Gene/Protein Disease Symptom Drug Enzyme Compound
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RNA interference (RNAi) is a highly efficient approach for gene silencing. Regulation of gene expression at post-transcriptional level provides great potential for curing diseases caused by abnormal overexpression of disease-related genes. However, the application of RNAi in the clinic has been hindered by the lack of efficient and biocompatible delivery systems. Therefore, the development of a safe and tissue-targeted double-stranded interfering RNA (siRNA) carrier for clinical application is urgently needed. Here we report the discovery of a highly efficient liposomal siRNA delivery agent based on a novel peptidomimetic built from natural amino acids. Fine tuning of the composition of amino acids, the type of amide linkage in the peptidomimetic, as well as the formulation and the physicochemical parameters of the novel lipoplex resulted in a lipid nanoparticle (LNP) that efficiently encapsulates and carries siRNA to mouse liver. In vivo experiments showed that a single injection of unmodified siRNA complexed to one of the peptidomimetics at a clinically feasible dose induced significant RNAi in mouse liver, resulting in a 90% decrease in apolipoprotein B (ApoB) mRNA level, as well as a 60% decrease in serum ApoB protein level. Analysis of mouse serum by ELISA indicated that the novel peptidomimetic based lipoplex did not elevate the level of liver enzymes (ALT, AST) in the serum. Our novel peptidomimetic-based lipoplex demonstrated great potential for the development of a safe and efficient siRNA delivery agent for clinical applications.
ACS Appl Mater Interfaces 2016 Mar
PMID:Design of Highly Potent Lipid-Functionalized Peptidomimetics for Efficient in Vivo siRNA Delivery. 2696 58

Large-scale applications of polymer electrolyte membrane fuel cells (PEMFCs) are throttled primarily by high initial cost and durability issues of the electrodes, which essentially consist of the nanoparticulate catalysts (e.g., Pt) having accessibility to electrons (e-), protons (H+), and fuel/oxidant through catalyst support, polymer electrolyte ionomer, and porous gas diffusion layer, respectively. Hence, to achieve high electrode performance in terms of activity and/or durability, understanding and optimization of the catalyst/support and catalyst/ionomer interfaces are of significant importance. Present study demonstrates an alternative route to inspect the catalyst/ionomer interface through an accelerated stress test combined with electrochemical impedance spectroscopy. Various interfaces are created through catalyst inks prepared using commercial Pt/C catalyst powder dispersed in different solvents. Electrode degradation pattern turns out to be a very useful tool to interpret a catalyst/ionomer interface structure. Variations of interfacial impedance, electrochemical surface area (ECSA), and double layer capacitance with the number of potential cycles suggested significant impact of catalyst/ionomer interface on the catalyst performance. A quantification of the degradation mechanisms responsible for ECSA loss during AST was employed to further understand the correlations between the electrochemical performance of the electrodes and their catalyst/ionomer interface structures. The knowledge may be implied to further optimize the electrode structure and hence to advance the PEMFC technology.
ACS Appl Mater Interfaces 2018 Nov 07
PMID:Zoom in Catalyst/Ionomer Interface in Polymer Electrolyte Membrane Fuel Cell Electrodes: Impact of Catalyst/Ionomer Dispersion Media/Solvent. 3036 Jan 11

We report a potent cationic lipid, SST-02 ((3-hydroxylpropyl)dilinoleylamine), which possesses a simple chemical structure and is synthesized just in one step. Cationic lipids are key components of siRNA-lipid nanoparticles (LNP), which may serve as potential therapeutic agents for various diseases. For a decade, chemists have given enhanced potency and new functions to cationic lipids along with structural complexity. In this study, we conducted a medicinal chemistry campaign pursuing chemical simplicity and found that even dilinoleylmethylamine (SST-01) and methylpalmitoleylamine could be used for the in vitro and in vivo siRNA delivery. Further optimization revealed that a hydroxyl group boosted potency, and SST-02 showed an ID50 of 0.02 mg/kg in the factor VII (FVII) model. Rats administered with 3 mg/kg of SST-02 LNP did not show changes in body weight, blood chemistry, or hematological parameters, while the AST level decreased at a dose of 5 mg/kg. The use of SST-02 avoids a lengthy synthetic route and may thus decrease the future cost of nucleic acid therapeutics.
ACS Med Chem Lett 2019 May 09
PMID:Simplifying the Chemical Structure of Cationic Lipids for siRNA-Lipid Nanoparticles. 3109 94