Bioconjugate Strategies for Antisense Therapeutic Delivery to Glioblastoma Stem Cells PDF Download
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Author: Amy Elizabeth Arnold
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Antisense therapeutics, including antisense oligonucleotides (AONs) and small interfering ribonucleic acids (siRNAs), are powerful tools for regulating genes, making them a promising therapy for diseases such as cancer where oncogenic genes are over-expressed. The delivery of antisense therapeutics to target cells presents a significant challenge due to the many barriers a nucleic acid must face in order to reach the cytoplasm where it exerts its effects. In this thesis, I explored multiple strategies for delivery of AONs and siRNAs, focusing on targeting the desired cell population, inducing endocytosis, and facilitating endosomal escape. This was done within the context of glioblastoma (GBM), and specifically the glioblastoma stem cells (GSCs), an aggressive subpopulation of GBM cells that are involved in resistance, migration, and recurrence. Antisense oligonucleotides against a relevant GBM gene were conjugated to an antibody engineered to target CD44, a cell surface receptor which is highly expressed on GSCs. Using this system, we demonstrated functional targeting, endocytosis, and gene knockdown in the GSCs, leading to a morphological change in the cells. This represented the first time an antibody-oligonucleotide conjugate was used to target the GSC population. We were challenged with a lack of endosomal escape when using the antibody delivery platform, so we next looked at using a protein with a native endosomal escape mechanism to facilitate oligonucleotide delivery. For the second strategy, I conjugated attenuated diphtheria toxin (aDT), a protein which escapes the endolysosomal pathway, to siRNAs against relevant gene targets involved in GSC proliferation and invasion. Using this aDT-siRNA conjugate, we could downregulate genes of interest in the glioblastoma stem cells, leading to significant changes in cell viability and the invasive capacity of these cells. This is the first diphtheria toxin-based siRNA delivery vehicle and represents a platform technology for siRNA- and AON-based therapies.
Author: Amy Elizabeth Arnold
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Antisense therapeutics, including antisense oligonucleotides (AONs) and small interfering ribonucleic acids (siRNAs), are powerful tools for regulating genes, making them a promising therapy for diseases such as cancer where oncogenic genes are over-expressed. The delivery of antisense therapeutics to target cells presents a significant challenge due to the many barriers a nucleic acid must face in order to reach the cytoplasm where it exerts its effects. In this thesis, I explored multiple strategies for delivery of AONs and siRNAs, focusing on targeting the desired cell population, inducing endocytosis, and facilitating endosomal escape. This was done within the context of glioblastoma (GBM), and specifically the glioblastoma stem cells (GSCs), an aggressive subpopulation of GBM cells that are involved in resistance, migration, and recurrence. Antisense oligonucleotides against a relevant GBM gene were conjugated to an antibody engineered to target CD44, a cell surface receptor which is highly expressed on GSCs. Using this system, we demonstrated functional targeting, endocytosis, and gene knockdown in the GSCs, leading to a morphological change in the cells. This represented the first time an antibody-oligonucleotide conjugate was used to target the GSC population. We were challenged with a lack of endosomal escape when using the antibody delivery platform, so we next looked at using a protein with a native endosomal escape mechanism to facilitate oligonucleotide delivery. For the second strategy, I conjugated attenuated diphtheria toxin (aDT), a protein which escapes the endolysosomal pathway, to siRNAs against relevant gene targets involved in GSC proliferation and invasion. Using this aDT-siRNA conjugate, we could downregulate genes of interest in the glioblastoma stem cells, leading to significant changes in cell viability and the invasive capacity of these cells. This is the first diphtheria toxin-based siRNA delivery vehicle and represents a platform technology for siRNA- and AON-based therapies.
Author: Nima Rezaei
Publisher: Springer Nature
ISBN: 3031147324
Category : Medical
Languages : en
Pages : 244
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Book Description
Brain tumors comprise about 5–9% of all human neoplasms; and interestingly the central nervous system (CNS) neoplasms are ranked among the most prevalent neoplasms of childhood as well. Besides to the morphologic and histopathologic characteristics, and as each pathologic states first starts with molecular alterations, each tumor may have its own story in the matter of activating tumorigenesis pathways and having specific molecular characteristics. Importantly, the molecular classification of tumors has been highly considered in the past few decades for taking the most appropriate therapeutic approach. On the other hand, the tumors shall have tumor-scape mechanisms preventing the immunologic system to eliminate its invasion. The failure of innate and acquired immune system to defeat tumorigenesis mechanisms would consequently result in tumor development. Interestingly, the neuro-immunologic mechanism plays a role in development of psychiatric manifestations of brain tumors as well. Taking all these to account, the different arms of innate immunity, acquired immunity, and genetics have been approached to defeat development and/or progression of such tumors. Accordingly, the activation immunotherapeutic approaches focus on activating or strengthening the anti-tumor immunologic pathways in order to assist the weakened immune system to defeat the tumor (such as Dendritic cell vaccination, DNA vaccines, peptide vaccines, viral vector-based vaccines, monoclonal antibodies, and CAR T-cell therapy). In addition to immunologic components of brain and spinal cord tumors, numerous genes and genetic pathways have been recognized to take part in tumorigenesis. Taking these non-immune genetic pathways to account, some other therapeutic approaches such as stem cell therapy and gene therapy have been developed in the new era of cancer treatment. Moreover, and besides the biologic and medical aspects of these tumors, different physical/mathematical models have been proposed to either explain or predict tumor behavior. Such models would be advantageous in developing new therapeutic modalities in pre-clinical stages and enter new eras in cancer treatment. The first book of Human Brain and Spinal Cord Tumors, Neuro-immunology and Neuro-genetics, will mainly discuss the neuro-immunology and neurogenetic pathways associated with development of brain and spinal cord tumor. After a short introduction chapter, this book will focus on the role of innate and acquired immunity on development of these tumors and then the immunotherapeutic approaches to defeat these tumorigenesis mechanisms. This book will then focus on genetic aspects of brain and spinal cord tumors and bioinformatics models to describe the behavioral patterns of these tumors, as well as associated therapeutic approaches such as stem cell therapy and gene therapy. This volume of book could be useful for experts in basic sciences, mainly geneticists and immunologists, and also physicians of different specialties, mainly neurosurgeons, neurologists, neuropathologists and neuroradiologists.
Author: Kewal K. Jain
Publisher: Humana Press
ISBN: 1493969668
Category : Technology & Engineering
Languages : en
Pages : 661
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Book Description
Nanomedicine is defined as the application of nanobiotechnology in clinical medicine, which is currently being used to research the pathomechanism of disease, refine molecular diagnostics, and aid in the discovery, development, and delivery of drugs. In The Handbook of Nanomedicine, Third Edition, Prof. Kewal K. Jain updates, reorganizes, and replaces information in the comprehensive second edition in order to capture the most recent advances in this dynamic field. Important components of nanomedicine such as drug delivery via nanobiotechnology and nanopharmaceuticals as well as nanooncology, where the greatest number of advances are occurring, are covered extensively. As this text is aimed at nonmedical scientists, pharmaceutical personnel, as well as physicians, descriptions of the technology involved and other medical terminology are kept as clear and simple as possible. In depth and cutting-edge, The Handbook of Nanomedicine, Third Edition informs its readers of the ever-growing field of nanomedicine, destined to play a significant role in the future of healthcare.
Author: Bin Wang
Publisher: CRC Press
ISBN: 9814411647
Category : Medical
Languages : en
Pages : 468
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Book Description
In the past few decades there has been incredible growth in "bionano"-related research, which has been accompanied by numerous publications in this field. Although various compilations address topics related to deoxyribonucleic acid (DNA) and protein, there are few books that focus on determining the structure of ribonucleic acid (RNA) and using RNA as building blocks to construct nanoarchitectures for biomedical and healthcare applications. RNA Nanotechnology is a comprehensive volume that details both the traditional approaches and the latest developments in the field of RNA-related technology. This book targets a wide audience: a broad introduction provides a solid academic background for students, researchers, and scientists who are unfamiliar with the subject, while the in-depth descriptions and discussions are useful for advanced professionals. The book opens with reviews on the basic aspects of RNA biology, computational approaches for predicting RNA structures, and traditional and emerging experimental approaches for probing RNA structures. This section is followed by explorations of the latest research and discoveries in RNA nanotechnology, including the design and construction of RNA-based nanostructures. The final segment of the book includes descriptions and discussions of the potential biological and therapeutic applications of small RNA molecules, such as small/short interfering RNAs (siRNAs), microRNAs (miRNAs), RNA aptamers, and ribozymes.
Author: Ülo Langel
Publisher: Springer
ISBN: 9811387478
Category : Science
Languages : en
Pages : 470
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Book Description
In this book, a summary and update of the most important areas of CPP research are presented, whilst raising relevant questions for further development. The CPP sequences are presented and discussed throughout the book. The methods for testing CPP mechanisms are discussed in detail. Various approaches for the testing of endocytotic pathways of CPP uptake are also described. Different CPP uptake experiments are compared since it is becoming clear that it is often best to apply several methods in a complementary manner in order to most comprehensively evaluate CPP uptake mechanisms due to the complexity of these processes. A brief summary of functionality issues of CPPs, both in vitro and in vivo are discussed. Therapeutic potential of CPPs and commercial developments are discussed. The monograph is written for researchers and students in the field.
Author: Yaoliang Tang
Publisher: Academic Press
ISBN: 0128004975
Category : Science
Languages : en
Pages : 287
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Book Description
Mesenchymal stem cell-derived exosomes are at the forefront of research in two of the most high profile and funded scientific areas – cardiovascular research and stem cells. Mesenchymal Stem Cell Derived Exosomes provides insight into the biofunction and molecular mechanisms, practical tools for research, and a look toward the clinical applications of this exciting phenomenon which is emerging as an effective diagnostic. Primarily focused on the cardiovascular applications where there have been the greatest advancements toward the clinic, this is the first compendium for clinical and biomedical researchers who are interested in integrating MSC-derived exosomes as a diagnostic and therapeutic tool. - Introduces the MSC-exosome mediated cell-cell communication - Covers the major functional benefits in current MSC-derived exosome studies - Discusses strategies for the use of MSC-derived exosomes in cardiovascular therapies
Author: Jens Kurreck
Publisher: Royal Society of Chemistry
ISBN: 0854041168
Category : Medical
Languages : en
Pages : 362
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Book Description
This book provides a compelling overall update on current status of RNA interference
Author: Chad A. Mirkin
Publisher: CRC Press
ISBN: 0429578067
Category : Medical
Languages : en
Pages : 1806
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Book Description
Spherical nucleic acids (SNAs) comprise a nanoparticle core and a densely packed and highly oriented nucleic acid shell, typically DNA or RNA. They have novel architecture-dependent properties that distinguish them from all other forms of nucleic acids and make them useful in materials synthesis, catalysis, diagnostics, therapeutics, and optics/plasmonics. This book covers over two decades of Dr. Mirkin’s research on SNAs and their anisotropic analogues, including synthesis and fundamental properties, and applications in colloidal crystallization, adaptive matter, and nanomedicine, spanning extra- and intracellular diagnostics, gene regulation, and immunomodulation. It is a reprint volume that compiles 101 key papers from high-impact journals in this research area published by the Mirkin Group at Northwestern University, Illinois, USA, within the International Institute for Nanotechnology, and collaborators. Volume 1 provides an overview and a historical framework of engineering matter from DNA-modified constructs and discusses the enabling features of nucleic acid–functionalized nanomaterials. Volume 2 covers design rules for colloidal crystallization, building blocks for crystal engineering, and DNA and RNA as programmable bonds. Volume 3 discusses colloidal crystallization processes and routes to hierarchical assembly, dynamic nanoparticle superlattices, surface-based and template-confined colloidal crystallization, optics and plasmonics with nanoparticle superlattices, and postsynthetic modification and catalysis with nanoparticle superlattices. Volume 4 covers diagnostic modalities, and intracellular therapeutic and diagnostic schemes based upon nucleic acid–functionalized nanomaterials.
Author: Nicolay Ferrari
Publisher: John Wiley & Sons
ISBN: 1118537335
Category : Medical
Languages : en
Pages : 576
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Book Description
A comprehensive review of contemporary antisense oligonucleotides drugs and therapeutic principles, methods, applications, and research Oligonucleotide-based drugs, in particular antisense oligonucleotides, are part of a growing number of pharmaceutical and biotech programs progressing to treat a wide range of indications including cancer, cardiovascular, neurodegenerative, neuromuscular, and respiratory diseases, as well as other severe and rare diseases. Reviewing fundamentals and offering guidelines for drug discovery and development, this book is a practical guide covering all key aspects of this increasingly popular area of pharmacology and biotech and pharma research, from the basic science behind antisense oligonucleotides chemistry, toxicology, manufacturing, to safety assessments, the design of therapeutic protocols, to clinical experience. Antisense oligonucleotides are single strands of DNA or RNA that are complementary to a chosen sequence. While the idea of antisense oligonucleotides to target single genes dates back to the 1970's, most advances have taken place in recent years. The increasing number of antisense oligonucleotide programs in clinical development is a testament to the progress and understanding of pharmacologic, pharmacokinetic, and toxicologic properties as well as improvement in the delivery of oligonucleotides. This valuable book reviews the fundamentals of oligonucleotides, with a focus on antisense oligonucleotide drugs, and reports on the latest research underway worldwide. • Helps readers understand antisense molecules and their targets, biochemistry, and toxicity mechanisms, roles in disease, and applications for safety and therapeutics • Examines the principles, practices, and tools for scientists in both pre-clinical and clinical settings and how to apply them to antisense oligonucleotides • Provides guidelines for scientists in drug design and discovery to help improve efficiency, assessment, and the success of drug candidates • Includes interdisciplinary perspectives, from academia, industry, regulatory and from the fields of pharmacology, toxicology, biology, and medicinal chemistry Oligonucleotide-Based Drugs and Therapeutics belongs on the reference shelves of chemists, pharmaceutical scientists, chemical biologists, toxicologists and other scientists working in the pharmaceutical and biotechnology industries. It will also be a valuable resource for regulatory specialists and safety assessment professionals and an important reference for academic researchers and post-graduates interested in therapeutics, antisense therapy, and oligonucleotides.
Author: Salvador Moncada
Publisher: Springer Science & Business Media
ISBN: 3540329676
Category : Medical
Languages : en
Pages : 344
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Book Description
This wide ranging work provides a complete representation of the present state of knowledge of the vascular endothelium. The volume comprises 20 chapters by experts who have made significant contributions to research in the vascular endothelium. The text discusses the structure, development and function of the normal vascular endothelium, considers conditions that lead to the disruption of vascular physiology and provides a comprehensive description of pathologies and their treatment.
