scholarly journals Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo

2018 ◽  
Author(s):  
Annabelle Biscans ◽  
Andrew Coles ◽  
Reka Haraszti ◽  
Dimas Echeverria ◽  
Matthew Hassler ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Therapeutic Intervention ◽  
Chemical Engineering ◽  
Adrenal Glands ◽  
Sirna Delivery ◽  
Distribution Profile ◽  
Wide Range ◽  
The Impact ◽  
Tissue Distribution Profile

AbstractRNAi-based therapeutics show promising clinical data for treatment of liver-associated disorders. However, siRNA delivery into extra-hepatic tissues remains an obstacle, limiting the use of siRNA-based therapies. Here we report on a first example of chemical engineering of lipophilic conjugates to enable extra-hepatic delivery. We synthesized a panel of fifteen lipophilic siRNA and evaluated the impact of their chemical configuration on siRNA tissue distribution profile. Generally, lipophilic conjugates allow siRNA distribution to a wide range of tissues, where the degree of lipophilicity defines the ratio of liver/spleen to kidney distribution. In addition to primary clearance tissues, several conjugates achieve significant siRNA distribution to lung, heart, adrenal glands, fat, muscle. siRNA tissue accumulation leads to productive silencing, shown with two independent targets. siRNA concentrations necessary for productive silencing are tissue and conjugate dependent, varying significantly from 5 to 200 ng/mg. The collection of conjugated siRNA described here enables functional gene modulation in vivo in lung, muscle, fat, heart, adrenal glands opening these tissues for future therapeutic intervention.

scholarly journals Albumin-Binding PSMA Radioligands: Impact of Minimal Structural Changes on the Tissue Distribution Profile

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2542 ◽  
Author(s):  
Luisa M. Deberle ◽  
Viviane J. Tschan ◽  
Francesca Borgna ◽  
Fan Sozzi-Guo ◽  
Peter Bernhardt ◽  
...  
Keyword(s):  
Protein Binding ◽  
Tissue Distribution ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Structural Changes ◽  
Albumin Binding ◽  
Distribution Profile ◽  
Tissue Distribution Profile

The concept of using ibuprofen as an albumin-binding entity was recently demonstrated by the development of [177Lu]Lu-Ibu-PSMA-01. In the present study, we designed a novel ibuprofen-containing radioligand (Ibu-PSMA-02) with subtle structural changes regarding the linker entity in order to investigate a potential impact on the in vitro and in vivo properties. Ibu-PSMA-02 was prepared using solid-phase synthesis techniques and labeled with lutetium-177. [177Lu]Lu-Ibu-PSMA-02 was evaluated in vitro with regard to its plasma protein-binding properties, PSMA affinity and uptake into PSMA-expressing PC-3 PIP tumor cells. The tissue distribution profile of [177Lu]Lu-Ibu-PSMA-02 was assessed in tumor-bearing mice and dose estimations were performed. The in vitro characteristics of [177Lu]Lu-Ibu-PSMA-02 were similar to those previously obtained for [177Lu]Lu-Ibu-PSMA-01 with respect to plasma protein-binding, PSMA affinity and tumor cell uptake. The in vivo studies revealed, however, an unprecedentedly high uptake of [177Lu]Lu-Ibu-PSMA-02 in PC-3 PIP tumors, resulting in an increased absorbed tumor dose of 7.7 Gy/MBq as compared to 5.1 Gy/MBq calculated for [177Lu]Lu-Ibu-PSMA-01. As a consequence of the high tumor accumulation, [177Lu]Lu-Ibu-PSMA-02 showed higher tumor-to-background ratios than [177Lu]Lu-Ibu-PSMA-01. This study exemplified that smallest structural changes in the linker entity of PSMA radioligands may have a significant impact on their pharmacokinetic profiles and, thus, may be applied as a means for ligand design optimization.

scholarly journals In VivoEfficacy of Anuran Trypsin Inhibitory Peptides against Staphylococcal Skin Infection and the Impact of Peptide Cyclization

2015 ◽  
Vol 59 (4) ◽  
pp. 2113-2121 ◽  
Author(s):  
U. Malik ◽  
O. N. Silva ◽  
I. C. M. Fensterseifer ◽  
L. Y. Chan ◽  
R. J. Clark ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Cyclic Peptide ◽  
Sequence Similarity ◽  
Infection Model ◽  
Content Type ◽  
Wide Range ◽  
Inhibitory Activities ◽  
The Impact

ABSTRACTStaphylococcus aureusis a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weakin vitroinhibitory activities againstS. aureus, but several had strong antibacterial activities againstS. aureusin anin vivomurine wound infection model. pYR, an immunomodulatory peptide fromRana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg−1. Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.

scholarly journals Inhibiting myosin-ATPase reveals a dynamic range of mitochondrial respiratory control in skeletal muscle

2011 ◽  
Vol 437 (2) ◽  
pp. 215-222 ◽  
Author(s):  
Christopher G. R. Perry ◽  
Daniel A. Kane ◽  
Chien-Te Lin ◽  
Rachel Kozy ◽  
Brook L. Cathey ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dynamic Range ◽  
Energy Charge ◽  
Respiratory Control ◽  
Basic Research ◽  
Dependent Manner ◽  
Atpase Inhibitor ◽  
Wide Range ◽  
The Impact

Assessment of mitochondrial ADP-stimulated respiratory kinetics in PmFBs (permeabilized fibre bundles) is increasingly used in clinical diagnostic and basic research settings. However, estimates of the Km for ADP vary considerably (~20–300 μM) and tend to overestimate respiration at rest. Noting that PmFBs spontaneously contract during respiration experiments, we systematically determined the impact of contraction, temperature and oxygenation on ADP-stimulated respiratory kinetics. BLEB (blebbistatin), a myosin II ATPase inhibitor, blocked contraction under all conditions and yielded high Km values for ADP of >~250 and ~80 μM in red and white rat PmFBs respectively. In the absence of BLEB, PmFBs contracted and the Km for ADP decreased ~2–10-fold in a temperature-dependent manner. PmFBs were sensitive to hyperoxia (increased Km) in the absence of BLEB (contracted) at 30 °C but not 37 °C. In PmFBs from humans, contraction elicited high sensitivity to ADP (Km<100 μM), whereas blocking contraction (+BLEB) and including a phosphocreatine/creatine ratio of 2:1 to mimic the resting energetic state yielded a Km for ADP of ~1560 μM, consistent with estimates of in vivo resting respiratory rates of <1% maximum. These results demonstrate that the sensitivity of muscle to ADP varies over a wide range in relation to contractile state and cellular energy charge, providing evidence that enzymatic coupling of energy transfer within skeletal muscle becomes more efficient in the working state.

scholarly journals Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways

2018 ◽  
Author(s):  
Maire F. Osborn ◽  
Andrew H. Coles ◽  
Annabelle Biscans ◽  
Reka A. Haraszti ◽  
Loic Roux ◽  
...  
Keyword(s):  
Sirna Delivery ◽  
Lipid Transport ◽  
Small Interfering Rnas ◽  
Transport Pathways ◽  
Efficient Delivery ◽  
Systemic Distribution ◽  
Lipoprotein Binding ◽  
The Impact ◽  
Plasma Half Life

AbstractEfficient delivery of therapeutic RNA is the fundamental obstacle preventing its clinical utility. Lipid conjugation improves plasma half-life, tissue accumulation, and cellular uptake of small interfering RNAs (siRNAs). However, the impact of conjugate structure and hydrophobicity on siRNA pharmacokinetics is unclear, impeding the design of clinically relevant lipid-siRNAs. Using a panel of biologically-occurring lipids, we show that lipid conjugation modulates siRNA hydrophobicity and governs spontaneous partitioning into distinct plasma lipoprotein classes in vivo. Lipoprotein binding influences siRNA distribution by delaying renal excretion and promoting uptake into lipoprotein receptor-enriched tissues. Lipid-siRNAs elicit mRNA silencing without causing toxicity in a tissue-specific manner. Lipid-siRNA internalization occurs independently of lipoprotein endocytosis, and is mediated by siRNA phosphorothioate modifications. Although biomimetic lipoprotein nanoparticles have been considered for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation.

scholarly journals Differential responsiveness of glabrous and non-glabrous skin to local transmural pressure elevations; the impact of 5 weeks of iterative local pressure loading

2021 ◽  
Author(s):  
Michail E. Keramidas ◽  
Roger Kölegård ◽  
Patrik Sundblad ◽  
Håkan Sköldefors ◽  
Ola Eiken
Keyword(s):  
Transmural Pressure ◽  
Glabrous Skin ◽  
Local Pressure ◽  
Wide Range ◽  
Forearm Skin ◽  
Differential Responsiveness ◽  
Pressure Resistance ◽  
The Impact ◽  
Pressure Perturbations

We examined the in vivo pressure-flow relationship in human cutaneous vessels during acute and repeated elevations of local transmural pressure. In 10 healthy men, red blood cell flux was monitored simultaneously on the non-glabrous skin of the forearm and the glabrous skin of a finger during a vascular pressure provocation, wherein the blood vessels of an arm were exposed to a wide range of stepwise increasing distending pressures. Forearm skin blood flux was relatively stable at slight and moderate elevations of distending pressure, whereas it increased ~3-4-fold at the highest levels (P = 0.004). Finger blood flux on the contrary, dropped promptly and consistently throughout the provocation (P < 0.001). Eight of the subjects repeated the provocation trial after a 5-week pressure-training regimen, during which the vasculature in one arm was exposed intermittently (40 min, 3 times･week-1) to increased transmural pressure (from +65 mmHg week-1 to +105 mmHg week-5). The training regimen diminished the pressure-induced increase in forearm blood flux by ~34% (P = 0.02), whereas it inhibited the reduction in finger blood flux (P < 0.001) in response to slight and moderate distending pressure elevations. The present findings demonstrate that, during local pressure perturbations, the cutaneous autoregulatory function is accentuated in glabrous compared to in the non-glabrous skin regions. Prolonged intermittent regional exposures to augmented intravascular pressure blunt the responsiveness of the glabrous skin, but enhance arteriolar pressure resistance in the non-glabrous skin.

scholarly journals Sensing through Non-Sensing Ocular Ion Channels

2020 ◽  
Vol 21 (18) ◽  
pp. 6925
Author(s):  
Meha Kabra ◽  
Bikash Ranjan Pattnaik
Keyword(s):  
Ion Channels ◽  
Visual Processing ◽  
Signal Transmission ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Cone Dystrophy ◽  
Wide Range ◽  
The Impact

Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. In the eye, ion channels are involved in various physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to an array of blindness, termed ocular channelopathies. These mutations result in either a loss- or gain-of channel functions affecting the structure, assembly, trafficking, and localization of channel proteins. A dominant-negative effect is caused in a few channels formed by the assembly of several subunits that exist as homo- or heteromeric proteins. Here, we review the role of different mutations in switching a “sensing” ion channel to “non-sensing,” leading to ocular channelopathies like Leber’s congenital amaurosis 16 (LCA16), cone dystrophy, congenital stationary night blindness (CSNB), achromatopsia, bestrophinopathies, retinitis pigmentosa, etc. We also discuss the various in vitro and in vivo disease models available to investigate the impact of mutations on channel properties, to dissect the disease mechanism, and understand the pathophysiology. Innovating the potential pharmacological and therapeutic approaches and their efficient delivery to the eye for reversing a “non-sensing” channel to “sensing” would be life-changing.

Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile

2018 ◽  
Vol 15 (3) ◽  
pp. 934-946 ◽  
Author(s):  
Martina Benešová ◽  
Christoph A. Umbricht ◽  
Roger Schibli ◽  
Cristina Müller
Keyword(s):  
Tissue Distribution ◽  
Albumin Binding ◽  
Distribution Profile ◽  
Tissue Distribution Profile

scholarly journals Fatigue Cracking of Additively Manufactured Materials—Process and Material Perspectives

2020 ◽  
Vol 10 (16) ◽  
pp. 5556
Author(s):  
Torsten Fischer ◽  
Bernd Kuhn ◽  
Detlef Rieck ◽  
Axel Schulz ◽  
Ralf Trieglaff ◽  
...  
Keyword(s):  
Additive Manufacturing ◽  
Fatigue Strength ◽  
Process Control ◽  
High Performance ◽  
Chemical Engineering ◽  
Fatigue Cracking ◽  
Metal Powders ◽  
Wide Range ◽  
Manufacturing Techniques ◽  
The Impact

Strong efforts are made internationally to optimize the process control of laser additive manufacturing processes. For this purpose, advanced detectors and monitoring software are being developed to control the quality of production. However, commercial suppliers of metal powders and part manufacturers are essentially focused on well-established materials. This article demonstrates the potential of optimized process control. Furthermore, we outline the development of a new high temperature structural steel, tailored to best utilize the advantages of additive manufacturing techniques. In this context, the impact of production-induced porosity on fatigue strength of austenitic 316L is presented. Additionally, we discuss the first conceptual results of a novel ferritic steel, named HiperFer (High Performance Ferrite), which was designed for increased fatigue strength. This ferritic, Laves phase-strengthened, stainless steel could be used for a wide range of structural components in power and (petro)chemical engineering at maximum temperatures ranging from about 580 to 650 °C. This material benefits from in situ heat treatment and counteracts process-related defects by “reactive” crack obstruction mechanisms, hampering both crack initiation and crack propagation. In this way, increased fatigue resistance and safety can be achieved.

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