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Advances in Nanomedicine for the Delivery
of Therapeutic Nucleic Acids
Related titles
Nanotechnology-based Approaches for Targeting and Delivery of Drugs and Genes
(ISBN 978-0-12-809717-5)
Fundamentals of Biologicals Regulation: Vaccines and Biotechnology Medicine
(ISBN 978-0-12-809290-3)
Nanomedicine: Technologies and Applications
(ISBN 978-0-85709-233-5)
Woodhead Publishing Series in Biomedicine
Advances in
Nanomedicine for the
Delivery of Therapeutic
Nucleic Acids
Edited by
Surendra Nimesh
Ramesh Chandra
Nidhi Gupta
Woodhead Publishing is an imprint of Elsevier
The Officers’ Mess Business Centre, Royston Road, Duxford, CB22 4QH, United Kingdom
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, OX5 1GB, United Kingdom
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described
herein. In using such information or methods they should be mindful of their own safety and
the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors,
assume any liability for any injury and/or damage to persons or property as a matter of
products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
List of contributors ix
Foreword xi
Preface xiii
Acknowledgments xv
Index 233
List of contributors
The book, Advances in Nanomedicine for the Delivery of Therapeutic Nucleic Acids,
edited by Dr. Surendra Nimesh, Dr. Nidhi Gupta and Prof. Ramesh Chandra (Nimesh
et al., 2017), is the second book by these authors on this subject. This new book is a
reflection of the rapid development in this area. It contains complete updates and an
overview of every aspect of this area since the previous book.
This book begins with an introduction on nanomedicine for therapeutics, including
the properties of nanoparticles and nanoparticle-based strategies for overcoming
in vitro and in vivo barriers. The more general aspects of nanoparticles as nucleic
acid delivery vectors and methods for the characterization of nanoparticles are then
described. This is followed by a brief account of various nanoparticles employed for
in vitro and in vivo gene delivery studies.
The chapters that follow describe various specific approaches in detail. This
includes nanoparticle-mediated studies of in vitro and in vivo gene silencing for
gene therapy. Gene silencing is a naturally occurring mechanism that takes place in
the cytoplasm of the cell to knock down the function of malfunctioning genes. The
next area is the use of nanoparticles for the delivery of locked nucleic acids for
gene therapy. This is followed by a discussion on nanotechnology-based vectors for
the delivery of therapeutic DNAzymes. A DNAzyme is a catalyst for the breakdown
of target mRNA sequences.
The last part of the book covers three important areas. (1) The first is pharmacoki-
netics and the biodistribution of nanoparticles. This chapter outlines the important
topic of strategies for detection and estimation of toxicity of nanoparticles employed
for nucleic acid delivery. (2) The next chapter describes the regulatory aspects of
nanoparticulate-mediated nucleic acid delivery systems. (3) The book ends with an
important chapter on the update of studies undergoing clinical trials, followed by a
conclusion and future prospects.
The initial publication (Chang, 1964) has evolved into many different areas of arti-
ficial cells (Chang, 2005, 2007) including nanomedicine (Chang, 2013). Advances in
Nanomedicine for the Delivery of Therapeutic Nucleic Acids is a detailed description
and update of one of the many areas of nanomedicine. The editors have contributed
greatly in the research and development in this specific area. This book reflects their
experience and expertise.
TMS Chang
xii Foreword
References
Chang TMS. Semipermeable microcapsules. Science 1964;146(3643):524e5.
Chang TMS. Therapeutic applications of polymeric artificial cells. Nat Rev Drug Discov 2005;4:
221e35.
Chang TMS. Monograph on “artificial cells: biotechnology, nanotechnology, blood substitutes,
regenerative medicine, bioencapsulation, cell/stem cell therapy”. World Scientific Publisher/
Imperial College Press; 2007. 435 pages. Available complimentary on: www.medicine.
mcgill.ca/artcell.
Chang TMS. “Artificial cells that started nanomedicine” opening chapter in book on “Selected
Topics in Nanomedicine”. World Science Publisher/Imperial College Press; 2013.
Nimesh S, Gupta N, Chandra R. Advances in nanomedicine for the delivery of therapeutic
nucleic acids, 2017.
Professor Thomas Ming Swi Chang, O.C., M.D., C.M., Ph.D., FRCPC, FRS[C]
Director, Artificial Cells & Organs Research Centre
Emeritus Professor,Departments of Physiology, Medicine & Biomedical Engineering
Faculty of Medicine, McGill University, Montreal, Quebec, Canada
Honorary President, Artificial Cells, Blood Substitutes & Biotechnology (an International Network)
Editor in Chief, Artificial Cells, Nanomedicine & Biotechnology, an International Journal
Editor in Chief, Regenerative Medicine, Artificial Cells & Nanomedicine, Book Series
Preface
The authors are indebted to their teachers and colleagues for their encouragement,
motivation, undying patience and critical evaluation through the various stages of
book manuscript preparation. They have been a source of inspiration all along, and
supportive with their inexhaustible knowledge. Their valuable input and fruitful sug-
gestions throughout this work is an asset.
Financial support is one of the foremost requirements for these kinds of projects.
Nidhi Gupta and Surendra Nimesh acknowledge the financial assistance from
the Science and Engineering Research Board (SERB) (SB/FT/LS-441/2012 and
SB/FT/LS-420/2012), Government of India, India.
Careful editing of the manuscript requires a lot of effort and work without much
appreciation. The authors acknowledge deep gratitude to their students Geeta,
R. Mankamna and Nikita for taking on this cumbersome job.
Further, we would like to thank the publishing team members of Elsevier for
supporting the publication of this book.
The authors are deeply grateful to their friends and families for their untiring efforts
and for helping to finalize this work.
1.1 Introduction
Specificity and accuracy are two important aspects in the design and development of
drug delivery strategies. In the initial stages, Paul Ehrlich had led a vision of
designing “magic bullets” that would deliver drugs with the utmost specificity to
the target tissue or cells. Nanotechnology is one step closer to the reality of this vision
that was initiated in the beginning of the 20th century (Kayser et al., 2005). As a
beginner, the best way to develop a drug delivery system (DDS) is to understand
the mechanism of targeting. One simple, chemical approach for designing DDS is
the use of modified forms of active drugs, also known as prodrugs, that can be
cleaved enzymatically or chemically to release an active drug. The prodrugs could
more easily access the target sites (Higuchi, 1975). Bioconjugate systems are also be-
ing developed that employ the use of monoclonal antibodies, polyclonal antibodies,
sugars or lectins as targeting moieties, coupled chemically with drug moiety to
increase target specificity of the latter. The ligand conjugated to the drug decides
the fate of the coupled molecule and underlines its importance in site-specific deliv-
ery of a drug.
A number of delivery or carrier systems for drugs have found place in research
since 1996, including strategies based on liposomes, nanoparticles, microparticles,
and microemulsions (Aynie et al., 1999; Fattal et al., 1998; Forssen and Tokes,
1983a,b; Gregoriadis, 1990; Landfester 2001, 2009; Lee et al., 2003; Rahman
et al., 1990; Tan and Gregoriadis, 1990; Zou et al., 1993a,b,c). The purpose of devel-
oping all these systems is to maximally avoid interactions with nontarget sites. Several
advantages are linked with the usage of carrier-conjugated drug delivery systems,
such as
1. prevention of the drug molecule from immunogenic attack and minimal exposure of the
drug to normal milieu;
2. minimal renal excretion that increases the half-life of the drug;
3. the drug can be maintained in its active form;
4. at the target site, the required therapeutic concentration can be prevailed;
5. at the disease site, the drug moiety can be activated; and
6. several physiological barriers could be overcome to finally ensure cell-specific interaction.
The foremost goal of controlled drug delivery is to deliver a particular drug to a
target site or a specific population of cells within a particular organ or tissue. For
designing a new system for the target-specific delivery of a drug, the following factors
should be taken into consideration:
1. The system should have the capability to differentiate between target and nontarget sites,
ultimately minimizing the toxic effects.
2. The system should be free of any toxic compounds on prolonged retention in the system.
3. The carrier system deployed should be biodegradable after its role imparted at the target site,
and the degraded components produced should be nontoxic to the system to which it is
administered.
The major problem faced during the process of the delivery of polymeric nanopar-
ticulate carriers in the body is the systemic scavenging machinery such as the reticu-
loendothelial system (RES). Herein, the nanoparticles or any other foreign body
entering into the vasculature system get surrounded or coated by various plasma pro-
teins and glycoproteins called opsonins by the process termed “opsonization.” Conse-
quently, the RES removes the carrier system from the blood circulation similar to the
mechanism followed in the removal of pathogens, dying cells, and foreign bodies from
the blood circulation by phagocytosis (M€ uller and Wallis, 1993). In addition, the
Kupffer cells, spleen, lungs, and circulating macrophages also play a significant role
in the removal of opsonized particles. It has been observed that the RES mainly de-
pends on the size and surface properties of the particles. As a result, the particulates
with greater hydrophobic surfaces get efficiently coated with opsonins and are rapidly
cleared from the circulation, whereas hydrophilic particle experiences prolonged circu-
lation as it escapes being recognized by the opsonins (Storm et al., 1995).
In the current scenario, antisense nucleotides such as siRNA have been employed
for the treatment of several infectious and inflammatory diseases including cancer
(Stephenson and Zamecnik, 1978; Zamecnik and Stephenson, 1978). This nucleic
acid (NA) therapeutics is considered to be more efficient compared to conventional
therapeutics as it works at the level of gene expression, inhibiting the expression of
target protein. Also, NA offers unique prospects in its therapeutic activity on
intractable targets, such as regulation of transcription factors for the expression of
entire groups of genes. Thus, NA could be either employed for incorporating desired
function or inhibition of the function at the molecular level known as gene therapy
(Scanlon, 2004). In gene therapy, generally large NA molecules are used for
expressing a desired protein, whereas small and specific NA sequences are used for
inhibiting target gene function. Though the therapeutic use of NA is considered to
display several benefits, it is hampered by challenges such as limited stability and
poor cellular internalization. Hence, there is a need of a carrier capable of
administering NA in vitro and in vivo efficiently, safely, and repeatedly that can be
attained by applying the use of nanoparticles.
Nanotechnology generally deals with the design, synthesis and application of ma-
terials in the nanometer range (usually 100 nm or smaller). Previous studies have
shown that nanocarriers could be used for successful delivery of drugs to the target tis-
sue with greater potential, penetration and improved efficacy. Among most of the
nanoparticles available, polymeric nanoparticles have evolved as one of the most
promising candidates, with rapid progress as vectors for targeted drug and gene delivery
Nanomedicine for delivery of therapeutic molecules 3
Nanospheres Nanocapsules
Figure 1.1 Types of nanoparticles.
(Peer et al., 2007). Thus polymeric nanocarriers could be exploited for the delivery of
several therapeutic agents such as low molecular weight drugs and macromolecules
involving proteins or NA. These nanocarriers could be categorized as (1) nano-
spheres, spherical nanometer range particles where the desired molecules can either
be entrapped inside the sphere or adsorbed on the outer surface or both (Fig. 1.1)
or (2) nanocapsules, solid polymeric shells with an inner liquid core, and the desired
molecules entrapped inside (Fig. 1.1) (Fattal et al., 1998; Mao et al., 2010; Reischl
and Zimmer, 2009). Basically, the fate of nanoparticles within the body is governed
by its size, shape, surface charge, and nature (hydrophobic or hydrophilic) of the poly-
mer (Alexis et al., 2008). So far, natural and synthetic polymers investigated for NA
delivery include chitosan, polyethylenimine (PEI), cyclodextrin-based polycations,
and polyethylene glycol (PEG), etc.
FOOTNOTES:
[2] See the Map of Brookdale, p. 14.
CHAPTER IV.
CRIME.