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"Synthetic short double-stranded small interfering RNAs (siRNAs) have the capacity to inhibit gene expression of a gene target; unfortunately, these RNAs display unfavorable metabolic stability and pharmacokinetic properties. In order to overcome these hurdles, it is possible to chemically alter the nucleotides that comprise the siRNA therapeutic to confer increased nuclease stability as well as alter their binding properties. It is also possible to use delivery vehicles, such as nanoparticles, to help improve their delivery into target cells. Therefore, in chapter 2 the creation of novel nucleoside analogues to first tackle the issue of metabolic stability will be reported; followed by chapter 3 which described the design of oligonucleotide-modified nanoparticles to increase cell permeation and allow for targeted delivery to DRR-expressing Glioblastoma multiformes cells. As such, we report on the synthesis of 2'-F,4'-OMe and 2',4'-diOMe ribo-uridine derivatives, their incorporation into siRNA duplexes, and the physicochemical and gene silencing properties of these novel 2',4'-modified siRNAs. Both nucleosides were prepared stereoselectively in 6 steps starting from 2'-F rU and 2'-OMe rU for 2'-F,4'-OMe and 2',4'-diOMe, respectively, and subsequently converted to the corresponding phosphoramidites through conventional oligonucleotide chemistry for incorporation into oligonucleotides through standard solid-phase chemistry. NMR analysis of these nucleosides revealed that the 4' substituent imparts a bias towards the North sugar pucker conformation in both cases. Incorporation of 2'-F,4'-OMe rU into DNA strands resulted in destabilizing thermal effects in DNA:DNA hybrids and slightly destabilizing effects in DNA:RNA hybrids, but neutral effects within modified RNA strands in RNA:RNA duplexes. Furthermore, the 2'-F,4'-OMe rU modification was shown to be tolerated in both the antisense and sense strand in siRNA-targeted luciferase gene knockdown, whereas the 2',4'-diOMe rU modification was shown to be tolerated in the sense strand only. The CD analysis of these same strands also confirmed that the incorporation of these novel modifications does not affect the formation of duplex; where the A-form duplex (typical of RNA duplexes) is observed. As for the nanoparticle design, a block co-polymer is functionalized with azide and furan groups on the corona to allow for conjugation of antisense oligonucleotides and antibodies targeting upregulated receptors in glioblastoma cells. In collaboration, we were able to create a modified vehicle strand necessary for conjugation to the nanoparticle corona, upon which we were successful in hybridizing the complementary antisense oligonucleotide. This duplex was then successfully conjugated to the azide groups on the surface of the nanoparticle by copper-free Click chemistry. Single-stranded and double-stranded (hybridized) antisense oligonucleotides were transfected into live DsredDRR cells and 50% knockdown of the DRR gene was observed. " --
This book presents the latest knowledge on a broad range of topics relating to the synthesis of natural and artificial oligonucleotides with therapeutic potential. Nucleic acid-based therapeutics are attracting much attention, and numerous therapeutic oligonucleotides, such as antisense oligonucleotides, siRNAs, splice-switching oligonucleotides, and nucleic acid aptamers, are being evaluated in clinical trials for the treatment of a variety of diseases. Synthesis of Therapeutic Oligonucleotides covers a broad range of topics in the field that are of high relevance to researchers, including the synthesis of natural and chemically modified oligonucleotides, the development of novel nucleic acid analogs, industrial scale synthesis and purification of oligonucleotides, and important aspects of chemistry, manufacturing, and controls (CMC). The aim is to provide new insights and inspire fresh ideas in nucleic acid chemistry that may ultimately lead to novel concepts and techniques and the discovery of more effective nucleic acid drugs. The book will be of high value for both established researchers in the field and students intending to specialize in nucleic acid chemistry research.
A collection of powerful new techniques for oligonucleotide synthesis and for the use of modified oligonucleotides in biotechnology. Among the protocol highlights are a novel two-step process that yields a high purity, less costly, DNA, the synthesis of phosphorothioates using new sulfur transfer agents, the synthesis of LNA, peptide conjugation methods to improve cellular delivery and cell-specific targeting, and triple helix formation. The applications include using molecular beacons to monitor the PCR amplification process, nuclease footprinting to study the sequence-selective binding of small molecules of DNA, nucleic acid libraries, and the use of small interference RNA (siRNA) as an inhibitor of gene expression.
Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.
Extensively revised and updated, Antisense Drug Technology: Principles, Strategies, and Applications, Second Edition reflects the logarithmic progress made in the past four years of oligonucleotide-based therapies, and, in particular, antisense therapeutics and research. Interpreting lessons learned from the clinical trials of first generati
Brain Targeted Drug Delivery Systems: A Focus on Nanotechnology and Nanoparticulates provides a guide on nanoparticulates to both academic and industry researchers. The book discusses key points in the development of brain targeted drug delivery, summarizes available strategies, and considers the main problems and pitfalls evidenced in current studies on brain targeted drug delivery systems. As the brain is the most important organ in the human body, and disorders of the central nervous system (CNS) are the most serious threat to human life, this book highlights advances and new research in drug delivery methods to the brain. Provides an overview of brain targeting drug delivery that is useful to both academic and industry-based researchers Discusses key points in developing brain targeting drug delivery systems Summarizes and presents currently available strategies for brain targeting drug delivery Covers not only current studies and their strengths, but also gives insight into the pitfalls of current research
Polymer Science and Nanotechnology: Fundamentals and Applications brings together the latest advances in polymer science and nanoscience. Sections explain the fundamentals of polymer science, including key aspects and methods in terms of molecular structure, synthesis, characterization, microstructure, phase structure and processing and properties before discussing the materials of particular interest and utility for novel applications, such as hydrogels, natural polymers, smart polymers and polymeric biomaterials. The second part of the book examines essential techniques in nanotechnology, with an emphasis on the utilization of advanced polymeric materials in the context of nanoscience. Throughout the book, chapters are prepared so that materials and products can be geared towards specific applications. Two chapters cover, in detail, major application areas, including fuel and solar cells, tissue engineering, drug and gene delivery, membranes, water treatment and oil recovery. Presents the latest applications of polymers and polymeric nanomaterials, across energy, biomedical, pharmaceutical, and environmental fields Contains detailed coverage of polymer nanocomposites, polymer nanoparticles, and hybrid polymer-metallic nanoparticles Supports an interdisciplinary approach, enabling readers from different disciplines to understand polymer science and nanotechnology and the interface between them
Provides insight into biopolymers, their physicochemical properties, and their biomedical and biotechnological applications This comprehensive book is a one-stop reference for the production, modifications, and assessment of biopolymers. It highlights the technical and methodological advancements in introducing biopolymers, their study, and promoted applications. "Biopolymers for Biomedical and Biotechnological Applications" begins with a general overview of biopolymers, properties, and biocompatibility. It then provides in-depth information in three dedicated sections: Biopolymers through Bioengineering and Biotechnology Venues; Polymeric Biomaterials with Wide Applications; and Biopolymers for Specific Applications. Chapters cover: advances in biocompatibility; advanced microbial polysaccharides; microbial cell factories for biomanufacturing of polysaccharides; exploitation of exopolysaccharides from lactic acid bacteria; and the new biopolymer for biomedical application called nanocellulose. Advances in mucin biopolymer research are presented, along with those in the synthesis of fibrous proteins and their applications. The book looks at microbial polyhydroxyalkanoates (PHAs), as well as natural and synthetic biopolymers in drug delivery and tissue engineering. It finishes with a chapter on the current state and applications of, and future trends in, biopolymers in regenerative medicine. * Offers a complete and thorough treatment of biopolymers from synthesis strategies and physiochemical properties to applications in industrial and medical biotechnology * Discusses the most attracted biopolymers with wide and specific applications * Takes a systematic approach to the field which allows readers to grasp and implement strategies for biomedical and biotechnological applications "Biopolymers for Biomedical and Biotechnological Applications" appeals to biotechnologists, bioengineers, and polymer chemists, as well as to those working in the biotechnological industry and institutes.
The availability of various in vitro and in vivo techniques has considerably advanced the research on drug transport and metabolism across the blood-brain barrier (BBB). These specialized and sophisticated experimental strategies are of fundamental importance if one is to gain a greater understanding of enhanced and selective drug delivery to the brain. The reader will find in this book methods for in vitro endothelial/astrocyte cell culture models, and for in vivo intracerebral microdialysis to study drug tranport across the BBB. This book, however, is not merely a laboratory manual consisting of recipes for BBB research; it permits the presentation of the different methods in fine detail, revealing tricks and short cuts that frequently do not appear in the literature. The researcher is well aware that differences (subtle or otherwise) in experimental steps used in different laboratories may influence the outcome of any particular procedure. The book also illustrates the accessibility and the application of the different methods in different species. Background information of the protocol is given in every chapter, which also contains a literature list that the reader may wish to refer to for further information. This volume will be invaluable to basic researchers as well as to those involved in the search for agents suitable for pharmaceutic intervention in the central nervous system.
This book elaborates on drug delivery targeting via intracellular delivery, specifically through the Receptor Mediated Endocytosis (RME) approach, due to the involvement of cellular receptors in various grave diseases. Targeted delivery relies on two basic approaches, passive and active targeting. While passive targeting approaches have shown great promise, the improved selectivity achieved with active targeting approaches has resulted in significantly higher efficacy. Interestingly there are numerous strategies for active targeting, many of which are already highlighted in , Targeted Drug Delivery: Concepts and Applications. Nevertheless an exciting and practical strategy for active targeting, which could enable high intracellular delivery, is through exploitation of RME. Cells in the body express receptors to enable various physiological and biochemical processes. As a result, many of these receptors are overexpressed in pathological conditions, or newer receptors expressed due to defective cellular functioning. RME is based on exploitation of such receptors to achieve intracellular delivery. While targeted delivery can have manifold applications, in this book we focus on two major and challenging therapeutic areas; i) Cancer and ii) Infectious Diseases. Targeted Intracellular Drug Delivery by Receptor Medicated Endocytosis discusses the major receptors that are useful for targeted delivery for these afflictions. A major section of this book is dedicated to details regarding their occurrence and location, the recognition domain of the receptor, structure activity relationship of substrate /ligand for selective binding, ligands explored, antagonists for ligand binding and relevance of these aspects for therapy of cancer and infectious diseases. These facets are elucidated with the help of specific examples from academic research and also emphasize commercial products, wherever relevant. In vitro cellular models relied on for assessing receptor mediated cellular targeting and in vivo models depicting clinical efficacy are focused on in a separate section. Finally, we briefly discuss the regulatory and toxicity issues that may be associated specifically with the RME approach of intracellular drug delivery.