Search

Automated synthesis of a radiopharmaceutical 3-((2-fluoro-4-(5-(2′-methyl-2-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl) (methyl-11C)amino)propanoic acid ([11C]CS1P1) for PET imaging sphingosine-1 phosphate receptor 1 (S1P1) was accomplished by a two-step-one-pot procedure in a Siemens CTI methylation automated module using TR-19 cyclotron. The synthesis of [11C]CS1P1 was successfully validated under current Good Manufacturing Practices (cGMP) conditions, resulting in a consistent average radiochemical yield of ∼15%, molar activity of ∼3129 GBq/μmol (decay corrected to end of bombardment, EOB), and radiochemical purity > 95%. The radiopharmaceutical product meets all quality control criteria for human use for an Investigational New Drug (IND) application to permit human studies.

Doxorubicin (DOX) is a potent chemotherapeutic drug but the clinical use was limited by its dose-dependent cardiotoxicity. Pinocembrin (PCB), a flavonoid originally isolated from honeybee propolis and rhizomes of Boesenbergia pandurate displays diverse biological activities. However, the role of PCB in DOX-induced cardiac injury and its underlying molecular mechanism are not fully elucidated. The present study was designed to evaluate the protective role of PCB in a DOX-induced cardiotoxicity in vivo and in vitro. Our results revealed that PCB administration greatly improved cardiac function and reduced cardiac fibrosis manifested by LVEF, LVFS, LVIDd, LVIDs, and myocardial fibrotic area which were impaired by DOX treatment. The cardiac injury evidenced by LDH and CK-MB activities were reduced while the levels of IL-1β and IL-18 were decreased following PCB treatment compared to DOX-treated mice. Mechanically, our present results showed that PCB significantly inhibited DOX-induced cardiomyocyte pyroptosis via activating Nrf2/Sirt3 signal pathway. Furthermore, the inhibition of Nrf2 in H9c2 cells abolished the protective role of PCB against DOX-induced cell toxicity, which was at least partly via upregulation of NLRP3-mediated pyroptosis. In conclusion, our study clearly demonstrated that PCB reduced cardiomyocyte pyroptosis to protect hearts from DOX-induced cardiotoxicity through activation of Nrf2/Sirt3 signal pathway.

In this study, we designed a novel nucleus-targeted nanocarrier (NLS-KALA-SA, NKSN) consisting of Kala peptide (KALA), nuclear localization signal (NLS) and stearic acid (SA) using Fmoc solid phase synthesis method. We chose Curcumin (CUR), Paclitaxel (PTX), Ginsenoside compound K(CK) as models of poorly water-soluble antitumor drugs, The drugs loaded NLS-KALA-SA nanoparticles (CUR/NKSN, PTX/NKSN, CK/NKSN) were obained by the dialysis method, their physicochemical properties were determined and antitumor activity were evaluated. The NLS-KALA-SA nanoparticles were spherical shaped with an average size of 76.4 ± 7.6 mm and a zeta potential of 43.7 ± 5.8 mV. The drug-loaded NLS-KALA-SA nanoparticles were above 86.1% and 17.1% in entrapment efficiency and drug loading capacity, and had sustained drug release behavior. Biodistribution and cellular uptake study exhibited that PTX/NKSN mainly distributed in tumor site of A549-bearing mice, and coumarin-6(C6) loaded NLS-KALA-SA nanoparticle (C6/NKSN) was predominantly accumulated in the nucleus of A549 cells. Western blot analysis indicated that PTX/NKSN could more remarkably inhibit Bcl-2 expression and enhance the expression of Bax and Caspase-3 as compared to the controls in A549 cells. Cell apoptosis and antitumor activity study showed that PXT/NKSN could more obviously induce apoptosis of A549 cells compared with free PXT, the PTX/NKSN administration was more effective than free PTX for lung cancer treatment and displayed mild toxicity in A549-bearing mice. The results demonstrates that the NLS-KALA-SA nanoparticles system could enhance the antitumor effects of the encapsulated drug and reduce tissue toxicity due to its long circulating properties and tumor targeting, which might provide a promising strategy for lung cancer treatment.

Leukocyte reduced NADP (NADPH) oxidase plays a key role in host defense and immune regulation. Genetic defects in NADPH oxidase result in chronic granulomatous disease (CGD), characterized by recurrent bacterial and fungal infections and aberrant inflammation. Key drivers of hyperinflammation induced by fungal cell walls in CGD are still incompletely defined. In this study, we found that CGD (CYBB−) neutrophils produced higher amounts of leukotriene B4 (LTB4) in vitro after activation with zymosan or immune complexes, compared with wild-type (WT) neutrophils. This finding correlated with increased calcium influx in CGD neutrophils, which was restrained in WT neutrophils by the electrogenic activity of NADPH oxidase. Increased LTB4 generation by CGD neutrophils was also augmented by paracrine cross talk with the LTB4 receptor BLT1. CGD neutrophils formed more numerous and larger clusters in the presence of zymosan in vitro compared with WT cells, and the effect was also LTB4- and BLT1-dependent. In zymosan-induced lung inflammation, focal neutrophil infiltrates were increased in CGD compared with WT mice and associated with higher LTB4 levels. Inhibiting LTB4 synthesis or antagonizing the BLT1 receptor after zymosan challenge reduced lung neutrophil recruitment in CGD to WT levels. Thus, LTB4 was the major driver of excessive neutrophilic lung inflammation in CGD mice in the early response to fungal cell walls, likely by a dysregulated feed-forward loop involving amplified neutrophil production of LTB4. This study identifies neutrophil LTB4 generation as a target of NADPH oxidase regulation, which could potentially be exploited therapeutically to reduce excessive inflammation in CGD.

The first example of visible light promoted fluoroalkylation reactions initiated via noncovalent interactions between acetone and fluoroalkyl iodides is presented. The reaction system features synthetic simplicity, mild reaction conditions without any photoredox catalyst, and high functional group tolerance. A wide range of substrate scopes such as alkenes, alkynes and (hetero)arenes were all compatible with the reaction system.

Studies have indicated that high levels of ethanol exposure impaired spermatogenesis in mice. However, the effects of chronic and low-dose alcohol consumption on susceptible populations remain unclear. The previous studies have confirmed that Immp2l mutant mice (Immp2lTg(Tyr)979Ove or Immp2l-/- ) suffered from increased levels of oxidative stress(OS) and male infertility, heterozygous lmmp2l mice (Immp2l+/- ) showed no altered ROS levels under physiological condition. Lycium barbarum polysaccharide (LBP) significantly scavenge oxygen free radicals and enhance antioxidant enzyme activity. The objectives of present study were to research the effects of chronic and low-dose alcohol-induced damage on Immp2l+/- , explore the protective function of LBP and possible mechanism. The results indicated that chronic ethanol exposure leads to spermatogenic impairment and triggered a toxic effect on germ cell, 10 mg/kg LBP administration improved the quality of spermatozoon, decreased the ratio of apoptotic germ cells and the expression of Col1a1 and Col1a2, while increased the level of TNP2 and RPL31. In conclusion, the study may provide basic knowledge about LBP's important role against ethanol-induced spermiotoxicity and testicular degeneration in Immp2l+/- mice, and the mechanism may be that LBP influenced the state of the spermatogenic epithelium by decreasing the expression of Collagen level leading to alterations in protein biosynthesis during the process of spermatogenesis.

The objective of this study was to develop a novel type of an antisense oligonucleotide (OGX-011) loaded Tat-tagged and folate-modified N-succinyl-chitosan (Tat-Suc-FA) nanoparticles (NPs) for improving tumor targetability. In this study, Tat-Suc-FA/OGX-011NPs were prepared and its physicochemical characterizations were also evaluated. The nanoparticles showed an average diameter of 73 ± 16.6 nm, the zeta potential of +23.6 ± 0.3 mV, and a high entrapment efficiency of 89.6 ± 6.6%. Transmission electron microscopy analysis showed the nanoparticles were mostly spherical and well dispersed. The delivery efficiency of this system was investigated both in vitro and in vivo. In comparison with nontargeted Lipofectamin2000/OGX-011 and free OGX-011, Tat-Suc-FA/GOX-011 showed the highest apoptosis rate of 14.2% ± 1.8% and significant uptake in A549 cells. Tat-Suc-FA NPs loaded with GOX-011 induced significant down-regulation of s-CLU mRNA and protein levels in A549 cells. In A549 tumor-bearing mice model, Tat-Suc-FA/GOX-011 produced a more efficient down-regulation of s-CLU compared to Lipofectamin2000/OGX-011. Furthermore, the combined use of Tat-Suc-FA/OGX-011 with DDP chemotherapy showed a most significant inhibition of tumor growth and greatly enhanced the survival rate of A549 tumor-bearing mice. These findings suggested successful application of Tat-Suc-FA NPs for the high efficiency and specificity in therapeutic delivery of OGX-011 to A549 cells.

In search of an effective and less toxic absorption enhancer, we synthesized primary amine acetylation of generation 2 polyamidoamine (G2 PAMAM) dendrimer (Ac-G2) by the reaction of G2 PAMAM dendrimer with acetic anhydride, and evaluated the effects of Ac-G2 on the intestinal absorption of poorly absorbable water-soluble drugs using an in situ closed-loop method in rats. The results indicated that Ac50-G2 had a greatest absorption enhancing effect for 5(6)-carboxyfluorescein (CF) in various acetylation levels of G2 PAMAM dendrimers. Ac50-G2 with various concentrations (0.1-1.0%, w/v) could significantly improve the intestinal absorption of alendronate, CF, and fluorescein isothiocyanate-labeled dextrans (FD4), although they did not enhance the absorption of macromolecular drug of FD10, and the absorption enhancement effect of Ac50-G2 was concentration-dependent. Furthermore, we examined the intestinal membrane damage with or without Ac50-G2. The results displayed Ac50-G2 at lower concentrations (0.1-0.5%, w/v) did not cause any observed toxic effect to the intestinal membranes. These findings suggested Ac50-G2 at lower concentrations (below 0.5%, w/v) might be promising as an effective and safe absorption enhancers to promote the intestinal absorption of poorly absorbable drugs.

The absorption-enhancing effects of glycol chitosan modified by 5β-cholanic acid nanoparticles (5β-CHA/GC-NPs) on a drug with poor absorption in the intestine were studied by the method of in situ closed loop. We chose fluorescein isothiocyanate-labeled dextrans (FDs) and insulin as the model drugs. 5β-CHA/GC-NPs loaded to different drugs were prepared by the dialysis method, and the physicochemical characteristics and in vitro release profiles of nanoparticles were also estimated. The results showed that 5β-CHA/GC-NPs markedly increased the absorption of insulin and FDs in the jejunum, ileum, and colon. The ratios of absorption for all the drugs in the jejunum were higher than those in the ileum and colon. In addition, the enhancing effect of 5β-CHA/GC-NPs for the absorption of FDs from the jejunum was decreased with increasing molecular weights. In the toxicity test, 5β-CHA/GC-NPs did not significantly increase the release of protein and the activities of LDH, indicating that the nanoparticles did not cause any membrane damage to the intestine. These findings suggested that 5β-CHA/GC-NPs were safe and useful carriers for enhancing the absorption of the drug with poor absorption by intestinal membranes.

Here, we describe a mild, catalyst-free and operationally-simple strategy for the direct fluoroalkylation of olefins driven by the photochemical activity of an electron donor−acceptor (EDA) complex between DMA and fluoroalkyl iodides. The significant advantages of this photochemical transformation are high efficiency, excellent functional group tolerance, and synthetic simplicity, thus providing a facile route for further application in pharmaceuticals and life sciences.

A catalyst free cycloaddition reaction of 3-oxo-1,2-pyrazolidinium ylides with β -trifluoroacetyl vinyl ethyl ether is reported, which proceeded smoothly at ambient temperature and afford the bicyclic pyrazolidinone products in good yield. This is the first report of synthesis of 6-trifluoroacetyl substituted bicyclic pyrazolidinones that are potentially anti-microbial and herbicidal.

5-Fluorouracil-loaded N-succinyl-chitosan nanoparticles (5-FU-Suc-Chi/NP) were prepared by emulsification solvent diffusion. Biodistribution and tumor targeting were evaluated after i.v. administration of 5-Fu-Suc-Chi/NPs in Sarcoma 180-bearing mice. Also, pharmacokinetic profiles were evaluated after intravenous injection of 5-Fu-Suc-Chi/NP via the tail vein to rats. Our experimental results showed the 5-FU-Suc-Chi/NPs could be sustained at a high level in the blood for a very long time, implying its long systemic retention in the circulation. 5-FU-Suc-Chi/NPs were distributed mainly in tumors and liver, with small quantities being found in kidney and spleen. 5-FU-Suc-Chi/NPs accumulated only slightly in the heart and lung, and lowered the toxic effect of 5-FU in the heart and lung. Pharmacokinetic analysis in plasma showed the area under plasma concentration-time curve (AUC), elimination half-life (t(1/2)), and residence time (MRT) were increased 2.5-fold, 10.98-fold, and 10.8-fold for 5-FU-Suc-Chi/NP compared with that of free 5-FU, respectively. These results indicate that a long half-life in the circulation and tumor targeting of 5-FU-Suc-Chi/NPs are possible.

The aim of this work is to prepare N-succinyl-chitosan (Suc-Chi) and measure physical-chemical properties for Suc-Chi as excipients. Suc-Chi were prepared via ring-opening reactions with succinic anhydride in Dimethyl Sulfoxide system. The physical-chemical properties of Suc-Chi, such as the degree of substitution (DS), solubility, isoelectric point (pI), glass transition temperature (Tg), partition coefficient (P(app)) and zata potential were detected respectively in order to evaluate their possibility as drug carriers. We obtained Suc-Chi DAC-90 (DS=0.33) and the data of physical-chemical properties for the product. The knowledges of physical-chemical properties for Suc-Chi are valuable for basic or applied purposes in biomedical and pharmaceutical sciences stabilization.

The purpose of this research was to prepare a novel type of Tat tagged and folate modified N-succinyl-chitosan (Tat-Suc-FA) self-assembly nanoparticles, to provide a new vector for tumor gene therapy. In this study, Tat-Suc-FA polymers was synthesized and characterized using (1)H NMR and FT-IR. The copolymer had a mean diameter of 65 ± 22.6 nm, a zeta potential of 40 ± 0.2 mV. The cytotoxicity assay showed that Tat-Suc-FA polymers were less toxic than chitosan in the tested concentration range (from 2 to 500 μg/ml). Tat-Suc-FA/DNA complexes at various weight ratios were formulated and characterized. Particle sizes of Tat-Suc-FA/DNA complexes were between 54 and 106 nm as determined by dynamic light scattering. Accordingly, Transmission electron microscope photo of Tat-Suc-FA/DNA complexes exhibited a spherical and compact morphology. Zeta potentials of these complexes changed as the weight ratio varied (from 3 to 44 mV). Agarose gel electrophoresis assay showed that Tat-Suc-FA could efficiently condense the DNA, when the weight ratio was above 1.5/1. Together, these results suggest that the low toxic Tat-Suc-FA cationic polymers could be considered for use as a novel type of gene delivery vectors.

A catalyst-free synthesis of heterocycle-fused 1,2,3-triazoles is achieved through 1,3-dipolar cycloaddition of the azide with cyclic ketene aminals followed by elimination of fluoroalkanesulfonamide.

A catalyst free cycloaddition reaction of 3-oxo-1,2-pyrazolidinium ylides with β -trifluoroacetyl vinyl ethyl ether is reported, which proceeded smoothly at ambient temperature and afford the bicyclic pyrazolidinone products in good yield. This is the first report of synthesis of 6-trifluoroacetyl substituted bicyclic pyrazolidinones that are potentially anti-microbial and herbicidal.

N-Succinyl-chitosan has favourable properties as a drug carrier, such as biocompatibility, low toxicity and long-term retention in the body. It is a good candidate for cancer chemotherapy as a polymeric drug carrier. This study describes the preparation and characterization of 5-fluorouracil-loaded N-succinyl-chitosan nanoparticles (5-FU-Suc-Chi/NP) by an emulsification solvent diffusion method. The influence of the initial 5-FU concentration on the nanoparticle characteristics and release behaviour in phosphate-buffered saline solution (PBS) was evaluated. The Suc-Chi nanoparticles had a particle diameter (Z-average) in the range 202∼273 nm and a negative zeta-potential (approx. −27 to −18 mV). The formulation with an initial 5-FU concentration of 1000 μg mL−1 provided the highest loading capacity (19%) and the highest extent of release (61% at 24 h). The 5-FU-Suc-Chi/NP showed good anti-tumour activity against Sarcoma 180 solid tumour and mild toxicity. According to the data obtained, this Suc-Chi-based nanotechnology opens new and interesting perspectives for cancer chemotherapy.