Oligonucleotide delivery with cell surface binding and cell penetrating peptide amphiphile nanospheres

Cataloged from PDF version of article.A drug delivery system designed specifically for oligonucleotide therapeutics can ameliorate the problems associated with the in vivo delivery of these molecules. The internalization of free oligonudeotides is challenging, and cytotoxicity is the main obstacle for current transfection vehicles. To develop nontoxic delivery vehicles for efficient transfection of oligonudeotides, we designed a self-assembling peptide amphiphile (PA) nanosphere delivery system decorated with cell penetrating peptides (CPPs) containing multiple arginine residues (R-4 and R-8), and a cell surface binding peptide (KRSR), and report the efficiency of this system in delivering G-3129, a Bcl-2 antisense oligonucleotide (AON). PA/AON (peptide amphiphile/antisense oligonucleotide) complexes were characterized with regards to their size and secondary structure, and their cellular internalization efficiencies were evaluated. The effect of the number of arginine residues on the cellular internalization was investigated by both flow cytometry and confocal imaging, and the results revealed that uptake efficiency improved as the number of arginines in the sequence increased. The combined effect of cell penetration and surface binding property on the cellular internalization and its uptake mechanism was also evaluated by mixing R-8-PA and KRSR-PA. R-8 and R-8/KRSR decorated PAs were found to drastically increase the internalization of AONs compared to nonbioactive PA control. Overall, the KRSR-decorated self-assembled PA nanospheres were demonstrated to be noncytotoxic delivery vectors with high transfection rates and may serve as a promising delivery system for AONs

Noncovalent funstionalization of mesoporous silica nanoparticles with amphiphilic peptides

Cataloged from PDF version of article.The surface of mesoporous silica nanoparticles (MSNs) has been modified for enhancing their cellular uptake, cell targeting, bioimaging, and controlled drug release. For this purpose, covalent anchorage on the silica surface was predominantly exploited with a wide range of bioactive molecules. Here, we describe a facile self-assembly method to prepare a hybrid peptide silica system composed of octyl-modified mesoporous silica nanoparticles (MSNs) and peptide amphiphiles (PAs). The hydrophobic organosilane surface of mesoporous silica was coated with amphiphilic peptide molecules. The peptide functionalized particles exhibited good cyto-compatibility with vascular smooth muscle and vascular endothelial cells. The peptide coating also improved the cellular uptake of particles up to 6.3 fold, which is promising for the development of highly efficient MSN based theranostic agents. © 2014 the Partner Organisations

Peptide nanofibers for controlled growth factor release

[No abstract available

Cellular Internalization of Therapeutic Oligonucleotides by Peptide Amphiphile Nanofibers and Nanospheres

Oligonucleotides are promising drug candidates due to the exceptionally high specificity they exhibit toward their target DNA and RNA sequences. However, their poor pharmacokinetic and pharmacodynamic properties, in conjunction with problems associated with their internalization by cells, necessitates their delivery through specialized carrier systems for efficient therapy. Here, we investigate the effects of carrier morphology on the cellular internalization mechanisms of oligonucleotides by using self-assembled fibrous or spherical peptide nanostructures. Size and geometry were both found to be important parameters for the oligonucleotide internalization process; direct penetration was determined to be the major mechanism for the internalization of nanosphere carriers, whereas nanofibers were internalized by clathrin- and dynamin-dependent endocytosis pathways. We further showed that glucose conjugation to carrier nanosystems improved cellular internalization in cancer cells due to the enhanced glucose metabolism associated with oncogenesis, and the internalization of the glucose-conjugated peptide/oligonucleotide complexes was found to be dependent on glucose transporters present on the surface of the cell membrane. © 2016 American Chemical Society

Fatal Rickettsia conorii subsp. israelensis Infection, Israel

Fatal Rickettsia conorii subsp. israelensis Infection, Israe

Head Lice in Norwegian Households: Actions Taken, Costs and Knowledge

Introduction: Head lice infestations cause distress in many families. A well-founded strategy to reduce head lice prevalence must shorten the infectious period of individual hosts. To develop such a strategy, information about the actions taken (inspection, treatment and informing others about own infestations), level of knowledge and costs is needed. The present study is the first to consider all these elements combined. Materials and Methods: A questionnaire was answered by 6203 households from five geographically separate

Robust Framework for PET Image Reconstruction Incorporating System and Measurement Uncertainties

In Positron Emission Tomography (PET), an optimal estimate of the radioactivity concentration is obtained from the measured emission data under certain criteria. So far, all the well-known statistical reconstruction algorithms require exactly known system probability matrix a priori, and the quality of such system model largely determines the quality of the reconstructed images. In this paper, we propose an algorithm for PET image reconstruction for the real world case where the PET system model is subject to uncertainties. The method counts PET reconstruction as a regularization problem and the image estimation is achieved by means of an uncertainty weighted least squares framework. The performance of our work is evaluated with the Shepp-Logan simulated and real phantom data, which demonstrates significant improvements in image quality over the least squares reconstruction efforts

Scatter correction for positron emission mammography

In this paper we present a scatter correction method for a regularized list mode maximum likelihood reconstruction algorithm for the positron emission mammograph (PEM) that is being developed at our laboratory. The scatter events inside the object are modeled as additive Poisson random variables in the forward model of the reconstruction algorithm. The mean scatter sinogram is estimated using a Monte Carlo simulation program. With the assumption that the background activity is nearly uniform, the Monte Carlo scatter simulation only needs to run once for each PEM configuration. This saves computational time. The crystal scatters are modeled as a shift-invariant blurring in image domain because they are more localized. Thus, the useful information in the crystal scatters can be deconvolved in high-resolution reconstructions. The propagation of the noise from the estimated scatter sinogram into the reconstruction is analyzed theoretically. The results provide an easy way to calculate the required number of events in the Monte Carlo scatter simulation for a given noise level in the image. The analysis is also applicable to other scatter estimation methods, provided that the covariance of the estimated scatter sinogram is available