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“This excellent book comes at a critical time to the field of delivery of therapeutic nucleic acids. I wish I had a book with a similar approach and design in the field of drug delivery when we started to develop Doxil®. I intend to use this book to cover nucleic acid delivery in my graduate course on drug delivery systems.” Prof. Yechezkel (Chezy) Barenholz Hebrew University of Jerusalem, Israel “This timely and nicely arranged book represents an excellent collection of cutting-edge studies and approaches for the delivery of nucleic acid–based therapeutics, including siRNA. The editor has built a volume in which leading scientists cover the broad variety of nucleic acid delivery platforms, such as lipid- and polymer-based systems, aptamers, and chemical conjugates, as well as biological properties of these systems.” Prof. Vladimir Torchilin Northeastern University, USA Nucleic acid (NA) therapeutics has been extensively studied both in the academia and in the pharmaceutical industry and is still considered the promise for new therapeutic modalities, especially in personalized medicine. The only hurdle that limits the translation of NA therapeutics from an academic idea to the new therapeutic modality is the lack of efficient and safe delivery strategies. In this book, written by world experts in the field of nanotechnology for NA delivery, the contributing authors bring together the state of the art in delivery strategies with strong emphasis on aspects that are of essence to the pharmaceutical industry, such as stability, general toxicity, immunetoxicity, pharmacokinetics, efficacy, and validation of new drug targets using unique approaches based on exquisite nanotechnology strategies. V335 ISBN 978-981-4411-04-2 9-78981-4411042 Nanotechnology for the Delivery of Therapeutic Nucleic Acids Peer Dan Peer is an associate professor and head of the laboratory of NanoMedicine at Tel Aviv University. His research was one of the first to demonstrate the systemic delivery of RNAi using targeted nanocarriers to the immune system and the first to demonstrate the in vivo validation of new drug targets using RNAi in the immune system. Prof. Peer has authored and edited several books on biomaterials and nanomedicine. He is on the editorial board of several journals, including Nanotechnology, Journal of Controlled Release, Journal of Biomedical Nanotechnology, Biomedical Microdevices, and Cancer Letters. Nanotechnology for the Delivery of Therapeutic Nucleic Acids “Nucleic acid–based therapy would have revolutionized medicine many times if the problem of delivery had been solved, at least in small part. However, that is proving to be as challenging a problem as any in the sciences—and of the few with truly transformational implications for the health of all. Thus, I welcome with enthusiasm this book, edited by my good friend and extraordinarily distinguished colleague Dan Peer. The topics featured in the various chapters offer a very sound review of the major problem areas, and some of the most promising strategies for addressing them.” Prof. Mauro Ferrari The Methodist Hospital Research Institute, USA Pan Stanford Series on Biomedical Nanotechnology Volume 4 Dan Peer Editor Nanotechnology for the Delivery of Therapeutic Nucleic Acids Pan Stanford Series on Biomedical Nanotechnology Series Editors Vladimir Torchilin and Monsoor Amiji Titles in the Series Vol. 1 Handbook of Materials for Nanomedicine Vladimir Torchilin and Monsoor Amiji, eds. 2010 Vol. 5 Inorganic Nanomedicine Bhupinder Singh Sekhon, ed. 2014 978-981-4267-55-7 (Hardcover) 978-981-4267-58-8 (eBook) Vol. 6 Nanotechnology for Cancer Vol. 2 Nanoimaging Julia Ljubimova, ed. 2014 Beth A. Goins and William T. Phillips, eds. 2011 978-981-4267-09-0 (Hardcover) 978-981-4267-91-5 (eBook) Vol. 3 Biomedical Nanosensors Joseph Irudayraj, ed. 2013 978-981-4303-03-3 (Hardcover) 978-981-4303-04-0 (eBook) Vol. 4 Nanotechnology for the Delivery of Therapeutic Nucleic Acids Dan Peer, ed. 2013 978-981-4411-04-2 (Hardcover) 978-981-4411-05-9 (eBook) Vol. 7 Nanotechnology for Delivery of DNA and Related Materials Bengt Fadeel, ed. 2015 Vol. 8 Translation Industrial Nanotechnology Thomas Redelmeier, ed. 2015 Nanotechnology for the Delivery of Therapeutic Nucleic Acids Dan Peer Editor Published by Pan Stanford Publishing Pte. Ltd. Penthouse Level, Suntec Tower 3 8 Temasek Boulevard Singapore 038988 Email: [email protected] Web: www.panstanford.com British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Nanotechnology for the Delivery of Therapeutic Nucleic Acids Copyright © 2013 Pan Stanford Publishing Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the publisher. For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher. ISBN 978-981-4411-04-2 (Hardcover) ISBN 978-981-4411-05-9 (eBook) Printed in the USA Contents Preface 1. Lipoplexes and Polyplexes: From Gene Delivery to Gene Expression Gerardo Byk, Mirit Cohen-Ohana, and Fiana Mirkin 1.1 Introduction 1.2 Lipopolyamines 1.3 Lipopolyamine Co-formulation with DNA Complexing Peptides 1.4 Lipopolyaminoguanidines 1.4.1 Biodegradable Lipoplexes: Reduction-Sensitive Lipopolyamines 1.4.2 Biodegradable Polyplexes: Reduction-Sensitive Dendrimers 1.5 Towards Non-Electrostatic DNA Complexing Agents 1.6 Site-Specific Chemical Ligation of Targeting Peptides to Plasmid DNA 1.7 Concluding Remarks and Future Directions Wahid Khan, Saravanan Muthupandian, and Abraham J. Domb 2.1 Introduction 2.2 Cationic Polymer Targeted Delivery of Nucleotides 2.3 Major Cationic Polymers Used for Delivery of Nucleotides 2.3.1 Polyethylenimine 2.3.2 Poly(L-lysine) 2.3.3 Cationic Polysaccharides 2. Cationic Polymers for the Delivery of Therapeutic Nucleotides xi 1 1 4 9 10 12 15 18 20 20 27 28 29 31 31 35 37 vi Contents 2.3.3.1 Chitosan 2.3.3.2 Cyclodextrins 2.3.3.3 Dextran, dextran-spermine 2.3.4 Dendrimers 2.3.5 Other Cationic Polymers 2.3.5.1 Cationic polyesters 2.3.5.2 Poly(amino ester)s 2.3.5.3 Poly(amido amine)s 2.4 Factors Influencing Cationic Polymer Mediated Nucleotides Delivery 2.5 Biomedical Applications 2.5.1 Tumor Therapy 2.5.2 siRNA Delivery 2.5.3 DNA Vaccination 2.5.4 Lung and Liver Delivery 2.5.5 Brain Delivery 2.6 Conclusion Younjee Chung and Leaf Huang 3.1 3.2 3.3 3.4 3. Membrane/Core Nanoparticles for Delivery of Therapeutic Nucleic Acid Introduction Challenges in Nanocarrier Systems Current Non-Viral Carrier Systems Membrane/Core NPs 3.4.1 LPD 3.4.1.1 Formulation of LPD 3.4.1.2 The effect of surface modification of LPD 3.4.1.3 Therapeutic applications of LPD 3.4.1.4 Modified LPD formulations 3.4.2 LCP 3.4.2.1 Physicochemical characteristic of LCP 3.4.2.2 Potential therapeutic effect of LCP 3.5 Conclusion 38 39 40 41 42 42 44 45 46 47 47 48 49 49 50 50 57 58 60 62 65 67 67 69 71 73 76 78 78 80 Contents 4. Delivery of Single siRNA Molecules Caroline Palm-Apergi and Steven F. Dowdy 4.1 Introduction 4.1.1 RNA Interference 4.1.2 Modification of siRNAs 4.1.3 Off-Target Effects 4.2 Delivery of siRNA 4.2.1 Peptide Transduction Domains 4.2.2 Delivery of siRNA-PTD Nanoparticles 4.2.3 RNA Binding Proteins 4.2.4 Delivery of Single siRNA Molecules by PTD-DRBD 4.3 Discussion 4.4 Conclusions Jiehua Zhou and John J. Rossi 5.1 Introduction 5.2 Generation of Cell-Specific Aptamers 5.2.1 Recombinant Protein-Based SELEX Procedure 5.2.2 Whole Cell-Based SELEX Procedure 5.3 Cell-Specific Aptamer-Functionalized RNAi 5.3.1 Cell-Specific Aptamer-Functionalized siRNAs 5.3.1.1 PSMA RNA aptamer-functionalized siRNAs 5.3.1.2 HIV gp120 RNA aptamerfunctionalized siRNAs 5.3.1.3 CD4 RNA aptamer-functionalized siRNAs 5.3.2 Cell-Specific Aptamer-Functionalized Therapeutic Nanocarriers 5.3.2.1 CD4 RNA aptamer-functionalized pRNA-nanoparticles 5. Cell-Specific Aptamer-Functionalized RNAi: A New Prospect for Targeted siRNA Delivery 93 94 94 95 96 96 96 97 98 99 100 102 107 108 111 111 112 114 115 115 116 117 117 118 vii viii Contents 5.3.2.2 PSMA RNA aptamer-functionalized polymer nanocarriers 5.3.2.3 CD30 RNA aptamer-functionalized polymer nanocarriers 5.4 Conclusions and Perspectives 6. Bioresponsive Nanoparticles for the Intracellular Delivery of RNAi Therapeutics Kenneth Alan Howard 6.1 Introduction 6.2 Repertoire of Potential RNAi Therapeutics 6.3 Nanoparticle-Based Delivery of RNAi Therapeutics 6.3.1 Polycation-Based Nanoparticles 6.3.2 Bioresponsive Systems 6.4 Copolypeptide System 6.5 Hyperbranched System 6.6 Conclusion James Dahlman, Robert Langer, and Michael Goldberg 7.1 Introduction 7.2 Motivation: Need for Novel siRNA Carriers in vivo 7.3 Approach: Efficient Chemistry Allows for HighThroughput Combinatorial Library Synthesis and Screening 7.4 Translation: Moving from in vitro to in vivo Screening 7.5 Optimization: Formulation Parameters Greatly Influence Carrier Efficacy 7.6 Synergy: Combining Existing Compounds to Achieve Improved Delivery 7.7 Next-Generation: Identifying Improved Carriers Using Innovative Chemistry 7.8 Applications: Using Lipidoids to Treat Disease Models 7.9 Future Directions and Conclusions 7. Lipid-Like Delivery Materials for Efficient siRNA Delivery 118 119 119 129 129 130 132 132 133 134 140 144 153 154 155 155 158 160 161 162 166 170 Contents 8. Manipulation of Leukocytes Using Therapeutic RNAi Delivered by Targeted and Stabilized Nanoparticles Dan Peer 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10 Introduction Strategies for RNAi Delivery into Leukocytes CpG-Conjugated siRNA Atelocollagen-Complexed siRNA Cationic Nona-d-Arginine Peptide-Complexed siRNA I-tsNP as RNAi Delivery Vehicle for LeukocyteAssociated Diseases Leukocyte Integrins as Targets for siRNA Delivery The Construction and Characterization of I-tsNP In vivo Gene Silencing Using I-tsNP-Entrapping siRNAs Conclusion 9. Lowering the siRNA Delivery Barrier: Alginate Scaffolds and Immune Stimulation 179 180 182 184 184 185 185 186 186 187 188 193 Jana McCaskill, Sherry Wu, Norliana Khairuddin, and Nigel A. J. McMillan 9.1 Introduction 9.2 siRNA Delivery Systems: A Brief Overview 9.2.1 siRNA Conjugate Delivery 9.2.2 Peptide-Based Delivery Particles 9.2.3 Polymer-Based Delivery Vectors 9.2.4 Lipid-Based Delivery Particles 9.3 HDFM: A Novel Method for Formulating Stable siRNA-Loaded Lipid Particles for in vivo Use 9.4 The Challenge of the Vaginal Tract 9.5 Vaginal Delivery of siRNA Using a Novel PEGylated Lipoplex-Entrapped Alginate Scaffold System 9.6 Thinking Outside the Box: Bi-Functional siRNAs 9.7 siRNA-Induced Immunostimulation Promotes Anti-tumoural Activity in vivo 9.8 Conclusion Index 193 194 194 195 196 197 198 200 202 205 208 210 217 ix Preface More than three decades ago, Paul Zamecnik and his colleagues suggested that nucleic acids (NA) could be used to block gene function by virtue of Watson–Crick base pairing. Since the discovery of RNAi in 1998 by Andrew Fire and Craig Melo and soon after the discovery that RNAi is found in mammals in 2001 by Thomas Tuschl’s group, synthetic small RNAs were shown to treat disease in mice. Small RNAs were quickly proclaimed as the “next new class of drugs.” Eagerness sprinted high because of the potential of these molecules to knock down any gene of interest to treat almost any disease by targeting otherwise “undruggable” targets such as molecules without ligand-binding domains or enzymatic function. Despite the promise, developing any NA as therapeutics has proven challenging. Like most drug development, there is no quick fix. Although many of the hurdles to developing NA-based drugs have been easily addressed, the main obstacle is figuring out how to deliver these molecules into cells in a therapeutically acceptable way. Small RNAs being considered therapeutic drugs include not only siRNAs designed to knock down one gene at a time but also mimics of endogenous microRNAs to suppress the expression of many genes, but with less efficient suppression of each one. The delivery hurdle that needs to be solved to administer siRNAs and imperfectly paired microRNA mimics is essentially the same (although antagonizing endogenous micro RNAs using single-stranded antisense oligonucleotides may be somewhat easier). When injected intravenously, NA are rapidly cleared by renal filtration and are susceptible to degradation by extracellular RNases or DNases. The NA half-life can be increased— even to days—by chemical modifications to eliminate susceptibility to endogenous exonucleases and endonucleases and by incorporating the NA into a larger moiety, above the molecular weight cutoff for kidney filtration. However, entering the cell is the biggest obstacle. Because of their large molecular weight and net negative charge, naked NA do not cross the plasma membrane. Although cells can endocytose many types of modified NA or NA-containing particles, another important bottleneck is getting these molecules xii Preface efficiently out of the endosome into the cytosol where the RNAi machinery resides or into the nucleus for DNA to work. NA therapeutics has been extensively studied both in the academia and in the pharmaceutical industry and is still considered the promise for new therapeutic modalities, especially in personalized medicine. The only hurdle that limits the translation of NA therapeutics from an academic idea to new therapeutic modality is the lack of efficient and safe delivery strategies. In this book, written by world experts in the field of nanotechnology for NA delivery, we bring together the state of the art in delivery strategies using lipids, polymers, chemical conjugates, NA aptamers, and proteins with strong emphasis on issues and aspects that are of essence to the pharmaceutical industry working in this area such as stability, general toxicity, immune-toxicity, pharmacokinetics and naturally efficacy and validation of new drug targets in vivo using unique approaches based on exquisite nanotechnology strategies. The work by Prof. Gerardo Byk and colleagues (Chapter 1) provides a tutorial overview of lipoplex and polyplex from a chemical standpoint. Discussions about lipopolyamines, lipopolyaminoguanidines, and reduction-sensitive lipopolyamine and dendrimers provide new insights into chemical modifications toward non-electrostatic DNA complexing agents. The work by Prof. Avi Domb and colleagues (Chapter 2) provides an excellent overview on the major cationic polymers used for the delivery of nucleotides, among them polyethylenimine, poly (L-lysine), cationic polysaccharides (such as chitosan, cyclodextrins, and dextran-spermine), dendrimers, cationic polyesters, poly(amino ester)s, and poly(amido amine)s. Factors influencing cationic polymer-mediated nucleotide delivery are also discussed. In addition, several biomedical applications are discussed, such as siRNA delivery, DNA vaccination, lung and liver delivery, brain delivery, and tumor delivery. Chapter 3, authored by Prof. Leaf Huang and colleagues, provides an introduction to the challenges in nanocarriers systems for NA delivery. It details two strategies of membrane/core NPs based on lipids, the LPD, and the LCD and discusses several applications in siRNA delivery using these strategies. Another interesting strategy is the delivery of single siRNA molecules by peptide transduction domains as described by Steve Dowdy and colleagues in Chapter 4. Additional RNA binding proteins are also detailed. Preface Chapter 5, written by Prof. John Rossi and colleagues, reviews the current advances of cell-specific aptamers in cell recognition and targeted delivery, with a particular focus on the development of the aptamer-functionalized siRNA or nanocarrier for targeted gene silencing. Prof. Ken Howard details in Chapter 6 bioresponsive nanoparticles based on copolypeptides and hyperbranched polymers for controlling the intracellular spatial and temporal effects of synthetic microRNA and siRNA. In Chapter 7, Prof. Robert Langer and Prof. Michael Goldberg describe the synthesis, screening, formulation, evolution, and application of “lipidoids,” a novel class of lipid-like molecules that highlights the utility of combinatorial approaches for the production of effective siRNA delivery vehicles. My personal contribution to this book is Chapter 8, in which I detail the use of integrin targeted and stabilized lipid-based nanoparticles for the manipulation of leukocytes’ function using RNAi. Finally, Prof. Nigel McMillan and his colleagues outline efforts to improve not only delivery but also RNAi efficacy in the vaginal mucosa as a means to treat genital infections, particularly virally driven cervical cancer, using various strategies. Clear, easy to understand, and focused on key issues for future research and development, this book provide new insights into the dynamic field of NA delivery using nanotechnology. I am grateful to all the authors who contributed to this book, among them Prof. Byk, from Bar-Ilan University, Prof. Domb from the Hebrew University in Jerusalem, Prof. Huang from the University of North Carolina at Chapel Hill, Prof. Dowdy from the University of California San Diego, Prof. Rossi from the City of Hope in California, Prof. Howard from the University of Aarhus, Prof. Langer from MIT, Prof. Goldberg from Harvard Medical School, and Prof. McMillan from the University of Queensland. Special thanks to my wife, Shlomit, and my children, Dor, Barak, and Naama, for their unrestricted support. This book is dedicated to the memory of my parents, Itta and Alexander Peer, who educated me to strive for knowledge and excellence. Dan Peer Tel Aviv, Winter 2012 xiii