In vivo evaluation of a mucoadhesive polymeric caplet for intravaginal anti-HIV-1 delivery and development of a molecular mechanistic model for thermochemical characterization

Context and objective: The aim of this study was to develop, characterize and evaluate a mucoadhesive caplet resulting from a polymeric blend (polymeric caplet) for intravaginal anti-HIV-1 delivery.

Materials and methods: Poly(lactic-co-glycolic) acid, ethylcellulose, poly(vinylalcohol), polyacrylic acid and modified polyamide 6, 10 polymers were blended and compressed to a caplet-shaped device, with and without two model drugs 3′-azido-3′-deoxythymidine (AZT) and polystyrene sulfonate (PSS). Thermal analysis, infrared spectroscopy and microscopic analysis were carried out on the caplets employing temperature-modulated DSC (TMDSC), Fourier transform infra-red (FTIR) spectrometer and scanning electron microscope, respectively. In vitro and in vivo drug release analyses as well as the histopathological toxicity studies were carried out on the drug-loaded caplets. Furthermore, molecular mechanics (MM) simulations were carried out on the drug-loaded caplets to corroborate the experimental findings.

Results and discussion: There was a big deviation between the T_g of the polymeric caplet from the T_g's of the constituent polymers indicating a strong interaction between constituent polymers. FTIR spectroscopy confirmed the presence of specific ionic and non-ionic interactions within the caplet. A controlled near zero-order drug release was obtained for AZT (20 d) and PSS (28 d). In vivo results, i.e. the drug concentration in plasma ranged between 0.012–0.332?mg/mL and 0.009–0.256?mg/mL for AZT and PSS over 1–28 d.

Conclusion: The obtained results, which were corroborated by MM simulations, attested that the developed system has the potential for effective delivery of anti-HIV-agents.     

致密油藏注天然气提高采收率研究现状

随着我国石油需求量不断增加,致密油藏的开发也愈发重要。如何高效开发致密油藏是一项重点难点,其中致密油藏注天然气提高采收率是一个极具潜力的研究方向。因此,本文着重介绍以天然气作为能量补充介质在国内外的研究现状和应用现状,并且从两相特征等方面总结了理论研究中的一些机理,对致密油藏注天然气提高采收率的发展前景进行了一定的展望。     

Oxide-Scale Evolution on a New Ni–Fe-Based Superalloy at High Temperature

Oxidation of Metals - The isothermal oxidation behavior and oxide-scale evolution on a newly developed Ni–Fe-based superalloy were investigated. Three oxidation stages were generally...     

以用户为中心的可见光通信协作传输中训练资源分配算法

以用户为中心的可见光通信协作传输是近年来出现的新架构,这导致虚拟小区之间出现重叠。为避免导频污染问题,每个虚拟小区中的光接入点(AP)或者虚拟小区中选择相同AP的用户发送的训练序列应该是正交的。针对可见光通信中以用户为中心的协作网络,研究训练资源的正交分配问题,提出了一种新的导频分配算法,联合导频分配和用户选择问题,以期最大限度地增加虚拟小区内可被接入的用户数。分析和仿真结果表明,该导频分配方案可以有效改善导频污染问题,提高训练资源利用率,并且相比已有的导频分配方案,性能有所改进。     

The use of natural (Pinus pinaster) resin in the production of printing ink and the printability effect

Alkyd resins are generally used in the production of printing inks. All industries look for alternative raw materials in the production of ink with the growing inclination toward using natural products. Resins forming the vehicle of the ink to be obtained from natural resources will provide benefits for the environment, nature, and living creatures. The aim of the study was to promote the use of natural resin in the ink system. Natural Pinus pinaster resin was added into vegetable and mineral oil-based solvents in pure form with alkyd resin in different amounts and ink varnishes of different combinations were prepared. Then, printing inks were produced from these varnishes in pure and hybrid form. Following the assessment of the rheological properties of the inks prepared, printing tests were conducted to assess the printing quality parameters. Ideal mixing ratios of the natural resins in the ink were determined for printability. The environmental importance and advantages of the use of natural resins were discussed. Recommendations were given in line with the results to encourage widespread use of natural resins in near future.     

Study on Wettability and Corrosion Behavior of Al2O3 Doped Polyurea Coatings

Protection of Metals and Physical Chemistry of Surfaces - The Al2O3 powder was added as a filler to polyurea and the effect of doping amount on Shore hardness and wetting property were...     

Methyltransferase Contingencies in the Pathway of Everninomicin D Antibiotics and Analogues

Everninomicins are orthoester oligosaccharide antibiotics with potent activity against multidrug-resistant bacterial pathogens. Everninomicins act by disrupting ribosomal assembly in a distinct region in comparison to clinically prescribed drugs. We employed microporous intergeneric conjugation with Escherichia coli to manipulate Micromonospora for targeted gene-replacement studies of multiple putative methyltransferases across the octasaccharide scaffold of everninomicin effecting the A₁, C, F, and H rings. Analyses of gene-replacement and genetic complementation mutants established the mutability of the everninomicin scaffold through the generation of 12 previously unreported analogues and, together with previous results, permitted assignment of the ten methyltransferases required for everninomicin biosynthesis. The in vitro activity of A₁- and H-ring-modifying methyltransferases demonstrated the ability to catalyze late-stage modification of the scaffold on an A₁-ring phenol and H-ring C-4’ hydroxy moiety. Together these results establish the potential of the everninomicin scaffold for modification through mutagenesis and in vitro modification of advanced biosynthetic intermediates.     

Supramolecular Assembly of Aminoethylene‐Lipopeptide PMO Conjugates into RNA Splice‐Switching Nanomicelles

Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile.