCs and promote osteogenic differentiation. Fe2O3@Ru and Fe2O3@Se could be used as T2-weighted MRI contrast agents. Fe2O3@Ru more effectively diffused in the cytoplasm and localized in the nuclei of MSCs, compared with Fe2O3@Se. RuNPs, Fe2O3@Ru, and Fe2O3@Se induced MSCs to differentiate into osteoblasts. Fe2O3@Ru, in particular, was a potent osteoinductive agent. Fe2O3@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 Fe2O3@Ru NPs expressing osteoblast surface markers.

Bone Targeted Delivery of SDF-1 via Alendronate Functionalized Nanoparticles in Guiding Stem Cell Migration.

Stem cells are well-known for their great capacity for tissue regeneration. This provides a promising source for cell-based therapies in treating various bone degenerative disorders. However, the major hurdles for their application in transplantation are the poor bone marrow homing and engraftment efficiencies. Stromal cell-derived factor 1 (SDF-1) has been identified as a major stem cell homing factor. With the aims of bone targeted SDF-1 delivery and regulating MSCs migration, alendronate modified liposomal nanoparticles (Aln-Lipo) carrying SDF-1 gene were developed in this study. Alendronate modification significantly increased the mineral binding affinity of liposomes, and facilitated the gene delivery to osteoblastic cells. Up-regulated SDF-1 expression in osteoblasts triggered MSCs migration. Systemic infusion of Aln-Lipo-SDF-1 with fluorescence labeling in mice showed the accumulation in osseous tissue by biophotonic imaging. Corresponding to the delivered SDF-1, the transplanted GFP+ MSCs were attracted to bone marrow and contributed to bone regeneration. This study may provide a useful technique in regulating stem cell migration.

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}.

Correction: Bioactive SiO2@Ru nanoparticles for osteogenic differentiation of mesenchymal stem cells via activation of Akt signaling pathways.

Correction for 'Bioactive SiO2@Ru nanoparticles for osteogenic differentiation of mesenchymal stem cells via activation of Akt signaling pathways' by Ying Liu et al., J. Mater. Chem. B, 2016, DOI: .

Bioactive SiO2@Ru nanoparticles for osteogenic differentiation of mesenchymal stem cells via activation of Akt signaling pathways.

The surface chemistry of materials has an interactive influence on cell behavior. It is now well established that surface chemistry can affect cell adhesion, proliferation, and differentiation. Although amino (NH2)-terminated surfaces generated by the modification of nanoparticles with silane can promote osteogenic differentiation of mesenchymal stem cells (MSCs), how silica surfaces with ruthenium nanoparticles (SiO2@Ru) act on MSCs remains largely unknown. A concentration of 5 µg mL-1 aminopropyltriethoxysilane (APTS)-modified SiO2 nanoparticles (SiO2-NH2) or SiO2@Ru was nontoxic to MSCs, based on MTT and apoptosis assays. In addition, SiO2-NH2 and SiO2@Ru did not affect the surface phenotype or morphology of MSCs. SiO2@Ru can be used to trigger the differentiation of MSCs into osteocytes, minimising the need for exogenous biological supplementation. TEM images revealed that SiO2@Ru might interact with proteins located in the cytoplasm, which would have a further impact on subsequent cellular signaling pathways. Activation of Akt signaling pathways was observed in MSCs cultured with SiO2@Ru and these enhancement effects could be blocked by the Akt inhibitor LY294002. SiO2@Ru exhibited in vitro osteocompatibility that surpassed that of SiO2-NH2, as well as supporting the proliferation and differentiation of MSCs. This demonstrates the potential of SiO2@Ru for use in bone regeneration.

Preparation of different sized nano-silver loaded on functionalized graphene oxide with highly effective antibacterial properties.

Graphene oxide (GO) has attracted great interest in many different areas, as a delivery vehicle for antibacterial agents, and has shown high potential. Although silver nanoparticles (AgNPs) have a strong antibacterial effect, the biological application of AgNPs is often hindered by their aggregation and low stability. In this study, we developed an approach of polyoxyethylene bis(amine) (PEG) directed AgNPs grown on GO, then we combined the two materials to prepare a series of functionalized GO bearing different sized AgNPs, and studied the size effects of AgNPs on growth inhibition of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). We evaluated the antibacterial effect of GO@PEG@AgNPs on E. coli and S. aureus by various methods such as minimum inhibitory concentration (MIC) experiment, cell wall/membrane integrity assay and scanning electron microscopy (SEM) characterisation of bacterial morphology. The GO@PEG@AgNPs composites exhibited markedly higher antibacterial efficacy than AgNPs alone. The smallest GO@PEG@AgNPs (10 nm) particularly demonstrated higher antibacterial activity than other sizes (30, 50, and 80 nm). We believe that these findings contribute to great potential application as a regulated graphene-based antibacterial solution.

Ruthenium (II) complexes interact with human serum albumin and induce apoptosis of tumor cells.

The interaction of ruthenium (II) complex [Ru(bpy)2(mal)](2+) (RBM) and [Ru(phen)2(mal)](2+) (RPM) (bpy = 2, 2-bipyridine, phen = 1,10-phenanthroline, mal = malonyl carboxylate) with human serum albumin (HSA) has been investigated by using fluorescence, UV absorption and circular dichroism (CD) spectroscopy approaches. A strong fluorescence quenching reaction of complexes to HSA was observed and the quenching mechanism was suggested as static quenching according to the Stern-Volmer (S-V) equation. The number of binding sites n and observed binding constant Kb was measured by fluorescence quenching method. The thermodynamic parameters ΔH, ΔS, and ΔG at different temperatures were calculated and the results indicate the binding reaction is mainly entropy-driven and Vander Waals force played a major role in the reaction. The result of CD showed that the secondary structure of HSA molecules was changed in the presence of the ruthenium (II) complexes. Furthermore, the cell viability of ruthenium (II) complexes was evaluated by MTT and complex RPM has shown significant higher anticancer potency than RBM against all the cell lines screened. RPM showed a significant antitumor activity through induction of apoptosis in A549 cells.

Multifunctional polyamidoamine-modified selenium nanoparticles dual-delivering siRNA and cisplatin to A549/DDP cells for reversal multidrug resistance.

Multidrug resistance (MDR) is a major barrier against effective cancer treatment. Dual-delivering a therapeutic small interfering RNA (siRNA) and chemotherapeutic agents has been developed to reverse drug resistance in tumor cells. In this study, amine-terminated generation 5 polyamidoamine (PAMAM) dendrimers (G5.NH2)-modified selenium nanoparticles (G5@Se NP) were synthesized for the systemic dual-delivery of mdr1 siRNA and cisplatin (cis-diamminedichloroplatinum-(II), DDP), which was demonstrated to enhance siRNA loading, releasing efficiency and gene-silencing efficacy. When the mdr1 siRNA was conjugated with G5@Se NP via electrostatic interaction, a significant down-regulation of P-glycoprotein and multidrug resistance-associated protein expression was observed; G5@Se-DDP-siRNA arrested A549/DDP cells at G1 phase and led to enhanced cytotoxicity in A549/DDP cells through induction of apoptosis involving the AKT and ERK signaling pathways. Interestingly, G5@Se-DDP NP were much less reactive than DDP in the reactions with both MT and GSH, indicating that loading of DDP in a nano-delivery system could effectively prevent cell detoxification. Furthermore, animal studies demonstrated that the new delivery system of G5@Se-DDP-siRNA significantly enhanced the anti-tumor effect on tumor-bearing nude mice, with no appreciable abnormality in the major organs. These results suggest that G5@Se NP could be a potential platform to combine chemotherapy and gene therapy technology in the treatment of human disease.

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.

Mo polyoxometalate nanoclusters capable of inhibiting the aggregation of Aß-peptide associated with Alzheimer's disease.

A neuropathological hallmark of Alzheimer's disease (AD) is aggregation of a forty-residue peptide known as amyloid beta forty (Aß40). While past work has indicated that blocking Aß40 aggregation could be an effective strategy for the treatment of AD, developing therapies with this goal has been met with limited success. Polyoxometalates (POMs) have been previously investigated for their anti-viral and anti-tumoral properties and we report here that three representative POM nanoclusters have been synthesized for use against Aß40 aggregation. Through the use of thioflavin T fluorescence, turbidity, circular dichroism spectroscopy, and transmission electron microscopy (TEM), we found that all three POM complexes can significantly inhibit both natural Aß40 self-aggregation and metal-ion induced Aß40 aggregation. We also evaluated the protective effect of POM complexes on Aß40-induced neurotoxicity in cultured PC12 cells and found that treatment with POM complexes can elevate cell viability, decrease levels of intracellular reactive oxygen species, and stabilize mitochondrial membrane potential. These findings indicate that all three representative POM complexes are capable of inhibiting Aß40 aggregation and subsequent neurotoxicity. While a complete mechanistic understanding remains to be elucidated, the synthesized POM complexes may work through a synergistic interaction with metal ions and Aß40. These data indicate that POM complexes have high therapeutic potential for use against one of the primary neuropathological features of AD.

Anticancer activity for targeting telomeric G-quadruplex and antiangiogenesis of a novel Ru(II)-Se complex.

A new Ru(II)-Se complex, Ru(bpy)2L2Cl2 (bpy = 2,2'-bipyridine, L = 1,10-phenanthrolineselenazole) (Ru-Se) has been synthesized and characterized. The G-quadruplex DNA-binding properties of the complex and its selenium ligand (Phen-Se) were evaluated by thermal denaturation study, polymerase chain reaction (PCR) stop assay, and telomerase repeat amplification protocol (TRAP). The results showed that the obtained complex could induce and stabilize G-quadruplex structure as well as exhibit potent inhibitory activity against telomerase. In vitro cytotoxicity studies showed that complex Ru-Se inhibited the cancer cell growth through apoptosis. However, the presence of the ligand Phen-Se did not appear to have a significant effect either on G-quadruplex binding or on biological activity. Furthermore, the cell migration assay and the tube formation assay also demonstrated that the complex Ru-Se significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration, and tube formation. These findings indicate that the Ru-Se complex may be a potential telomerase inhibitor and a viable drug candidate in antiangiogenesis for anticancer therapies.