Hydrazine Bond Research Articles

Polyphosphazene nanodrugs for targeting delivery and inflammation responsive release of curcumin to treat acute lung injury by effectively inhibiting cytokine storms

An excessive inflammatory response induced by cytokine storms is the primary reason for the deterioration of patients with acute lung injury (ALI). Though natural polyphenols such as curcumin (CUR) have anti-inflammation activity for ALI treatment, they often have limited efficacy due to their poor solubility in water and oxidising tendency. This study investigates a highly cross-linked polyphosphazene nano-drug (PHCH) developed by copolymerisation of CUR and acid-sensitive units (4-hydroxy-benzoic acid (4-hydroxy-benzylidene)-hydrazide, D-HBD) with hexachlorotripolyphosphonitrile (HCCP) for improved treatment of ALI. PHCH can prolong the blood circulation time and targeted delivery into lung inflammation sites by enhancing CUR's water dispersion and anti-oxidant properties. PHCH also demonstrates the inflammation-responsive release of CUR in an inflammation environment due to the acid-responsive degradation of hydrazine bonds and triphosphonitrile rings in PHCH. Therefore, PHCH has a substantial anti-inflammation activity for ALI treatment by synergistically improving CUR's water-solubility, bioavailability and biocompatibility. As expected, PHCH attenuates the cytokine storm syndrome and alleviates inflammation in the infected cells and tissues by down-regulating several critical inflammatory cytokines (TNF-α, IL-1β, and IL-8). PHCH also decreases the expression of p-p65 and C-Caspase-1, inhibiting NLRP3 inflammasomes and suppressing NF-κB signalling pathways. The administrated mice experiments confirmed that PHCH accumulation was enhanced in lung tissue and showed the efficient scavenging ability of reactive oxygen species (ROS), effectively blocking the cytokine storm and alleviating inflammatory damage in ALI. This smart polyphosphazene nano-drug with targeting delivery property and inflammation-responsive release of curcumin has excellent potential for the clinical treatment of various inflammatory diseases, including ALI.

Molecular basis of enzymatic nitrogen-nitrogen formation by a family of zinc-binding cupin enzymes

Molecules with a nitrogen-nitrogen (N-N) bond in their structures exhibit various biological activities and other unique properties. A few microbial proteins are recently emerging as dedicated N-N bond forming enzymes in natural product biosynthesis. However, the details of these biochemical processes remain largely unknown. Here, through in vitro biochemical characterization and computational studies, we report the molecular basis of hydrazine bond formation by a family of di-domain enzymes. These enzymes are widespread in bacteria and sometimes naturally exist as two standalone enzymes. We reveal that the methionyl-tRNA synthase-like domain/protein catalyzes ATP-dependent condensation of two amino acids substrates to form a highly unstable ester intermediate, which is subsequently captured by the zinc-binding cupin domain/protein and undergoes redox-neutral intramolecular rearrangement to give the N-N bond containing product. These results provide important mechanistic insights into enzymatic N-N bond formation and should facilitate future development of novel N-N forming biocatalyst.

Bioinspired dual dynamic network hydrogels promote cartilage regeneration through regulating BMSC chondrogenic differentiation

How to improve the therapeutic efficacy of cell delivery during mechanical injection has been a great challenge for tissue engineering. Here, we present a facile strategy based on dynamic chemistry to prepare injectable hydrogels for efficient stem cell delivery using hyaluronic acid (HA) and poly(γ-glutamic acid) (γ-PGA). The combination of the guest–host (GH) complexation and dynamic hydrazone bonds enable the HA/γ-PGA hydrogels with physical and chemical dual dynamic network and endow hydrogels a stable structure, rapid self-healing ability, and injectability. The mechanical properties, self-healing ability, and adaptability can be programmed by changing the ratio of GH network to hydrazine bond cross-linked network. Benefitting from the dynamic cross-linking networks, mild preparation process, and cytocompatibility of HA/γ-PGA hydrogels, bone marrow mesenchymal stem cells (BMSCs) show high cell viability in this system following mechanical injection. Moreover, HA/γ-PGA hydrogels can promote BMSC proliferation and upregulate the expression of cartilage-critical genes. Notably, in a rabbit auricular cartilage defect model, BMSC-laden HA/γ-PGA hydrogels can effectively promote cartilage regeneration. Together, we propose a general strategy to develop injectable self-healing HA/γ-PGA hydrogels for effective stem cell delivery in cartilage tissue engineering.

Hydrazine decomposition on nickel-embedded graphene

In this article, the catalytic effect of the Ni-embedded graphene has been investigated for hydrazine (N2H4) decomposition reaction through Density Functional Theory (DFT) calculations with Grimme-D2 dispersion correction. Nickel embedded graphene systems are expected to be much cheaper than pristine nickel surfaces in the future because of relatively few numbers of Ni atom usage, experimentally synthesizable, and limit the Ni usage. The transformation of N2H4 has been taken into account in two different ways. The first way is sequential N–H and, the second one is the N–N bond cleavage from the gauche conformation which is the most stable conformation in gas phase and sole conformation observed on the Ni site. According to our findings, ·NH2 formation breaking the N–N bond in hydrazine has lower activation energy than hydrogen abstraction from hydrazine. The difficulty of breaking N–H bonds stems from the spatial accumulation of negative and positive charges, so it causes a mismatch between hydrogen atoms and negatively charges carbon atoms. NH3 formation pathway through the interaction of N2Hx (x = 1 → 4) species with co-adsorbed ·NH2 radicals is accompanied by much lower activation barriers and highly exothermic. Nevertheless, metal-embedded graphene systems are promising materials for hydrazine dehydrogenation and can be tailored to have more efficient charge distribution.

Dual-pH Sensitive Charge-Reversal Drug Delivery System for Highly Precise and Penetrative Chemotherapy.

The complex physiological barriers impose extremely conflicting demands on systemic drug delivery, so both particle size and surface charge of the nanoplatforms become vital factors. As a carbon-based nanomaterial with excellent optical properties, carbon dots are not suitable for direct systemic transport in vivo, which limits their application in the field of biomedical imaging, especially in the areas of diagnosis and cancer treatment. Liposomes have been developed as universal nanocarriers for various drugs. In this study, we aimed to build a highly precise and penetrative drug delivery system (DDS) using carbon dots encapsulated by liposomes. Carbon dots (CDs) were synthesized by the hydrothermal method using citric acid and ethylenediamine. Furthermore, simian virus 40 large T-antigen derived the nuclear targeting sequence (NLS) was bonded on the surface of CDs to obtain CDs-NLS. The antitumor drug doxorubicin was loaded onto the CDs-NLS through an acid-labile hydrazine bond to obtain DOX@CDs. Finally, DOX@CDs were encapsulated in aqueous centers of folate-coated and pH-sensitive liposomes, named pHSL-FA. In this paper, a nucleus-targeted nanocomposite (DOX@CDs), which bonds with the nuclear targeting sequence (NLS) and the anticancer drug doxorubicin (DOX), has physicochemical properties of particle size of about 3.8nm, zeta potential of +31.8mV and high quantum yield of 64.53%. The negatively charged folate-coated and pH-sensitive liposomes (pHSL-FA) are used as a carrier to reverse the surface charge of DOX@CDs. Compared to free DOX@CDs, pHSL-FA show higher tumor accumulation in 4T1 tumor-bearing mice and further improve cytotoxicity to tumor cells. This work proposes a unique nanomedical approach that enables the precise delivery of chemotherapy drugs and significantly reduces side effects, which is promising for clinical translation.

Study on a pH-sensitive controlled release nano-drug delivery system based on gold nanorods combined with hyperthermia in the treatment of cancer in vivo

Objective To investigate the in vivo anti-tumor effect combined with hyperthermia of a pH sensitive nano-drug delivery system based on the gold nanorods (AuNR). Methods AuNR was prepared by seed mediated growth method firstly, and then it was modified with SH-PEG2000-NH2. Finally, doxorubicin (DOX) was connected through hydrazine bond to construct the AuNR-polyethylene glycol (PEG)-DOX nano-drug delivery system with pH-sensitive controlled release effect. Ultraviolet-Visible spectroscopy (UV-Vis) and transmission electron microscope (TEM) were used to detect the characteristic absorption peaks, shape and size of AuNR, respectively. The products of each step of chemical reaction was determined by fourier transform infrared spectroscopy (FT-IR). High performance liquid chromatography (HPLC) was used for the investigation of drug loading efficiency and pH sensitive controlled release effect. The ex vitro and in vivo imaging effect of this drug delivery system was detected by X-Ray CT. And the tumor-bearing mice were randomly divided into groups to investigate the anti-tumor effect of nano-drug delivery system combined with hyperthermia in vivo. Results The prepared AuNR has stable morphology, uniform rod-like distribution, the aspect ratio was 3.6∶1.0, and the long-diameter characteristic absorption peak at -800 nm, which can be used as a near infrared (NIR) hyperthermia sensitizer for futher research. The FT-IR result showed that DOX can be connected to the carrier surface through hydrazine bond. The drug loading efficiency and encapsulation efficiency of DOX were (12.3±2.4)% and (58.3±4.7)%, respectively. When the pH of the release medium decreased from 7.4 to 5.5, the cumulative release rate of DOX increased from (14.5±2.5)% to (80.3±2.1)%, indicating that AuNR-PEG-DOX has good pH sensitivity effect. In vivo and in vitro X-Ray imaging results showed that the drug delivery system can enhance the contrast of X-Ray CT imaging, which can be used for in vivo real-time observation. And these results also can prove that the drug delivery system has good tumor accumulation ability. Anti-tumor experiments showed that the relative volume of tumor was 0.9 which had significant difference with all of the other groups, respectively, demonstrating that AuNR-PEG-DOX combined with hyperthermia could effectively inhibit the occurrence and development of tumors in vivo. Conclusion AuNR-PEG-DOX nano-drug delivery system has pH sensitive controlled release effect, X-Ray imaging enhancement and NIR hyperthermia effect, which can effectively inhibit the proliferation of tumors in vivo. Key words: Gold nanorods; PH sensitive; X-Ray imaging; Hyperthermia; Nano-drug delivery system

Hydrazone-linked soybean protein isolate-carboxymethyl cellulose conjugates for pH-responsive controlled release of pesticides

To improve the utilization of pesticides and reduce the amount of pesticides used, sustained-release nanoparticles were prepared. Soybean protein isolate (SPI) and carboxymethyl cellulose (CMC) were modified to obtain hydrazine-modified SPI and aldehyde-modified CMC, respectively, and SPI-CMC was prepared by the condensation of hydrazine and aldehyde groups, forming a hydrazone bond. SPI-CMC was heated and loaded with avermectin (AVM) to obtain AVM/SPI-CMC. The encapsulation efficiency property, anti-ultraviolet property, sustained-release characteristics, pH responsiveness, and toxicological profiles were studied. The particles in the formulation were spherical-like, with sizes ranging between 150 and 250 nm. The encapsulation efficiency increased with the addition of SPI, which reached 44.49% when SPI was added in a mass ratio of mSPI-HYD:mCMC-ALD = 2:1. The percentage of remaining AVM in AVM/SPI-CMC was 31.47% higher than that in the AVM solution after UV irradiation for 43 h. Moreover, the nanoparticles were responsive to pH. SPI-CMC had no significant effect on the insecticidal toxicity of AVM. Environmental friendly SPI-CMC could protect and release pesticides continuously, which could improve the efficiency of pesticides. Soybean protein isolate (SPI) was bonded to carboxymethyl cellulose (CMC) by a hydrazine bond to prepare SPI-CMC carriers for pesticide applications. AVM/SPI-CMC was obtained by encapsulating avermectin (AVM) with SPI-CMC through thermal denaturation. SPI-CMC could improve the anti-UV performance of AVM and slow down the decomposition rate of AVM. The hydrazone bond and carboxyl groups showed pH responsiveness, which could release drugs rapidly in an acidic environment. Environmentally friendly SPI-CMC could protect and release pesticides continuously, which could improve the efficiency of pesticides.

Enhanced Endocytic and pH-Sensitive Poly(malic acid) Micelles for Antitumor Drug Delivery.

Poly(β-benzyl malate) (PBM), a derivative of poly(β-malic acid) (PMLA), is a potential antitumor drug carrier due to its desirable biocompatibility and nontoxicity. In this study, micelles based on PBM-PEG polymers were prepared, which possessed several key features, including (i) micelle formation via self-assembly with a size of approximately 100 nm, (ii) π-π stacking interactions between the polymer chains and between the polymer and the drug, improving the stability of micelles and drug loading capacity (drug loading rate increased to 20 wt%), (iii) the cell penetrating peptide (TAT) was shielded by a long PEG chain before reaching the tumor site and exposed to tumor tissue, and (iv) high efficiency tumor uptake via exposure to TAT. At the site of a tumor, the extracellular pH level caused cleavage of the hydrazine bond, which led to the exposure of TAT on the polymeric micelles, thus enhancing cellular internalization. Then, the polymeric micelles disintegrated and DOX was released in response to the acidic pH in the lysosomal and endosomal compartments within the tumor cells. Both in vitro and in vivo efficacy studies indicated that this pH-sensitive PBM polymeric micelle is a promising antitumor drug carrier.

PH-triggered intracellular release of doxorubicin from polyaspartamide-encapsulated mesoporous silica nanoparticles

Mesoporous silica nanoparticles (MSNs) conjugating doxorubicin (DOX) via a pH-sensitive cleavable linkage, hydrazine (HYD) were synthesized. MSN-HYD-DOX were encapsulated with the polyaspartamide (PASPAM) grafted with the hydrophilic o-(2-aminoethyl)-o′-methylpoly(ethylene glycol) (PEG) and the cell permeating ligand, biotin (Biotin). The chemical structure of the synthesized MSN-HYD-DOX and PASPAM-g-PEG/Biotin was confirmed using FT-IR and 1H-NMR spectroscopy. The mean diameter of the MSN-HYD-DOX@PASPAM-g-PEG/Biotin nanoparticle was 142 nm and 121 nm, respectively, examined by dynamic light scattering (DLS) and transmission electron microscope (TEM). The HYD bond was effectively cleaved in acidic condition, and thus DOX was released much faster at pH 5.0 than at pH 7.4. The cell viability in MSN-HYD-DOX@PASPAM-g-PEG/Biotin system was much lower than that of the free DOX drug because of efficient intracellular drug delivery associated with the biotin ligand.

Characterization of a smart pH-cleavable PEG polymer towards the development of dual pH-sensitive liposomes

To facilitate the development of PEG-cleavable pH-sensitive liposomes (CL-pPSL), this study aimed to fully characterize a new pH-sensitive polymer, PEGB-Hz-CHEMS. Polyethylene glycol (PEG) functionalised with 4-carboxybenzaldehyde (PEGB) was linked to cholesteryl hemisuccinate (CHEMS) via an acid labile hydrazide–hydrazone hybrid bond (CONHNCH) to form PEGB-Hz-CHEMS. The polymer was post-inserted into DOPE/CHEMS liposomes to form CL-pPSL. A validated stability-indicating HPLC-UV method was developed with the aid of multiple linear regression for the mobile phase. The assay was used to evaluate the pH-sensitivity, pathways of cleavage of the polymer and the PEGylation degree of CL-pPSL. The pH-sensitivity of CL-pPSL was compared with conventional PEGylated pH-sensitive (pPSL) using a calcein leakage assay. At 37 °C, PEGB-Hz-CHEMS was relatively stable at pH 7.4 with a half-life of 24 h. In comparison, at pH 5.5 and pH 6.5 PEG detachment within 1 h was determined as 80%, and 50%, respectively. PEG detachment of the polymer was through simultaneous cleavage of the hydrazine (CON) and hydrazone (NC) bonds, depending on pH, thus the polymer is more pH-sensitive than those with a hydrazine bond only. The grafting densities of PEGB-Hz-CHEMS on CL-pPSL were optimised to achieve a PEG density of 1.7% (mol). The unilamellar CL-pPSL (123 nm) were shown to be sable at least for 3 months at 4 °C and have enhanced pH-sensitivity compared with pPSL in the calcein leakage assay. Therefore, the smart cleavable PEG polymer is promising in liposome formulation to overcome the PEG dilemma.

Preparation and performance of pH-responsive nanocarriers for mucus penetration

Objective To prepare pH-responsive osmotic nanocarriers (pMPPs), observe their distribution in the genital tract mucosa in mice, and evaluate their radiosensitizing effects in tumor cells. Methods Amphiphilic polymers containing pH-sensitive hydrazone bonds were synthesized and pMPPs were prepared by ultrasonic emulsification. At the same time, the hydrophobic polymer polylactic acid-glycolic acid copolymer (PLGA) and the amphiphilic polymer PLGA-polyethylene glycol without hydrazine bond were selected, and the mucoadhesive nanoparticles(MPs) and mucus-penetrating particles (MPPs) were prepared in the same way. Fluorescence microscopy was used to observe the distribution of three kinds of nanocarriers labeled with fluorescent dye Cy5.5 in the genital tract mucosa. The toxicity of nanocarriers to human cervical cancer cell line HeLa was tested by thiazolyl blue assay. The amphiphilic polymer containing pH-sensitive hydrazone bond was combined with oil-soluble gold nanoparticles to form a multi-encapsulated nanocarrier, and its radiotherapy sensitization effect in HeLa cells was evaluated by thiazole blue assay. Results The pMPPs were successfully prepared with relatively uniform particle size and good dispersion. Fluorescence microscopy showed that pMPPs not only had good mucus permeability, but also could improve the endocytosis efficiency of the nanocarriers in reproductive tract mucosa. The results of thiazolyl blue test showed that when the concentration of the carrier reached to 0.80 mg/ml, the survival rate of HeLa cells in the pMPPs group was higher than 90% which was higher than that in the MPs and the MPPs groups, indicating that pMPPs had good biosafety. The HeLa cell survival rate of the CMNa group (0.80 mg/ml) was higher than that of the multi-package nanocarrier group under different doses of X-ray irradiation (4 Gy: 82.90% vs. 61.79%; 8 Gy: 64.75% vs. 42.36%). This result indicated that compared with the CMNa, a commonly used clinical radiotherapy sensitizer, the multi-encapsulated nanocarriers can more effectively enhance the sensitivity of tumor cells to radiation therapy, thereby improving the lethality of radiation therapy on tumor cells. Conclusion This study solved the conflict between mucus permeation and endocytosis design of nanocarriers in mucosal tissue application, and provided new insight for the treatment of mucosal tissue diseases. Key words: pH-responsive mucus-penetrating particles; Mucoadhesive nanoparticles; Mucus-penetrating particles; Mucus; Permeability

PH-responsive nanoreservoirs based on hyaluronic acid end-capped mesoporous silica nanoparticles for targeted drug delivery

Mesoporous silica nanoparticles (MSNs) are greatly appealing for efficient drug delivery due to their excellent drug loading capacities. However, it remains as a major challenge to realize site-specific controlled release with MSNs. This work examines a smart pH-responsive drug release system using MSNs for CD44-targeting drug delivery. Specifically, hyaluronic acid (HA) was applied as an end-capping agent to seal drug loads inside the mesoporous of MSNs through the acid labile hydrazine bonds. HA exposed on the surface of the particles can also serve as a targeting agent at the same time, enable site specific targeting toward CD-44 overexpressing cells. The system showed a good stability at physiological pHs, yet drug release could be triggered in response to changes in pH. Further studies showed that the HA-fabricated particles could achieve much enhanced cellular uptake via CD44 receptor-mediated endocytosis by Hela cells (CD44 receptor-positive), and as a result, doxorubicin-loaded MSNs exhibited significantly enhanced drug efficacy toward cancer cells overexpressing CD44 receptor (IC50 = 0.56 μg/mL), whereas the normal cells showed weakly cytotoxicity (IC50 = 1.03 μg/mL). Such a fabrication strategy may provide a new platform for preparation of high performance drug delivery systems for cancer therapy.

Comparison between Glass and Stainless-Steel Vessels in Differential Scanning Calorimetry Estimation

Differential scanning calorimetry (DSC) provides easy screening for thermal hazard evaluation. Here, we investigate the difference between using glass and stainless-steel vessels on the DSC measurement of exothermic decomposition energy (QDSC) for 41 chemical substances (containing nitro, halogen, peroxide, and sulfur groups, and hydrazine bonds). Two borosilicate glass vessels (capillary and ampule) and one stainless-steel vessel were used. All QDSC values obtained were investigated with reference to the permissible fluctuation range specified by the ASTM (American Society for Testing and Materials) international Both glass vessels produced very similar QDSC values, despite different sample scales. The QDSC values obtained with the glass vessels were generally roughly within the variation tolerance range of the stainless-steel vessel. Notable exceptions were halogen- or sulfur-containing compounds; these exhibited smaller QDSC values with glass vessels in almost all cases. We will investigate whether certain structures in compounds react with stainless steel. The vessel material choice is crucial in evaluating the true reactivity of a substance.

Synthesis and Characterization of Doxorubicin Loaded pH-Sensitive Magnetic Core–Shell Nanocomposites for Targeted Drug Delivery Applications

In order to improve the effects of medical therapy for cancer, we prepared magnetic nanocomposites (Fe3O4@SiO2–NH–NH[Formula: see text] as doxorubicin (DOX) carriers via two different schemes. Scheme (I): the carriers were synthesized from magnetic silica nanoparticles (Fe3O4@SiO[Formula: see text] via layer by layer modification, scheme (II): the carriers were obtained from amino-modified magnetic silica nanoparticles (Fe3O4@SiO2–NH[Formula: see text] synthesized by one-step, and followed by surface modification. In order to load DOX effectively, the surface of the carriers were further modified to make the surface with a large number of hydrazine bonds which can form a pH-sensitive bond (hydrazone bond) with DOX. The two kinds of carriers both exhibited a size around 80[Formula: see text]nm, high stability and superparamagnetic behavior. However, DOX-loaded carriers (Fe3O4@SiO2–DOX(2)) performed relatively poorer performance in terms of drug loading and releasing (the loading efficiency of DOX decreased from 67.33% to 42.15%, while the releasing efficiency of DOX decreased from 66.16% to 62.23% within 72[Formula: see text]h at pH 4.0). Water-soluble tetrazolium salts (WST-1) assays in cancer cells (Hela) demonstrated that the Fe3O4@SiO2–DOX presented high anti-tumor activity, while the carriers were nearly nontoxic. Thus, the results suggested that the magnetic nanocomposites synthesized by the two different methods both can be employed to deliver DOX, while the carriers obtained via the first method may perform better and would be applied in the field of cancer therapy in the future.

Doxorubicin-tethered fluorescent silica nanoparticles for pH-responsive anticancer drug delivery

The therapeutic potential of doxorubicin hydrochloride (DOX), an anticancer drug, is limited by its dose-related side effects and non-selective delivery to healthy and cancerous cells. Here we show a drug delivery system based on doxorubicin-tethered fluorescent silica nanoparticles (DOX-Hyd@FSiNPs). The DOX was conjugated to the FSiNPs through a hydrazone linkage. After uptake into the acidic environment of cancer cells, DOX was released from the FSiNPs’ surfaces because of the breakage of the pH-sensitive hydrazine bond. The decreased viability of cells in the HeLa cancer cell line indicates that DOX-Hyd@FSiNPs are potential candidates for cancer therapy. Nuclear staining and Z-axis scanning with confocal laser scanning microscopy demonstrated that DOX-Hyd@FSiNPs were effectively delivered into the cytoplasm of HeLa cells; the released DOX accumulating in the nucleus. The fluorescence of the FSiNPs also allowed the live-tracking of the nanoparticles in the cell.

Hydrazone-bearing PMMA-functionalized magnetic nanocubes as pH-responsive drug carriers for remotely targeted cancer therapy in vitro and in vivo.

To develop vehicles for efficient chemotherapeutic cancer therapy, we report a remotely triggered drug delivery system based on magnetic nanocubes. The synthesized magnetic nanocubes with average edge length of around 30 nm acted as cores, whereas poly(methyl methacrylate) (PMMA) was employed as an intermediate coating layer. Hydrazide was then tailored onto PMMA both for doxorubicin (DOX) loading and pH responsive drug delivery via the breakage of hydrazine bonds. The successful fabrication of the pH responsive drug carrier was confirmed by transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and magnetic hysteresis loops, respectively. The carrier was stable at neutral environment and doxorubicin released at pH of 5.0. Cell viability assay and confocal laser scanning microscopy observations demonstrated that the loaded DOX could be efficiently released after cellular endocytosis and induced cancer cells apoptosis thereby. More importantly, the carrier could be guided to the tumor tissue site with an external magnetic field and led to efficient tumor inhibition with low side effects, which were reflected by magnetic resonance imaging (MRI), change of tumor size, TUNEL staining, and H&E staining assays, respectively. All results suggest that hydrazide-tailoring PMMA-coated magnetic nanocube would be a promising pH-responsive drug carrier for remotely targeted cancer therapy in vitro and in vivo.

Structural and mechanistic insights into the kynurenine aminotransferase-mediated excretion of kynurenic acid

Kynurenine aminotransferase (KAT) is a homodimeric pyridoxal protein that mediates the catalytic conversion of kynurenine (KYN) to kynurenic acid (KYA), an endogenous N-methyl-d-aspartate (NMDA) receptor antagonist. KAT is involved in the biosynthesis of glutamic and aspartic acid, functions as a neurotransmitter for the NMDA receptor in mammals, and is regulated by allosteric mechanisms. Its importance in various diseases such as schizophrenia makes KAT a highly attractive drug target. Here, we present the crystal structure of the Pyrococcus horikoshii KAT (PhKAT) in complex with pyridoxamine phosphates (PMP), KYN, and KYA. Surprisingly, the PMP was bound to the LYS-269 of phKAT by forming a covalent hydrazine bond. This crystal structure clearly shows that an amino group of KYN was transaminated to PLP, which forms a Schiff's base with the LYS-269 of the KYN. Thus, our structure confirms that the PMPs represent an intermediate state during the KAT reaction. Thus, PhKAT catalyzes the sequential conversion of KYN to KYA via the formation of an intermediate 4-(2-aminophenyl)-2,4-dioxobutanoate (4AD), which is spontaneously converted to KYA in the absence of an amino group acceptor. Furthermore, we identified the two entry and exit sites of the PhKAT homodimer for KYN and KYA, respectively. The structural data on PhKAT presented in this manuscript contributes to further the understanding of transaminase enzyme reaction mechanisms.

N′-[(2Z)-4-Oxo-4-phenylbut-2-en-2-yl]pyridine-4-carbohydrazide

There are significant twists in the title compound, C16H15N3O2, as seen in the dihedral angle between the benzene and adjacent but-2-enal group [29.26 (4)°] and between the pyridine ring and amide group [24.79 (6)°]. A twist is also evident around the hydrazine bond [the C—N—N—C torsion angle is −138.25 (13)°]. The conformation about the ethene bond is Z. An intra­molecular N—H⋯O hydrogen bond involving the benzoyl O atom and leading to an S(6) motif is formed. Significant delocalization of π-electron density is found in this part of the mol­ecule. In the crystal, helical supra­molecular chains aligned along the b axis and mediated by N—H⋯O hydrogen bonds are formed.

Correction to Synthesis and Reaction of Monomeric Germanium(II) and Lead(II) Dimethylamide and the Synthesis of Germanium(II) Hydrazide by Cleavage of One N−H Bond of Hydrazine

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Synthesis and Reaction of Monomeric Germanium(II) and Lead(II) Dimethylamide and the Synthesis of Germanium(II) Hydrazide by Cleavage of One N−H Bond of HydrazineAnukul Jana, Herbert W. Roesky*, Carola Schulzke, Prinson P. Samuel, and Alexander DöringCite this: Inorg. Chem. 2010, 49, 21, 10208–10209Publication Date (Web):September 30, 2010Publication History Received8 September 2010Published online30 September 2010Published inissue 1 November 2010https://doi.org/10.1021/ic101845tCopyright © 2010 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views575Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (644 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Crystals,Hydrogen,Molecular structure,Nitrogen,Structural analysis Get e-Alerts

A Novel Poly(l-glutamic acid) Dendrimer Based Drug Delivery System with Both pH-Sensitive and Targeting Functions

The functionalization of pH-sensitiveness and cellular targeting is a promising strategy to fabricate drug delivery systems with high efficiency, high selectivity and low toxicity. In this paper, a poly(l-glutamic acid) dendrimer based drug delivery system with both pH-sensitive and targeting functions is reported. Poly(l-glutamic acid) dendrimers with a polyhedral oligomeric silsesquioxane (POSS) nanocubic core were synthesized. Its globular morphology and compact structure with multiple peripheral functional groups made it suitable for drug delivery. The OAS-G(3)-Glu dendrimer was conjugated with doxorubicin via pH-sensitive hydrazine bonds and targeting moiety (biotin). The cellular internalization and antitumor effects of the conjugates was evaluated in vitro. Both DLS and TEM results indicated that the conjugates aggregated into nanoparticles with diameters around 50 nm. The release rates of doxorubicin at pH 5.0 were much faster than those at pH 7.0 due to the acid cleavage of the hydrazine bonds. The internalization study revealed that the cellular uptake of the biotin modified conjugates was mainly through receptor-mediated endocytosis. These results indicate that our poly(l-glutamic acid) dendrimers with OAS core are promising vectors for fabricating smart and targeting drug delivery systems.