A library of aminoglycoside-derived lipopolymer nanoparticles for delivery of small molecules and nucleic acids.

Simultaneous delivery of small molecules and nucleic acids using a single vehicle can lead to novel combination treatments and multifunctional carriers for a variety of diseases. In this study, we report a novel library of aminoglycoside-derived lipopolymers nanoparticles (LPNs) for the simultaneous delivery of different molecular cargoes including nucleic acids and small-molecules. The LPN library was screened for transgene expression efficacy following delivery of plasmid DNA, and lead LPNs that showed high transgene expression efficacies were characterized using hydrodynamic size, zeta potential, 1H NMR and FT-IR spectroscopy, and transmission electron microscopy.

Accelerated Materials Discovery Using Chemical Informatics Investigation of Polymer Physicochemical Properties and Transgene Expression Efficacy.

Quantitative approaches to structure-property relationships are critical for the accelerated design and discovery of biomaterials in biotechnology and medicine. However, the absence of definitive structures, unlike those available for small molecules or 3D crystal structures available for some proteins, has limited the development of Quantitative Structure-Property Relationship (QSPR) models for investigating physicochemical properties and biological activity of polymers. In this study, we describe a combined experimental and cheminformatics paradigm for first developing QSPR models of polymer physicochemical properties, including molecular weight, hydrophobicity, and DNA-binding activity.

An inhibitor screen identifies histone-modifying enzymes as mediators of polymer-mediated transgene expression from plasmid DNA.

Effective transgene expression in mammalian cells relies on successful delivery, cytoplasmic trafficking, and nuclear translocation of the delivered vector, but delivery is impeded by several formidable physicochemical barriers on the surface of and within the target cell. Although methods to overcome cellular exclusion and endosomal entrapment have been studied extensively, strategies to overcome inefficient nuclear entry and subsequent intranuclear barriers to effective transient gene expression have only been sparsely explored. In particular, the role of nuclear packaging of DNA with histone proteins, which governs endogenous gene expression, has not been extensively elucidated in the case of exogenously delivered plasmids.

Aminoglycoside-derived amphiphilic nanoparticles for molecular delivery.

The development of effective drug carriers can lead to improved outcomes in a variety of disease conditions. Aminoglycosides have been used as antibacterial therapeutics, and are attractive as monomers for the development of polymeric materials in various applications. Here, we describe the development of novel aminoglycoside-derived amphiphilic nanoparticles for drug delivery, with an eye towards ablation of cancer cells.

The histone deacetylase inhibitor Entinostat enhances polymer-mediated transgene expression in cancer cell lines.

Eukaryotic cells maintain an immense amount of genetic information by tightly wrapping their DNA around positively charged histones. While this strategy allows human cells to maintain more than 25,000 genes, histone binding can also block gene expression. Consequently, cells express histone acetyl transferases (HATs) to acetylate histone lysines and release DNA for transcription.

Kinome-level screening identifies inhibition of polo-like kinase-1 (PLK1) as a target for enhancing non-viral transgene expression.

Human cells contain hundreds of kinase enzymes that regulate several cellular processes, which likely include transgene delivery and expression. We identified several kinases that influence gene delivery and/or expression by performing a kinome-level screen in which, we identified small-molecule kinase inhibitors that significantly enhanced non-viral (polymer-mediated) transgene (luciferase) expression in cancer cells. The strongest enhancement was observed with several small-molecule inhibitors of Polo-like Kinase 1 (PLK 1) (e.

Discovery of antibiotics-derived polymers for gene delivery using combinatorial synthesis and cheminformatics modeling.

We describe the combinatorial synthesis and cheminformatics modeling of aminoglycoside antibiotics-derived polymers for transgene delivery and expression. Fifty-six polymers were synthesized by polymerizing aminoglycosides with diglycidyl ether cross-linkers. Parallel screening resulted in identification of several lead polymers that resulted in high transgene expression levels in cells.

Applying horizontal gene transfer phenomena to enhance non-viral gene therapy.

Horizontal gene transfer (HGT) is widespread amongst prokaryotes, but eukaryotes tend to be far less promiscuous with their genetic information. However, several examples of HGT from pathogens into eukaryotic cells have been discovered and mimicked to improve non-viral gene delivery techniques. For example, several viral proteins and DNA sequences have been used to significantly increase cytoplasmic and nuclear gene delivery.

Defining new insight into atypical arrhythmia: a computational model of ankyrin-B syndrome.

Normal cardiac excitability depends on the coordinated activity of specific ion channels and transporters within specialized domains at the plasma membrane and sarcoplasmic reticulum. Ion channel dysfunction due to congenital or acquired defects has been linked to human cardiac arrhythmia. More recently, defects in ion channel-associated proteins have been associated with arrhythmia.

Oxidized calmodulin kinase II regulates conduction following myocardial infarction: a computational analysis.

Calmodulin kinase II (CaMKII) mediates critical signaling pathways responsible for divergent functions in the heart including calcium cycling, hypertrophy and apoptosis. Dysfunction in the CaMKII signaling pathway occurs in heart disease and is associated with increased susceptibility to life-threatening arrhythmia. Furthermore, CaMKII inhibition prevents cardiac arrhythmia and improves heart function following myocardial infarction.