103 research outputs found
Pathways of cellular internalisation of liposomes delivered siRNA and effects on siRNA engagement with target mRNA and silencing in cancer cells
Design of an efficient delivery system is a generally recognised bottleneck in translation of siRNA technology into clinic. Despite research efforts, cellular processes that determine efficiency of siRNA silencing achieved by different delivery formulations remain unclear. Here, we investigated the mechanism(s) of cellular internalisation of a model siRNA-loaded liposome system in a correlation to the engagement of delivered siRNA with its target and consequent silencing by adopting siRNA molecular beacon technology. Probing of cellular internalisation pathways by a panel of pharmacological inhibitors indicated that clathrin-mediated (dynamin-dependent) endocytosis, macropinocytosis (dynamine independent), and cell membrane cholesterol dependent process(es) (clathrin and caveolea-independent) all play a role in the siRNA-liposomes internalization. The inhibition of either of these entry routes was, in general, mirrored by a reduction in the level of siRNA engagement with its target mRNA, as well as in a reduction of the target gene silencing. A dramatic increase in siRNA engagement with its target RNA was observed on disruption of endosomal membrane (by chloroquine), accompanied with an increased silencing. The work thus illustrates that employing molecular beacon siRNA technology one can start to assess the target RNA engagement â a stage between initial cellular internalization and final gene silencing of siRNA delivery systems
Properties and applications of precision oligomer materials; where organic and polymer chemistry join forces
Precise oligomeric materials constitute a growing area of research with implications for various applications as well as fundamental studies. Notably, this field of science which can be termed macroâorganic chemistry, draws inspiration from both traditional polymer chemistry and organic synthesis, combining the molecular precision of organic chemistry with the materials properties of macromolecules. Discrete oligomers enable access to unprecedented materials properties, for example, in selfâassembled structures, crystallization, or optical properties. The degree of control over oligomer structures resembles many biological systems and enables the design of materials with tailored properties and the development of fundamental structureâproperty relationships. This Review highlights recent developments in macroâorganic chemistry from synthetic concepts to materials properties, with a focus on selfâassembly and molecular recognition. Finally, an outlook for future research directions is provided
Nucleases as a barrier to gene silencing in the cotton boll weevil, Anthonomus grandis.
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Loading of PNA and other molecular payloads on inorganic nanostructures for theranostics
Peptide Nucleic Acids (PNAs) are oligonucleotide mimics that can be used as drugs as they can interact with DNA and RNA targets in organisms. Loading PNAs into inorganic nanocarriers can improve their cellular uptake and co-delivering them together with drugs can improve the therapy efficacy by synergic effects. Furthermore, the functionalization of the carriers with labels allows theranostics, and the possibility to monitor the efficacy of the therapy in real time. The present protocol describes the synthesis of Zeolites-L nanocrystals and mesoporous silica nanoparticles and their loading with cationic PNAs and other smaller molecular weight payloads towards theranostics applications
Assessment of in Vivo siRNA delivery in cancer mouse models
RNA interference (RNAi) has rapidly become a powerful tool for target discovery and therapeutics. Small interfering RNAs (siRNAs) are highly effective in mediating sequence-specific gene silencing. However, the major obstacle for using siRNAs as cancer therapeutics is their systemic delivery from the administration site to target cells in vivo. This chapter describes approaches to deliver siRNA effectively for cancer treatment and discusses in detail the current methods to assess pharmacokinetics and biodistribution of siRNAs in vivo
Problems in the Diagnostics and Treatment of Transtiretinum Amyloidosis with Heart Disease in the Elderly: Clinical Experience
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