Coordination Patterns of the Diphosphate in IDP Coordination Complexes: Crystal Structure and Chirality.

The knowledge of accurate geometrical parameters from X-ray diffraction studies in the solid state of metal nucleotide is very important for understanding the relationship between structures and properties, including biochemical processes and even enzyme-metal-substrate interactions. The research is also very necessary to precisely and controllably design the functional materials. Here, seven types of coordination polymers of inosine 5'-diphosphate nucleotide (IDP) with transition metals, {[Zn(HIDP)(azpy)(H2O)2]·4H2O}n (1), {[Cd2(IDP)2(bpda)2]·[Cd(H2O)6]·11H2O}n (2), {[Cd3(IDP)2(4,4'-bipy)2(H2O)3]·6H2O}n (3), {[Cd2(IDP)2(bpe)2(H2O)2]·(H2bpe)·26H2O}n (4), {[Cu3(IDP)2(azpy)2(H2O)5]·5H2O}n (5), {[Cu3(IDP)2(bpe)2(H2O)5]·9H2O}n (6), and {[Co(HIDP)(azpy)(H2O)2]·7H2O}n (7) [4,4'-bipy = 4,4'-bipyridine, azpy = 4,4'-azopyridine, bpe = 1,2-bis(4-pyridyl)ethene, and bpda = 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene], were designed, synthesized, and firmly characterized using single-crystal X-ray diffraction. The coordination patterns of the diphosphate group of IDP in these complexes were studied by crystallographic analysis, namely, open, close, and open-close hybrid types. We have investigated the diverse coordination patterns of the diphosphate group and its spatial relationship relative to the pentose ring on the basis of two conformational parameters, the pseudorotation phase angle and the degree of puckering. Crystallographic studies clearly reveal the correlation between the backbone torsion angle (ω' and φ) of the sugar-diphosphate and the conformational preference of the pentose ring, i.e., the signs of the backbone torsion angles ω' and φ are both plus (+) or minus (-), the conformation of the pentose ring is envelope form (E), while when one of the two signs is plus (+) and the other is minus (-), the pentose ring is in the twist form (T). This is the first time elucidation of the coordination pattern of diphosphate relative to the conformation of the pentose ring in nucleotide metal complexes, which are different from the other inorganic or organic diphosphate compounds. The chirality of these coordination polymers was examined by combining solid-state circular dichroism spectroscopy measurements with the explanation of their crystal structures. The results presented in this paper are very important for understanding their nucleotide coordination chemistry, their supramolecular chemistry, and even their biochemistry.

One-step preparation of nano-in-micro poly(vinyl alcohol) embolic microspheres and used for dual-modal T1/T2-weighted magnetic resonance imaging.

It is crucial to develop dual or multi-modal self-imaging embolic microspheres to evaluate the effects of transcatheter arterial embolization therapy of tumor. However, the preparation of such hybrid microspheres always involved in multiple steps or complicated conditions. Here, poly(vinyl alcohol) (PVA) hybrid microspheres with dual-modal T1/T2-weighted magnetic resonance imaging (MRI) have been prepared based on microfluidic technique in one step. Gd2O3 and Fe3O4 nanoparticles with a size of ~5 nm act as T1- and T2-weighted MRI contrast agents, respectively, which are simultaneously in-situ synthesized in the PVA matrix via the reaction of metal ions and alkali with PVA chains as a soft template. Meanwhile, these metallic-oxide nanoparticles act as cross-linker to gelatinize the PVA droplets to obtain nano-in-micro PVA microspheres in one step. This procedure is simple, economic and feasible. The obtained nano-in-micro PVA microspheres show good magnetothermal effect, enhanced T1- and T2-weighted MRI and embolization effect.

[Fracture analyses of casting framework removable partial dentures].

OBJECTIVE: To compare the clinical fracture rates of removable partial denture (RPD) made of titanium with that of Co-Cr alloy, to analyze the fracture modes and reasons of two kinds of metal frameworks, and to explore the effect of defects on the fracture process. METHODS: Following totally 30 618 RPDs made by titanium and by Co-Cr alloy, the fracture rates in 18-month were calculated individually. The fractured surfaces of failed RPDs were examined by fractography investigations using a field emission scanning electron microscope to disclose the fracture mode and damage character. The energy-dispersive X-ray spectroscopy analysis was performed to examine the chemical compositions. RESULTS: The fracture rate of titanium framework was 1.75%, comparing with 0.57% of Co-Cr alloy framework. The reasons included teeth preparing, framework design, and defects during casting. The fracture modes of titanium and Co-Cr alloy framework performed toughness fracture character. The fissures were found in both titanium and Co-Cr alloy frameworks, and pores were detected in titanium frameworks. CONCLUSION: The higher fracture rate of titanium framework is related to the defects during casting.

[Strength of bi-layer dental ceramic evaluated by MSP testing].

OBJECTIVE: To evaluate strength of bi-layer alumina/Y-TZP specimens, compared with 3-point bending test and to estimate the reliability of MSP testing used in dental ceramics. METHODS: The single-layer/bi-layer alumina/Y-TZP specimens were produced by the clinical methods. Strength of these specimens was determined by MSP testing and 3-point bending test respectively. Fractured pieces of each bi-layer specimen were collected and studied with optical microscope and SEM. RESULTS: The MSP fracture strength was lower than bending strength in all the specimens. The strength of single-layer Y-TZP was the highest and the strength of bi-layer samples was lower than that of the single-layer samples respectively. Delamination and interface destruction were found in bi-layer alumina specimens, and not in bi-layer Y-TZP specimens. CONCLUSION: MSP testing is a convenient and feasible method to evaluate mechanical properties of dental ceramics.

Controllable synthesis of two adenosine 5'-monophosphate nucleotide coordination polymers via pH regulation: crystal structure and chirality.

Two types of Cu(ii)-AMP-4,4'-bipy coordination polymers, {[Cu(AMP)(4,4'-bipy)(H2O)3]·5H2O}n (1) and {[Cu2(HAMP)2(4,4'-bipy)2(H2O)4]·2NO3·11H2O}n (2) (Na2AMP = adenosine 5'-monophosphate disodium salt), were synthesised through pH control. X-ray single-crystal diffraction analysis revealed that 1 and 2 are one-dimensional (1D) coordinating coordination polymers. The nucleotide in 1 was not protonated whereas that in 2 was protonated. With the protonated NO3- in 2 entering the crystal lattice, it plays a role in balancing the charge. The chirality was studied using solid-state circular dichroism (CD) spectroscopy based on the analysis of crystal structures.

Tumor Microenvironment-"AND" Near-Infrared Light-Activated Coordination Polymer Nanoprodrug for On-Demand CO-Sensitized Synergistic Cancer Therapy.

Carbon monoxide (CO) as an emerging treatment holds great promise for inducing the apoptosis of cancer cells. Here coordination assembled strategy is first reported for synthesis of Cu(II)-flavone coordination polymer (NCu-FleCP) CO nanoprodrug that is stable in normal physiological conditions, and yet readily reduces to small size prodrug complex and releases CO on demand under glutathione (GSH) and near infrared (NIR) light. Specifically, after uptaking by cancer cells, local GSH attacked coordination bond within NCu-FleCP, resulting in the release of Cu(I) and free Fle. The CC bond of Fle is cleavage under NIR light to release CO for gas therapy, and Cu(I) reacts with local H2 O2 through Fenton like reaction to generate hydroxyl radicals (• OH) for chemodynamic therapy. Detailed in vitro and in vivo experiments demonstrate that the CO prodrug system in generating a sufficient quantity of CO and • OH offers remarkable destructive effects against cancer cells without causing toxicity to surrounding normal tissues. The study provides a solid foundation to develop smart coordination polymer CO prodrugs with on-demand CO release, enhanced permeability and retention effect, and biodegradability for multimodal synergistic therapy.

Anions reversibly responsive luminescent nanocellulose hydrogels for cancer spheroids culture and release.

Artificial stimuli-responsive hydrogels that can mimic natural extracellular matrix for growth and release of cancer spheroids (CSs) have attracted much attention. However, such hydrogels still face a challenge in regulating CSs growth and controlled release as well as keeping CSs integrity. Herein, a new class of ClO-/SCN- reversibly responsive nanocellulose hydrogel with fluorescence on-off reporter is developed. Upon addition of ClO-, the gel network of nanocellulose hydrogel was destructed, accompanying by the fluorescent quenching. Notably, when introducing of SCN-, a red fluorescence filamentous hydrogel was recovered by coordination cross-linking. The hydrogel reforms in a completely reversible process through the regulation of ClO-/SCN-. Benefit from the above response features of the hydrogel, the growth of cancer spheroids (CSs) in the hydrogel and on demand release of CSs from the hydrogel could be easily achieved through ClO-/SCN- regulation. Importantly, the growth and release of CSs can be monitored in real time by fluorescence imaging. Overall, such design strategy based on ClO-/SCN--responsive fluorescent hydrogels provided a new type of multi-responsive hydrogels as main scaffolds for cancer research and cancer drug screening.

Facile preparation of a Ca(ii) carboxymethyl cellulose complex with enhanced calcium bioavailability for treatment of osteoporosis.

At present, though calcium (Ca) reagents with high calcium contents are widely synthesized, their wide application is limited due to their low absorption rates and poor bioavailability. Here we use a carboxymethyl cellulose (CMC) derivative with high water solubility and biocompatibility as a ligand to bind Ca2+. The resulting CaCMC complex exhibits remarkable solubility and absorbability under both basic and acidic conditions as well as in stomach mimicking and the gastrointestinal tract. Importantly, this Ca reagent shows high in vivo calcium bioavailability. Data from osteoporosis mouse models show that the CaCMC complex is superior to calcium carbonate in the treatment of osteoporosis. Therefore, the resulting CaCMC complex is used as a new, highly effective and desirable Ca supplement for daily life and clinical applications.

A polyethylenimine-modified carboxyl-poly(styrene/acrylamide) copolymer nanosphere for co-delivering of CpG and TGF-ß receptor I inhibitor with remarkable additive tumor regression effect against liver cancer in mice.

Cancer immunotherapy based on nanodelivery systems has shown potential for treatment of various malignancies, owing to the benefits of tumor targeting of nanoparticles. However, induction of a potent T-cell immune response against tumors still remains a challenge. In this study, polyethylenimine-modified carboxyl-styrene/acrylamide (PS) copolymer nano-spheres were developed as a delivery system of unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides and transforming growth factor-beta (TGF-ß) receptor I inhibitors for cancer immunotherapy. TGF-ß receptor I inhibitors (LY2157299, LY) were encapsulated to the PS via hydrophobic interaction, while CpG oligodeoxynucleotides were loaded onto the PS through electrostatic interaction. Compared to the control group, tumor inhibition in the PS-LY/CpG group was up to 99.7% without noticeable toxicity. The tumor regression may be attributed to T-cell activation and amplification in mouse models. The results highlight the additive effect of CpG and TGF-ß receptor I inhibitors co-delivered in cancer immunotherapy.

Glioma-targeting micelles for optical/magnetic resonance dual-mode imaging.

Surgical resection is the primary mode for glioma treatment, while gross total resection is difficult to achieve, due to the invasiveness of the gliomas. Meanwhile, the tumor-resection region is closely related to survival rate and life quality. Therefore, we developed optical/magnetic resonance imaging (MRI) bifunctional targeted micelles for glioma so as to delineate the glioma location before and during operation. The micelles were constructed through encapsulation of hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) with polyethylene glycol-block-polycaprolactone (PEG-b-PCL) by using a solvent-evaporation method, and modified with a near-infrared fluorescent probe, Cy5.5, in addition to the glioma-targeting ligand lactoferrin (Lf). Being encapsulated by PEG-b-PCL, the hydrophobic SPIONs dispersed well in phosphate-buffered saline over 4 weeks, and the relaxivity (r 2) of micelles was 215.4 mM(-1)·s(-1), with sustained satisfactory fluorescent imaging ability, which might have been due to the interval formed by PEG-b-PCL for avoiding the fluorescence quenching caused by SPIONs. The in vivo results indicated that the nanoparticles with Lf accumulated efficiently in glioma cells and prolonged the duration of hypointensity at the tumor site over 48 hours in the MR image compared to the nontarget group. Corresponding with the MRI results, the margin of the glioma was clearly demarcated in the fluorescence image, wherein the average fluorescence intensity of the tumor was about fourfold higher than that of normal brain tissue. Furthermore, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay results showed that the micelles were biocompatible at Fe concentrations of 0-100 µg/mL. In general, these optical/MRI bifunctional micelles can specifically target the glioma and provide guidance for surgical resection of the glioma before and during operation.

pH/temperature sensitive magnetic nanogels conjugated with Cy5.5-labled lactoferrin for MR and fluorescence imaging of glioma in rats.

Glioma is the most common primary brain tumor and causes a disproportionate level of morbidity and mortality across a wide range of individuals. From previous clinical practices, definition of glioma margin is the key point for surgical resection. In order to outline the exact margin of glioma and provide a guide effect for the physicians both at pre-surgical planning stage and surgical resection stage, pH/temperature sensitive magnetic nanogels conjugated with Cy5.5-labled lactoferrin (Cy5.5-Lf-MPNA nanogels) were developed as a promising contrast agent. Due to its pH/te mperature sensitivity, Cy5.5-Lf-MPNA nanogels could change in its hydrophilic/hydrophobic properties and size at different pH and temperatures. Under physiological conditions (pH 7.4, 37 °C), Cy5.5-Lf-MPNA nanogels were hydrophilic and swollen, which could prolong the blood circulation time. In the acidic environment of tumor tissues (pH 6.8, 37 °C), Cy5.5-Lf-MPNA nanogels became hydrophobic and shrunken, which could be more easily accumulated in tumor tissue and internalized by tumor cells. In addition, lactoferrin, an effective targeting ligand for glioma, provides active tumor targeting ability. In vivo studies on rats bearing in situ glioma indicated that the MR/fluorescence imaging with high sensitivity and specificity could be acquired using Cy5.5-Lf-MPNA nanogels due to active targeting function of the Lf and enhancement of cellular uptake by tailoring the hydrophilic/hydrophobic properties of the nanogels. With good biocompatibility shown by cytotoxicity assay and histopathological analysis, Cy5.5-Lf-MPNA nanogels are hopeful to be developed as a specific and high-sensitive contrast agent for preoperative MRI and intraoperative fluorescence imaging of glioma.

Role of cellular uptake in the reversal of multidrug resistance by PEG-b-PLA polymeric micelles.

Understanding the processes involved in the cellular uptake of nanoparticles is critical for developing effective nano drug delivery systems. In this paper we found that PEG-b-PLA polymeric micelles firstly interacted with cell membrane using atomic force microscopy (AFM) and then released their core-loaded agents into the cell membrane by fluorescence resonance energy transfer (FRET). The released agents were internalized into the cells via lipid raft/caveolae-mediated endocytosis using total internal reflection fluorescence microscopy (TIRFM) and endocytic inhibitors. Further studies revealed that paclitaxel (PTX)-loaded PEG-b-PLA micelles (M-PTX) increased the cellular accumulation of PTX in PTX-resistant human ovarian cell line A2780/T which resulted in more apoptosis as measured by flow cytometry and the cleavage of poly (ADP-ribose) polymerase (PARP) compared with free PTX. PEG-b-PLA micelles inhibited P-glycoprotein (Pgp) function and Pgp ATPase activity but had no effect on Pgp protein expression. The membrane microenvironment studies showed that PEG-b-PLA micelles induced cell membrane depolarization and enhanced membrane microviscosity. These results suggested that PEG-b-PLA micelles might inhibit Pgp function to reverse multidrug resistance (MDR) via interaction with cell membrane to affect the membrane microenvironment. This study provides a foundation for understanding the mechanism of reversing MDR by nanoparticles better and designing more effective nano drug carriers.

Using a novel petroselinic Acid embedded cellulose acetate membrane to mimic plant partitioning and in vivo uptake of polycyclic aromatic hydrocarbons.

A new type of composite membrane is introduced to mimic plant uptake of hydrophobic organic contaminants (HOCs). Petroselinic acid (cis-6-octadecenoic acid), the major component of plant lipids, was embedded in the matrix of cellulose acetate polymer to form the petroselinic acid embedded cellulose acetate membrane (PECAM). Accumulation of the polycyclic aromatic hydrocarbons (PAHs) naphthalene (Nap), phenanthrene (Phe), pyrene (Pyr), and benz(a)pyrene (Bap) by PECAM was compared with their uptake by plants. The accumulation of Nap, Phe, Pyr, and Bap by PECAM reached equilibrium in 24, 48, 144, and 192 h, respectively. The petroselinic acid-water partition coefficients (log K(pw), 3.37, 4.90, 5.24, and 6.28 for Nap, Phe, Pyr, and Bap, respectively) were positively correlated with the hydrophobicity of the compounds (R(2) = 0.995) and were almost the same as the lipid-normalized root partition coefficients (log K(lip)) for the corresponding compounds. Their relationship can be expressed as log K(pw) = 0.98 log K(lip). The normalized plant uptake coefficients (log K(u)) obtained by in vivo experiments with a range of plant species (2.92, 4.43, 5.06, and 6.13 on average for Nap, Phe, Pyr, and Bap, respectively) were slightly lower than those of the log K(pw) values for the corresponding compounds, presumably due to their acropetal translocation and biodegradation inside plants. This work suggests that PECAMs can well mimic plant partitioning and in vivo uptake of PAHs and may have good potential as a nonliving accumulator to mimic plant uptake of PAHs and perhaps other HOCs.

Protective effect of PEGylation against poly(amidoamine) dendrimer-induced hemolysis of human red blood cells.

Poly(amidoamine) (PAMAM) dendrimers are widely used in medical applications. However, dendrimers bearing positively charged surface groups are prone to destabilize cell membrane and cause cell lysis. The lytic effect of dendrimers on red blood cells (RBCs) namely hemolysis is extremely dangerous when administered in vivo. To diminish the hematologic toxicity, we modified PAMAM dendrimers with poly(ethylene glycol) (PEG) of three molecular weights (2k, 5k, and 20k). The protective effect of PEGylation against PAMAM dendrimer-induced hemolysis was studied. RBCs morphology and surface structure were analyzed by optical microscopy (OM) and atomic force microscopy (AFM). The results indicated that PAMAM and PEG-2k modified dendrimers induced hemolysis at 0.1 and 0.5 mg/mL respectively, whereas PEG-5k and PEG-20k modified dendrimers showed no significant difference in hemolysis compared with control even at 5 mg/mL. OM and AFM investigation indicated PAMAM and PEG-2k modified dendrimers caused RBCs aggregation and lysis. However, no changes were observed in the overall shape of RBCs treated with PEG-5k and PEG-20k modified dendrimers. The surface roughness of RBCs treated with PEGylated dendrimers were far lower than that of RBCs treated with PAMAM dendrimers. This study demonstrated that hemocompatibility of PAMAM dendrimers could be greatly enhanced by PEGylation.