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DRUG DELIVERY APPROACHES
AND NANOSYSTEMS
Volume 1: Novel Drug Carriers
DRUG DELIVERY APPROACHES
AND NANOSYSTEMS
Volume 1: Novel Drug Carriers

Edited by
Raj K. Keservani, MPharm
Anil K. Sharma, MPharm
Rajesh K. Kesharwani, PhD
Apple Academic Press Inc. Apple Academic Press Inc.
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Drug delivery approaches and nanosystems / edited by Raj K. Keservani, MPharm, Anil K. Sharma,
MPharm, Rajesh K. Kesharwani, PhD.
Includes bibliographical references and indexes.
Contents: Volume 1. Novel drug carriers -- Volume 2. Drug targeting aspects of nanotechnology.
Issued in print and electronic formats.
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1. Drug delivery systems. 2. Nanotechnology. 3. Nanostructures. I. Kesharwani, Rajesh Kumar, 1978-,
editor II. Sharma, Anil K., 1980-, editor III. Keservani, Raj K., 1981-, editor
RS420.D78 2017 615.1'9 C2017-902014-5 C2017-902015-3
Library of Congress Cataloging-in-Publication Data
Names: Keservani, Raj K., 1981- editor. | Sharma, Anil K., 1980- editor. | Kesharwani, Rajesh Kumar,
1978- editor.
Title: Drug delivery approaches and nanosystems / editors, Raj K. Keservani, Anil K. Sharma, Rajesh K.
Kesharwani.
Other titles: Novel drug carriers. | Drug targeting aspects of nanotechnology. Description: Toronto ; New
Jersey : Apple Academic Press, 2017. | Includes bibliographical references and index.
Identifiers: LCCN 2017012335 (print) | LCCN 2017013149 (ebook) | ISBN 9781315225371 (ebook)
| ISBN 9781771885836 (hardcover ; v. 1 : alk. paper) | ISBN 9781771885843 (hardcover ; v. 2 : alk.
paper) | ISBN 9781771885850 (hardcover ; set : alk. paper) | ISBN 9781315225371 (eBook)
Subjects: | MESH: Drug Delivery Systems | Nanotechnology | Nanostructures
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The Present Book Is Dedicated To
Our Beloved
Aashna,
Atharva
Vihan
&
Vini
CONTENTS

List of Contributors ..................................................................................... ix

List of Abbreviations ................................................................................. xiii
Preface ...................................................................................................... xix
About the Editors..................................................................................... xxiii
1. Introduction to Nanotechnology in Drug Delivery ................................. 1
Raj K. Keservani, Rajesh K. Kesharwani, and Anil K. Sharma
2. Nanoparticles: General Aspects and Applications ................................ 21
Onur Alpturk and Ceyda Tuba Sengel-Turk
3. Nanotechnology in Medicine: Drug Delivery Systems.......................... 55
Elena Campano-Cuevas, Ana Mora-Boza, Gabriel Castillo-Dalí,
Agustín Rodríguez-Gonzalez-Elipe, María-Angeles Serrera-Figallo,
Angel Barranco, and Daniel Torres-Lagares
4. Polymeric Matrix Systems for Drug Delivery ....................................... 95
Snežana Ilić-Stojanović, Ljubiša Nikolić, Vesna Nikolić,
Dušica Ilić, Ivan S. Ristić, and Ana Tačić
5. Applications of Nanobiomaterials in Drug Delivery ........................... 133
Yaser Dahman and Hamideh Hosseinabadi
6. Carbon Nanotubes Used as Nanocarriers in Drug and
Biomolecule Delivery ............................................................................. 163
Hua He, Deli Xiao, Lien Ai Pham-Huy, Pierre Dramou,
and Chuong Pham-Huy
7. Dendrimers: A Glimpse of History, Current Progress,
and Applications ..................................................................................... 213
Surya Prakash Gautam, Arun Kumar Gupta, Revati Gupta,
Tapsya Gautam, and Maninder Pal Singh
8. Nanofibers: Production Techniques and Applications ........................ 237
Hemant K. S. Yadav, Nour A. H. Alhalabi,
and Ghufran A. R. Alsalloum
viii Contents

9. Drug and Food Applications of Liposomes and Nanoparticles:

From Benchmark to Bedside?............................................................... 299
Marcus Vinícius Dias-Souza and Renan Martins dos Santos
10. Nanotechnology for Cosmetic Herbal Actives:
Is It a New Beauty Regime? .................................................................. 327
Ranjita Shegokar
11. Antimicrobial Activity of Nanotechnological Products ...................... 361
Leonardo Quintana Soares Lopes, Márcia Ebling de Souza,
Rodrigo de Almeida Vaucher, and Roberto Christ Vianna Santos
12. Drug Targeting: Principles and Applications ...................................... 383
Ruslan G. Tuguntaev, Ahmed Shaker Eltahan, Satyajeet S. Salvi,
and Xing-Jie Liang
Index ......................................................................................................... 417
LIST OF CONTRIBUTORS

Nour A. H. Alhalabi
Department of Pharmaceutics, RAK College of Pharmaceutical Sciences, RAK Medical & Health
Sciences University, UAE

Onur Alpturk
Department of Chemistry, Istanbul Technical University, 34469, Maslak, Istanbul, Turkey

Ghufran A. R. Alsalloum
Department of Pharmaceutics, RAK College of Pharmaceutical Sciences, RAK Medical & Health
Sciences University, UAE

Angel Barranco
CSIC, Institute of Material Science, Seville, Spain

Elena Campano-Cuevas
School of Dentistry, University of Seville, Seville, Spain

Gabriel Castillo-Dalí
School of Dentistry, University of Seville, Seville, Spain

Yaser Dahman
Department of Chemical Engineering, Ryerson University, Toronto, Ontario, M5B 2K3, Canada

Marcus Vinícius Dias-Souza

Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil; Integrated
Pharmacology and Drug Interactions Research Group (GPqFAR), Brazil

Pierre Dramou
China Pharmaceutical University, Nanjing, China

Ahmed Shaker Eltahan

Laboratory of Controllable Nanopharmaceuticals, CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing,
China

Surya Prakash Gautam

CT Institute of Pharmaceutical Sciences, Shahpur Campus, Jalandhar, India

Tapsya Gautam
CT Institute of Pharmaceutical Sciences, Shahpur Campus, Jalandhar, India

Arun Kumar Gupta

RKDF Institute of Pharmaceutical Sciences, Indore, India

Revati Gupta
RKDF Institute of Pharmaceutical Sciences, Indore, India

Hua He
China Pharmaceutical University, Nanjing, China, Key Laboratory of Drug Quality Control and
Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, China
x List of Contributors

Hamideh Hosseinabadi
Department of Mechanical and Industrial Engineering, Ryerson University, Toronto, Ontario, M5B
2K3, Canada

Dušica Ilić
Faculty of Technology, University of Niš, Bulevar oslobodjenja 124, 16000 Leskovac, Republic of
Serbia

Snežana Ilić-Stojanović
Faculty of Technology, University of Niš, Bulevar oslobodjenja 124, 16000 Leskovac, Republic of
Serbia

Raj K. Keservani
Faculty of Pharmaceutics, Sagar Institute of Research and Technology-Pharmacy, Bhopal–462041,
India

Rajesh K. Kesharwani
Department of Biotechnology, NIET, NIMS University, Shobha Nagar, Jaipur, Rajasthan–303121,
India

Xing-Jie Liang
Laboratory of Controllable Nanopharmaceuticals, CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing,
China

Leonardo Quintana Soares Lopes

Microbiology Laboratory Research, Centro Universitário Franciscano, Santa Maria-RS, Brazil

Ana Mora-Boza
CSIC, Institute of Material Science, Seville, Spain

Ljubiša Nikolić
Faculty of Technology, University of Niš, Bulevar oslobodjenja 124, 16000 Leskovac, Republic of
Serbia
Vesna Nikolić
Faculty of Technology, University of Niš, Bulevar oslobodjenja 124, 16000 Leskovac, Republic of
Serbia

Chuong Pham-Huy
Faculty of Pharmacy, University of Paris V, 4 avenue de l’Observatoire, 75006 Paris, France

Lien Ai Pham-Huy
Department of Pharmacy, Lucile Packard Children’s Hospital Stanford, Palo Alto, CA, USA

Ivan S. Ristić
Faculty of Technology, University of Novi Sad, Bulevar Cara Lazara 1, 21000 Novi Sad, Republic
of Serbia

Agustín Rodríguez-Gonzalez-Elipe
CSIC, Institute of Material Science, Seville, Spain

Satyajeet S. Salvi
Hampshire College, Amherst, MA 01002, USA

Renan Martins dos Santos

List of Contributors xi

Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil; Integrated
Pharmacology and Drug Interactions Research Group (GPqFAR), Brazil

Roberto Christ Vianna Santos

Microbiology and Parasitology Department, Federal University of Santa Maria, Santa Maria-RS,
Brazil

Ceyda Tuba Sengel-Turk

Department of Pharmaceutical Technology, Faculty of Pharmacy, Ankara University, 06100, Ankara,
Turkey

María-Angeles Serrera-Figallo
School of Dentistry, University of Seville, Seville, Spain

Anil K. Sharma
Delhi Institute of Pharmaceutical Sciences and Research, Formerly College of Pharmacy, University
of Delhi, Pushp Vihar, Sector III, New Delhi–110017, India

Ranjita Shegokar
Free University of Berlin, Kelchstr. 31, Berlin, Germany

Maninder Pal Singh

CT Institute of Pharmaceutical Sciences, Shahpur Campus, Jalandhar, India

Márcia Ebling de Souza

Microbiology Laboratory Research, Centro Universitário Franciscano, Santa Maria-RS, Brazil

Ana Tačić
Faculty of Technology, University of Niš, Bulevar oslobodjenja 124, 16000 Leskovac, Republic of
Serbia

Daniel Torres-Lagares
School of Dentistry, University of Seville, Seville, Spain

Ruslan G. Tuguntaev
Laboratory of Controllable Nanopharmaceuticals, CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing,
China

Rodrigo de Almeida Vaucher

Microbiology Laboratory Research, Centro Universitário Franciscano, Santa Maria-RS, Brazil

Deli Xiao
China Pharmaceutical University, Nanjing, China

Hemant K. S. Yadav
Department of Pharmaceutics, RAK College of Pharmaceutical Sciences, RAK Medical & Health
Sciences University, UAE
LIST OF ABBREVIATIONS

a-CDs a-cyclodextrins
AAO anodized aluminum oxide
AAS Aconitum sinomontanum
ACV acyclovir
AD Alzheimer's disease
AFM atomic force microscopy
AGNPS silver nanoparticles
AIST National Institute of Advanced Industrial Science and
Technology
ALG alginate
APP amyloid precursor protein
ASGP-R asialoglycoprotein receptors
BALF bronchoalveolar lavage fluid
BBB blood–brain barrier
bFGF basic fibroblast growth factor
BG bioactive glass
BLPs biotinylated liposomes
BRCAA1 breast cancer-associated antigen 1
BSA bovine serum albumin
CAFs cancer-associated fibroblasts
CF cystic fibrosis
CMC critical micelle concentration
CMs cardiomyocytes
CNS central nervous system
CNTs carbon nanotubes
Col collagen
CP capillary electrophoresis
CPT camptothecin
CS chitosan
CS chondroitin sulfate
xiv List of Abbreviations

CVD chemical vapor deposition

DA deoxycholic acid
DC dendritic cells
DDAB dimethyl-dioctadecylammonium bromide
DDS drug delivery system
DEX dexamethasone
DLS dynamic light scattering
DM diabetes mellitus
DMAP 4-(dimethylamino) pyridine
DMSA dimercaptosuccinic acid
DOEPC 1,2-dioleoyl-sn-glycerol-3-ethylphosp hocholine
DOX doxorubicin hydrochloride
DPP-4 dipeptidyl peptidase-4
DPPC dipalmitoylphosphatidylcholine
DPSCs dental pulp stem cells
DSC differential scanning colorimeter
DSPE 1,2-distearoyl-sn-glycero-3-phosphatidyl ethanolamine
DW distilled water
ECM extracellular matrix
ECN econazole
EE entrapment efficiency
EGF epidermal growth factor
EGFR epidermal growth factor receptor
EMT epithelial–mesenchymal transition
EndMT endothelial-mesenchymal transition
EPC egg yolk phosphatidylcholine
EPO erythropoietin
EPR enhanced permeability and retention
ESR electron spin resonance
FA folic acid
FAP fibroblast-activated-protein
FD&C Act Federal Food, Drug, and Cosmetic Act
FDA Food and Drug Administration
FGF fibroblast growth factor
FUS focused ultrasound
GAG glycosaminoglycan
List of Abbreviations xv

GF growth factor
GFP green fluorescence protein
GI gastrointestinal
GLP glucagon-like peptide
GSH glutathione
GTP green tea polyphenol
HA hydroxyapatite
HAART highly active antiretroviral therapy
HAuCl4 hydrogen tetrachloroaurate
HB-EGF heparin-binding EGF
HCV hepatitis C virus
HER human epidermal receptor
HER-2 human epidermal receptor-2
HGF hepatocyte growth factor
HI hydrophobic interaction
HIF hypoxia-inducible transcription factors
HLB hydrophilic-lipophilic balance
HPH high-pressure homogenization
HPLC high-performance liquid chromatography
HPMA N-(2-hydroxypropyl)-methacrylamide copolymer
IBM International Business Machines
IGF1 insulin-like growth factor 1
IGF2 insulin-like growth factor 2
IND Investigational New Drug
INS insulin
IR infrared
IVDs intervertebral discs
JAK Janus activated kinase
LA lappacontine
LCST lower critical solution temperature
LOX lysyl oxidase
LRT loratadine
MBC minimal bactericidal concentration
MCAO middle cerebral artery occlusion
MCNT magnetic carbon nanotube
MED minimal erythema dose
xvi List of Abbreviations

MIC minimum inhibitory concentration

MMA methyl methacrylate
MMIPs magnetic molecularly imprinted polymers
MMPs matrix metalloproteases
MNPs magnetic nanoparticles
MP macrophages
MPLA monophosphoryl lipid A
MPO myeloperoxidase
MPS mononuclear phagocyte system
MRI magnetic resonance imaging
MSCs mesenchymal stem cells
MV multilamellar vesicles
MWCNTs multiwalled carbon nanotubes
MWNTs multi-walled carbon nanotubes
NCs nanocomplexes
NDDS novel drug delivery systems
NF-κB nuclear factor-kappa B
NIR near infrared
NLC nanostructured lipid carriers
NMR nuclear magnetic resonance
NMs Nanomaterials
NP nanoparticles
NSCs neural stem cells
NSERC Natural Sciences and Engineering Research Council of
Canada
NSP nanosilver particles
OV oligolamellar vesicles
PAMAM polyamidoamine
PAMAMOS poly (amidoamine) organosilicon
PAs peptide-amphiphiles
PCL poly(ε-caprolactone)
PDGF platelet-derived growth factor
PDLA poly(D-lactide)
PEG poly(ethylene glycol)
PEI polyethylenimine
PEO polyethylene oxide
List of Abbreviations xvii

PET polyethylene terephthalate

PET positron emission tomography
PEUU poly(ester-urethane)urea
PGA poly L-glutamic acid
PGA poly(glycolic acid)
PHB poly(hydroxybutyrate)
PK pharmacokinetic
PLA poly(lactic acid)
PLGA poly(lactic-coglycolic) acid
PLLA poly(L-lactic acid)
PMMA polymethyl methacrylate
PP pancreatic polypeptide
PPO polypropylene oxide
PR polyrotaxane
PVA poly(vinyl alcohol)
PVP poly N-vinyl-2-pyrrolidone
QDs quantum dots
RAN ranaconitine
RES reticuloendothelial system
RSV respiratory syncytial virus
SELEX systemic evolution of ligands by exponential enrichment
SEM scanning electron microscopy
SFRP1 secreted frizzled-related protein 1
SLN solid lipid nanoparticle
SPE solid-phase extraction
SPIO super-paramagnetic iron oxide
SSMs sterically stabilized micelles
STAT3 signal transducer activator of transcription3
SWCNT single-walled carbon nanotubes
TAM tumor-associated macrophages
TCV tumor cell vaccine
TDDS transdermal drug delivery system
TEG triethylene glycol
TEM transmission electron microscopy
TGA thermal gravimetric analysis
TGF-α transforming growth factor-α
xviii List of Abbreviations

TGF-β transforming growth factor-β

UV ultraviolet spectrophotometry
UV unilamellar vesicles
VCAM vascular cell adhesion molecules
VEGF vascular endothelial growth factor
VEGF-2 vascular endothelial growth factor receptor 2
VSM vibrating sample magnetometer
XRD x-ray diffraction
PREFACE

This edited book, Drug Delivery Approaches and Nanosystems, comprised

of two volumes—Volume I: Novel Drug Carriers and Volume II: Drug
Targeting Aspects of Nanotechnology, presents a full picture of the state-
of-the-art research and development of actionable knowledge discovery in
the real-world discovery of drug delivery systems using nanotechnology
and its applications.
The book is triggered by the ubiquitous applications of nanotechnol-
ogy, or nano-sized materials, in the medical field, and the real-world chal-
lenges and complexities to the current drug delivery methodologies and
techniques.
As we have seen, and as is often addressed at different conferences
and seminars, many methods have been used but very few of them have
been validated in medical use.
A major reason for the above situation, we believe, is the gap between
academia and research and the gap between academic research and real-
time clinical applications and needs.
This book, Drug Delivery Approaches and Nanosystems: Novel Drug
Carriers, includes 12 chapters that contain information on the preparation
and characterization of nanocomposite materials used in drug delivery
systems; advanced research of carbon nanotubes; nanocomposite materi-
als and polymer-clay, ceramic, silicate glass-based nanocomposite materi-
als; and the functionality of graphene nanocomposites.
This edited book provides a detailed application of nanotechnology in
drug delivery systems in health care system and medical applications.
Chapter 1, Introduction to Nanotechnology in Drug Delivery, is writ-
ten by Raj K. Keservani and colleagues, discusses general characteristics
of several nanosystems that have applications in drug delivery. The discus-
sion has been supported by suitable examples wherever necessary.
Chapter 2, Nanoparticles: General Aspects and Applications, written
by Onur Alpturk and Ceyda Tuba Sengel-Turk, provides a discussion of
the general features of nanoparticles encompassing preparation methods,
xx Preface

evaluations parameters, and different polymers used in formulation. The

commercial applications have also been listed in the chapter.
The role of nanotechnology in therapeutics, nowadays termed as ‘nano-
medicine’, is explained in Chapter 3, Nanotechnology in Medicine: Drug
Delivery Systems, written by Elena Campano-Cuevas and colleagues. The
chapter describes how the robotic devices are emerging as a tool to pro-
vide numerous biomedical applications.
The diverse nanotechnology-based drug delivery systems have been
presented in Chapter 4, Polymeric Matrix Systems for Drug Delivery, writ-
ten by Snežana Ilić-Stojanović and associates. This chapter provides an
overview of the drug delivery systems, (DDS), based on natural and/or
synthetic polymers as carriers for the active substances, proteins, or cells.
The materials used to design nanosystems have also been discussed with
suitable instances.
Chapter 5, Applications of Nanobiomaterials in Drug Delivery, writ-
ten by Yaser Dahman and Hamideh Hosseinabadi, deals with biomaterials
used for drug delivery. The biomaterials of natural as well as synthetic
ones are discussed in this chapter. The biocompatibility of these polymers
imparts them preference over their counterparts.
Chapter 6, Carbon Nanotubes Used as Nanocarriers in Drug and
Biomolecule Delivery, written by Hua He and associates, deals with
the applications of CNTs used as nanocarriers in drug and biomolecule
delivery for chemotherapeutic use and also studies the pharmacokinetics,
metabolism and toxicity of different forms of CNTs. Finally, it discusses
the prospect of this promising bio-nanotechnology in the future clinical
exploitation.
An overview of dendrimers has been presented in Chapter 7,
Dendrimers: A Glimpse of History, Current Progress and Applications,
written by Surya Prakash Gautam and associates. The key features of
dendrimers with therapeutic relevance have been discussed. The journey
of these nanometric carriers from emergence to until today have been
explained in chronological order. The utility of dendrimers beyond thera-
peutics has also been described.
Chapter 8, Nanofibers: Production Techniques and Applications, writ-
ten by Hemant K. S. Yadav and colleagues, explains the general aspects
of nanofibers and enumerates various preparation techniques. The authors
Preface xxi

then go on to give manifold applications of these nanometric architects.

Biomimetic nanofibers as drug delivery devices that are responsive to dif-
ferent stimuli, such as temperature, pH, light, and electric/magnetic field
for controlled release of therapeutic substances, are the new thrust area of
research.
A historical map of liposomes and nanoparticles is presented in
Chapter 9, Drug and Food Applications of Liposomes and Nanoparticles:
From Benchmark to Bedside?, written by Marcus Vinícius Dias-Souza and
Renan Martins dos Santos. Controlled and vectorized release of different
compounds is among the main features that stimulate research on the use
of liposomes and nanoparticles in health sciences.
The chapter that talks about the everlasting desire of majority of human
beings to look beautiful is Chapter 10, Nanotechnology for Cosmetic
Herbal Actives: Is It a New Beauty Regime?, written by Ranjita Shegokar.
To state precisely, hair care and dermal care products are the everyday
need of modern women. Men are not behind; today many men have
become conscious of their looks and appearance also. Natural products
are among the favorite and are traditionally used for beauty care. It is well
known that Cleopatra used to apply donkey’s milk to her skin. The science
of cosmetology is believed to have originated in Egypt and India, but the
earliest records of cosmetic substances and their application dates back to
circa 2500 and 1550 B.C. to the Indus valley civilization.
The applications of nanotechnology-based products listed as carriers of
antibacterial actives are provided in Chapter 11, Antimicrobial Activity of
Nanotechnological Products, written by Leonardo Quintana Soares Lopes
and colleagues. The effectiveness of antimicrobial therapy is usually low
because of limited access to infected site or prevalence of dose-related
adverse effects. Nanocarriers have enabled the researchers to reduce the
dose of drug with improved control over the growth of microorganisms.
Chapter 12, Drug Targeting: Principles and Applications, written
by Ruslan G. Tuguntaev and associates, explains the targeting poten-
tial of nanosystems. Drug targeting is a promising strategy for the effi-
cient treatment of various serious diseases such as cancer. The primary
goal of this concept is to provide precise delivery of therapeutic agents
into pathological areas, while avoiding negative impacts on healthy tis-
sues. Through this approach, high therapeutic efficacy of the drug can be
xxii Preface

attained while experiencing minimum side effects. Recently, nano-sized

carriers have received great attention as delivery systems that can load,
bring, and release the drugs to a localized area. Accurate drug delivery
can be achieved either via passive targeting, which is based on enhanced
vascular permeability into the affected zone, or active targeting, which can
be achieved by decoration of nanocarriers surface with ligands that have
high affinity toward the targeted area. In this chapter, general methods and
means of drug targeting-based on nanomedicine have been discussed.
The book also provides detailed information on the application of nan-
otechnology in drug delivery systems in health care systems and medicine.
The book describes how nanostructures are synthesized and draw atten-
tion to wide variety of nanostructures available for biological research and
treatment applications.
This valuable volume provides a wealth of information that will be
valuable to scientists and researchers, faculty, and students.
ABOUT THE EDITORS

Raj K. Keservani, MPharm

Faculty of Pharmaceutics, Sagar Institute of Research and
Technology-Pharmacy, Bhopal, India

Raj K. Keservani, MPharm, has more than seven years of academic

(teaching) experience from various institutes of India in pharmaceuti-
cal education. He has published 25 peer-reviewed papers in the field of
pharmaceutical sciences in national and international journals, 15 book
chapters, two co-authored books, and two edited books. He is also active
as a reviewer for several international scientific journals. Mr. Keservani
graduated with a pharmacy degree from the Department of Pharmacy
Kumaun University, Nainital (UA), India. He received his Master of
Pharmacy (MPharm) (specialization in pharmaceutics) from the School
of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya,
Bhopal, India. His research interests include nutraceutical and functional
foods, novel drug delivery systems (NDDS), transdermal drug delivery/
drug delivery, health science, cancer biology, and neurobiology.

Anil K. Sharma, MPharm

Delhi Institute of Pharmaceutical Sciences and Research,
University of Delhi, India

Anil K. Sharma, MPharm, is working as a lecturer at the Delhi Institute of

Pharmaceutical Sciences and Research, University of Delhi, India. He has
more than seven years of academic experience in pharmaceutical sciences.
He has published 25 peer-reviewed papers in the field of pharmaceutical
sciences in national and international journals as well as 12 book chap-
ters. He received a bachelor’s degree in pharmacy from the University of
Rajasthan, Jaipur, India, and a Master of Pharmacy degree from the School
of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya,
xxiv About the Editors

Bhopal, India, with a specialization in pharmaceutics. His research inter-

ests encompass nutraceutical and functional foods, novel drug delivery
systems (NDDS), drug delivery, nanotechnology, health science/life sci-
ence, and biology/cancer biology/neurobiology.

Rajesh K. Kesharwani, PhD

Faculty, Department of Biotechnology, NIET, NIMS University, India

Rajesh K. Kesharwani, PhD, has more than seven years of research and
two years of teaching experience in various institutes of India, impart-
ing bioinformatics and biotechnology education. He has received sev-
eral awards, including the NASI-Swarna Jayanti Puruskar-2013 by The
National Academy of Sciences of India. He has authored over 32 peer-
reviewed articles and 10 book chapters. He has been a member of many sci-
entific communities as well as a reviewer for many international journals.
Dr. Kesharwani received a BSc in biology from Ewing Christian College,
Allahabad, India, an autonomous college of the University of Allahabad;
his MSc (Biochemistry) from Awadesh Pratap Singh University, Rewa,
Madhya Pradesh, India; and MTech-IT (specialization in Bioinformatics)
from the Indian Institute of Information Technology, Allahabad, India.
He earned his PhD from the Indian Institute of Information Technology,
Allahabad, and received a Ministry of Human Resource Development
(India) Fellowship and Senior Research Fellowship from the Indian
Council of Medical Research, India. His research fields of interest are
medical informatics, protein structure and function prediction, computer-
aided drug designing, structural biology, drug delivery, cancer biology,
and next-generation sequence analysis.
CHAPTER 1

INTRODUCTION TO
NANOTECHNOLOGY IN DRUG
DELIVERY
RAJ K. KESERVANI,1,* RAJESH K. KESHARWANI,2 and
ANIL K. SHARMA3
1
Faculty of Pharmaceutics, Sagar Institute of Research and
Technology-Pharmacy, Bhopal–462041, India, *E-mail: rajksops@
gmail.com
Department of Biotechnology, NIET, NIMS University, Shobha
2

Nagar, Jaipur, Rajasthan–303121, India

Delhi Institute of Pharmaceutical Sciences and Research,
3

University of Delhi, New Delhi–110017, India

CONTENTS

Abstract ..................................................................................................... 1
1.1 Introduction ...................................................................................... 2
1.2 Delivery Method/Routes of Administration for Nanoparticles ........ 4
1.3 Conclusion ..................................................................................... 12
Keywords ................................................................................................ 13
References ............................................................................................... 13

ABSTRACT

The science has been ever evolving and credit goes to the numer-
ous researchers working with a goal to enhance the quality of life.
2 Drug Delivery Approaches and Nanosystems: Volume 1

The nanoscience has become a boon to mankind by offering a number

of advantages over conventional drug formulations. This has subse-
quently led to rethink the game plan to battle against diseases/disorders.
The apparent benefit are reduction in adverse effects by offering site spe-
cific drug delivery, reduced dosing, access to small apertures too. Overall
the patient compliance has been observed to be improved upon use of
nanotechnology-based products. The present chapter focuses on general
aspects of nanotechnology and applications embracing manifold routes of
application.

1.1 INTRODUCTION

There’s plenty of room at the bottom is the title of a lecture in 1959 by

Richard Feynman, that introduced the concept of nanotechnology as
an important field for future scientific researches (Feynman, 1960).
Nanotechnology research can be developed to advances in communica-
tions, engineering, chemistry, physics, robotics, biology, and medicine.
Nanotechnology has been used in medicine for therapeutic drug delivery
and the development of treatments for a variety of diseases and disorders.
So, there are very significant advances in these disciplines.
Nanoparticles used as drug delivery vehicles are generally <100 nm
in at least one dimension, and consist of different biodegradable materials
such as natural or synthetic polymers, lipids, or metals. Nanoparticles are
taken up by cells more efficiently than larger micromolecules and there-
fore, could be used as effective transport and delivery systems. For thera-
peutic applications, drugs can either be integrated in the matrix of the
particle or attached to the particle surface. A drug targeting system should
be able to control the fate of a drug entering the biological environment.
Nanosystems with different compositions and biological properties have
been extensively investigated for drug and gene delivery applications
(Brannon-Peppas and Blanchette, 2004; Pison et al., 2006; Schatzlein,
2006; Stylios et al., 2005; Yokoyama 2005).
Recent years have witnessed unprecedented growth of research and
applications in the area of nanoscience and nanotechnology. There is
increasing optimism that nanotechnology, as applied to medicine, will
bring significant advances in the diagnosis and treatment of disease.
Introduction to Nanotechnology in Drug Delivery 3

Anticipated applications in medicine include drug delivery, both in

vitro and in vivo diagnostics, nutraceuticals and production of improved
biocompatible materials (Duncan, 2003; De Jong et al., 2005; ESF, 2005;
Ferrari, 2005).
Drug delivery systems can improve the properties of free drugs by
increase their in vivo stability and biodistribution, solubility and even by
modulation of pharmacokinetics, promoting the transport and even more
important the release of higher doses of the drug in the target site in order
to be efficient (Cai, 2008; De Jong and Borm, 2008; Drbohlavova et al.,
2013; Ghosh, 2008). As far as drug delivery is concerned, the most impor-
tant nanoparticle platforms are liposomes, polymer conjugates, metallic
nanoparticles (e.g., AuNPs), polymeric micelles, dendrimers, nanoshells,
and protein and nucleic acid-based nanoparticles (Davis et al., 2008;
Pathak et al., 2009).
The aims for nanoparticle entrapment of drugs are enhanced deliv-
ery to, or uptake by, target cells and/or a reduction in the toxicity of the
free drug to nontarget organs. Both situations will result in an increase of
therapeutic index, the margin between the doses resulting in a therapeu-
tic efficacy (e.g., tumor cell death) and toxicity to other organ systems.
For these aims, creation of long-lived and target-specific nanoparticles
is needed. Most of the compounds are biodegradable polymers result-
ing in drug release after degradation. One of the problems in the use of
particulate drug carriers including nanomaterials is the entrapment in
the mononuclear phagocytic system as present in the liver and spleen
(Demoy et al., 1997; Gibaud et al., 1996; Lenaerts et al., 1984; Moghimi
et al., 2001).
Nature is the ultimate in nanotechnology, producing nanostructures
that offer functional proteins and many other compounds at cellular level
of great significance to life on earth. It is thought that one of the functions
of proteins and compounds that exist at cellular level is that of nanotech-
nological separations. Biological systems are thought by some scientists to
have come about through a process of dynamic self-assembly comprising
separation and compartmentalization of many substances into the desired
pattern or device (Eijkel and Berg, 2006).
Research presently seeks systematic approaches to fabricate man-made
objects at nanoscale and to incorporate nanostructures into macrostructures
4 Drug Delivery Approaches and Nanosystems: Volume 1

as nature does (Roco, 1999, 2003; Smith, 2006). Such approaches and
concept – which may differ from the living systems in aqueous medium – as
self-assembly, templating of atomic and molecular structures on other nano-
structures, interaction on surfaces of various shapes, self-repair and integra-
tion on multiple length scales may be used as models (Roco, 1999, 2003).
Nanotechnology, being an interdisciplinary field, has three main exten-
sively overlapping areas: nanoelectronics, nanomaterials and nanobio-
technology which find applications in materials, electronics, environment,
metrology, energy, security, robotics, healthcare, information technology,
biomimetics, pharmaceuticals, manufacturing, agriculture, construction,
transport, and food processing and storage (Miyazaki and Islam, 2007;
Ochekpe et al., 2009; Shea, 2005; Tratnyek and Johnson, 2006).

1.2 DELIVERY METHOD/ROUTES OF ADMINISTRATION

FOR NANOPARTICLES

Several methods of drug administration were employed in delivery

nanotechnological product such as oral, injectables, transdermal, topical,
pulmonary, and nasal and implantable drug delivery system. Each delivery
system described in the following subsections in detail.

1.2.1 ORAL ADMINISTRATION

Oral drug delivery is the most widely used route of administration among
all the routes that have been explored for systemic delivery of drugs via
pharmaceutical products of different dosage form. Oral route is considered
most natural, convenient and safe due to its ease of administration, patient
acceptance, and cost effective manufacturing process. Pharmaceutical
products designed for oral delivery are mainly immediate release type or
conventional drug delivery systems, which are designed for immediate
release of drug for rapid absorption (Ummadi et al., 2013).
Oral administration is most preferred because of the various advan-
tages over other routes of drug delivery. The advantages include patient
convenience and compliance, which increase the therapeutic efficacy of
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Dying, his lord he own’d; view’d him all o’er
With eager eyes, then closed those eyes, well pleased.
Of lesser ills the Muse declines to sing,
Nor stoops so low; of these, each groom can tell
The proper remedy. But oh! what care,
What prudence, can prevent madness, the worst
Of maladies? Terrifick pest! that blasts
The huntsman’s hopes, and desolation spreads
Through all the unpeopled kennel, unrestrain’d;
More fatal than the envenom’d viper’s bite,
Or that Apulian spider’s poisonous sting,
Heal’d by the pleasing antidote of sounds.
When Sirius reigns, and the sun’s parching beams
Bake the dry gaping surface, visit thou
Each even and morn, with quick observant eye,
Thy panting pack. If, in dark sullen mood,
The glouting hound refuse his wonted meal,
Retiring to some close obscure retreat,
Gloomy, disconsolate; with speed remove
The poor infectious wretch, and in strong chains
Bind him, suspected. Thus that dire disease,
Which art can’t cure, wise caution may prevent.
But, this neglected, soon expect a change,
A dismal change, confusion, frenzy, death!
Or, in some dark recess, the senseless brute

BOOK IV THE CHASE v. 210-234.

Sits, sadly pining; deep melancholy,
And black despair, upon his clouded brow
Hang lowering; from his half-opening jaws,
The clammy venom, and infectious froth,
Distilling fall; and from his lungs, inflamed,
Malignant vapours taint the ambient air,
Breathing perdition; his dim eyes are glazed,
He droops his pensive head; his trembling limbs
No more support his weight; abject he lies,
Dumb, spiritless, benumb’d; till death, at last,
Gracious attends, and kindly brings relief.
Or, if outrageous grown, behold, alas!
A yet more dreadful scene; his glaring eyes
Redden with fury; like some angry boar,
Churning, he foams, and, on his back, erect
His pointed bristles rise; his tail incurved
He drops; and, with harsh broken howlings, rends
The poison-tainted air; with rough hoarse voice
Incessant bays, and snuffs the infectious breeze;
This way and that he stares, aghast, and starts
At his own shade; jealous, as if he deem’d
The world his foes. If haply toward the stream
He cast his roving eye, cold horrour chills
His soul; averse, he flies, trembling, appall’d:
Now frantick, to the kennel’s utmost verge,

BOOK IV THE CHASE v. 235-259.

Raving, he runs, and deals destruction round.
The pack fly diverse; for whate’er he meets,
Vengeful, he bites, and every bite is death.
If now, perchance, through the weak fence escaped,
Far up the wind he roves, with open mouth
Inhales the cooling breeze, nor man, nor beast,
He spares, implacable. The hunter-horse,
Once kind associate of his sylvan toils,
Who haply, now, without the kennel’s mound,
Crops the rank mead, and, listening, hears with joy
The cheering cry, that morn and eve salutes
His raptured sense, a wretched victim falls.
Unhappy quadruped! no more, alas!
Shall thy fond master with his voice applaud
Thy gentleness, thy speed; or with his hand
Stroke thy soft dappled sides, as he each day
Visits thy stall, well pleased: no more shalt thou
With sprightly neighings, to the winding horn
And the loud-opening pack, in concert join’d,
Glad his proud heart; for, oh! the secret wound,
Rankling, inflames; he bites the ground, and dies.
Hence to the village, with pernicious haste,
Baleful, he bends his course: the village flies,
Alarm’d; the tender mother, in her arms,
Hugs close the trembling babe; the doors are barr’d;

BOOK IV THE CHASE v. 260-282.

And flying curs, by native instinct taught,
Shun the contagious bane; the rustick bands
Hurry to arms, the rude militia seize
Whate’er at hand they find; clubs, forks, or guns,
From every quarter charge the furious foe,
In wild disorder and uncouth array;
Till now, with wounds on wounds, oppress’d and gored,
At one short poisonous gasp he breathes his last.
Hence, to the kennel, Muse, return, and view,
With heavy heart, that hospital of woe,
Where horrour stalks at large! insatiate death
Sits growling o’er his prey; each hour presents
A different scene of ruin and distress.
How busy art thou, fate! and how severe
Thy pointed wrath! the dying and the dead
Promiscuous lie; o’er these, the living fight
In one eternal broil; not conscious why,
Nor yet with whom. So drunkards, in their cups,
Spare not their friends, while senseless squabble reigns.
Huntsman! it much behoves thee to avoid
The perilous debate. Ah! rouse up all
Thy vigilance, and tread the treacherous ground
With careful step. Thy fires unquench’d preserve,

BOOK IV THE CHASE v. 283-307.

As erst the vestal flame; the pointed steel
In the hot embers hide; and if, surprised,
Thou feel’st the deadly bite, quick urge it home
Into the recent sore, and cauterize
The wound: spare not thy flesh, nor dread the event;
Vulcan shall save, when Æsculapius fails.
Here, should the knowing Muse recount the means
To stop this growing plague. And here, alas!
Each hand presents a sovereign cure, and boasts
Infallibility, but boasts in vain.
On this depend; each to his separate seat
Confine, in fetters bound; give each his mess
Apart, his range in open air; and then,
If deadly symptoms, to thy grief, appear,
Devote the wretch; and let him greatly fall,
A generous victim for the public weal.
Sing, philosophick Muse, the dire effects
Of this contagious bite on hapless man!
The rustick swains, by long tradition taught,
Of leeches old, as soon as they perceive
The bite impress’d, to the sea-coasts repair.
Plunged in the briny flood, the unhappy youth
Now journeys home, secure; but soon shall wish
The seas, as yet, had cover’d him beneath
The foaming surge, full many a fathom deep.

BOOK IV THE CHASE v. 308-332.

A fate more dismal, and superiour ills,
Hang o’er his head devoted. When the moon,
Closing her monthly round, returns again
To glad the night, or when, full-orb’d, she shines
High in the vault of heaven, the lurking pest
Begins the dire assault. The poisonous foam,
Through the deep wound instill’d, with hostile rage,
And all its fiery particles, saline,
Invades the arterial fluid; whose red waves
Tempestuous heave, and, their cohesion broke,
Fermenting boil; intestine war ensues,
And order to confusion turns, embroil’d.
Now the distended vessels scarce contain
The wild uproar, but press each weaker part,
Unable to resist: the tender brain
And stomach suffer most; convulsions shake
His trembling nerves, and wandering pungent pains
Pinch sore the sleepless wretch; his fluttering pulse
Oft intermits; pensive and sad, he mourns
His cruel fate, and to his weeping friends
Laments in vain: to hasty anger prone,
Resents each slight offence, walks with quick step,
And wildly stares: at last, with boundless sway,
The tyrant frenzy reigns; for, as the dog,
Whose fatal bite convey’d the infectious bane,

BOOK IV THE CHASE v. 333-356.

Raving, he foams, and howls, and barks, and bites!
Like agitations in his boiling blood,
Present like species to his troubled mind;
His nature, and his actions, all canine.
So, as old Homer sung, the associates wild
Of wandering Ithacus, by Circe’s charms
To swine transformed, ran gruntling through the groves,
Dreadful example to a wicked world!
See, there distress’d he lies! parch’d up with thirst,
But dares not drink; till now, at last, his soul
Trembling escapes, her noisome dungeon leaves,
And to some purer region wings away.
One labour yet remains, celestial Maid!
Another element demands thy song.
No more o’er craggy steeps, through coverts thick
With pointed thorn, and briers intricate,
Urge on, with horn and voice, the painful pack;
But skim, with wanton wing, the irriguous vale,
Where winding streams, amid the flowery meads,
Perpetual glide along, and undermine
The cavern’d banks, by the tenacious roots
Of hoary willows arch’d; gloomy retreat
Of the bright scaly kind; where they, at will,
On the green watery reed, their pasture, graze,

BOOK IV THE CHASE v. 357-381.

Suck the moist soil, or slumber at their ease,
Rock’d by the restless brook, that draws aslope
Its humid train, and laves their dark abodes.
Where rages not oppression? where, alas,
Is innocence secure? Rapine and spoil
Haunt even the lowest deeps; seas have their sharks;
Rivers and ponds inclose the ravenous pike;
He, in his turn, becomes a prey; on him
The amphibious otter feasts. Just is his fate,
Deserved; but tyrants know no bounds: nor spears
That bristle on his back, defend the perch
From his wide greedy jaws; nor burnish’d mail
The yellow carp; nor all his arts can save
The insinuating eel, that hides his head
Beneath the slimy mud; nor yet escapes
The crimson-spotted trout, the river’s pride,
And beauty of the stream. Without remorse,
This midnight pillager, ranging around,
Insatiate, swallows all. The owner mourns
The unpeopled rivulet, and gladly hears
The huntsman’s early call, and sees with joy
The jovial crew, that march upon its banks
In gay parade, with bearded lances arm’d.
This subtle spoiler of the beaver kind,
Far off perhaps, where ancient alders shade

BOOK IV THE CHASE v. 382-406.

The deep still pool, within some hollow trunk
Contrives his wicker couch; whence he surveys
His long purlieu, lord of the stream, and all
The finny shoals his own. But you, brave youths,
Dispute the felon’s claim; try every root,
And every reedy bank; encourage all
The busy spreading pack, that fearless plunge
Into the flood, and cross the rapid stream.
Bid rocks and caves, and each resounding shore,
Proclaim your bold defiance; loudly raise
Each cheering voice, till distant hills repeat
The triumphs of the vale. On the soft sand,
See there, his seal impress’d; and, on that bank,
Behold the glittering spoils, half-eaten fish,
Scales, fins, and bones, the leavings of his feast.
Ah! on that yielding sag-bed, see, once more
His seal I view. O’er yon dank rushy marsh
The sly goose-footed prowler bends his course,
And seeks the distant shallows. Huntsman! bring
Thy eager pack, and trail him to his couch.
Hark! the loud peal begins; the clamorous joy,
The gallant chiding, loads the trembling air.
Ye Naiads fair, who o’er these floods preside,
Raise up your dripping heads above the wave,
And hear our melody. The harmonious notes

BOOK IV THE CHASE v. 407-431.

Float with the stream; and every winding creek,
And hollow rock, that o’er the dimpling flood
Nods pendent, still improve, from shore to shore,
Our sweet reiterated joys. What shouts!
What clamour loud! What gay, heart-cheering sounds
Urge, through the breathing brass their mazy way!
Not choirs of Tritons glad, with sprightlier strains,
The dancing billows, when proud Neptune rides
In triumph o’er the deep. How greedily
They snuff the fishy steam, that to each blade,
Rank-scenting, clings! See! how the morning dews
They sweep, that from their feet, besprinkling, drop,
Dispersed, and leave a track oblique behind.
Now on firm land they range; then in the flood
They plunge tumultuous; or through reedy pools,
Rustling, they work their way: no holt escapes
Their curious search. With quick sensation now
The fuming vapour stings, flutters their hearts,
And joy, redoubled, bursts from every mouth,
In louder symphonies. Yon hollow trunk,
That, with its hoary head incurved, salutes
The passing wave, must be the tyrant’s fort,
And dread abode. How these impatient climb,
While others, at the root, incessant bay:
They put him down. See, there he dives along!

BOOK IV THE CHASE v. 432-456.

The ascending bubbles mark his gloomy way.
Quick fix the nets, and cut off his retreat
Into the sheltering deeps. Ah, there he vents!
The pack plunge headlong, and protended spears
Menace destruction: while the troubled surge
Indignant foams, and all the scaly kind,
Affrighted, hide their heads. Wild tumult reigns,
And loud uproar. Ah, there once more he vents!
See, that bold hound has seized him; down they sink
Together, lost: but soon shall he repent
His rash assault. See, there escaped, he flies,
Half-drown’d, and clambers up the slippery bank,
With ooze and blood distain’d. Of all the brutes,
Whether by nature formed, or by long use,
This artful diver best can bear the want
Of vital air. Unequal is the fight,
Beneath the whelming element. Yet there
He lives not long; but respiration needs,
At proper intervals: again he vents;
Again the crowd attack. That spear has pierced
His neck; the crimson waves confess the wound.
Fix’d is the bearded lance, unwelcome guest,
Where’er he flies; with him it sinks beneath,
With him it mounts; sure guide to every foe.
Inly he groans; nor can his tender wound

BOOK IV THE CHASE v. 457-480.

Bear the cold stream. Lo! to yon sedgy bank
He creeps, disconsolate: his numerous foes
Surround him, hounds, and men. Pierced through and through,
On pointed spears they lift him high in air;
Wriggling, he hangs, and grins, and bites in vain.
Bid the loud horns, in gaily-warbling strains,
Proclaim the felon’s fate; he dies, he dies!
Rejoice, ye scaly tribes; and, leaping, dance
Above the wave, in sign of liberty
Restored: the cruel tyrant is no more.
Rejoice, secure and bless’d; did not as yet
Remain, some of your own rapacious kind;
And man, fierce man, with all his various wiles.
O happy, if ye knew your happy state,
Ye rangers of the fields! whom nature boon
Cheers with her smiles, and every element
Conspires to bless. What, if no heroes frown
From marble pedestals; nor Raphael’s works,
Nor Titian’s lively tints, adorn our walls?
Yet these the meanest of us may behold;
And, at another’s cost, may feast at will
Our wondering eyes; what can the owner more?
But vain, alas! is wealth, not graced with power.
The flowery landscape, and the gilded dome,

BOOK IV THE CHASE v. 481-505.

And vistas opening to the wearied eye,
Through all his wide domain; the planted grove,
The shrubby wilderness, with its gay choir
Of warbling birds, can’t lull to soft repose
The ambitious wretch, whose discontented soul
Is harrow’d day and night; he mourns, he pines,
Until his prince’s favour makes him great.
See there he comes, the exalted idol comes!
The circle’s form’d, and all his fawning slaves
Devoutly bow to earth; from every mouth
The nauseous flattery flows, which he returns
With promises, that die as soon as born.
Vile intercourse! where virtue has no place.
Frown but the monarch, all his glories fade;
He mingles with the throng, outcast, undone,
The pageant of a day; without one friend
To sooth his tortured mind; all, all are fled.
For though they bask’d in his meridian ray,
The insects vanish, as his beams decline.
Not such our friends; for here no dark design,
No wicked interest, bribes the venal heart;
But inclination to our bosom leads,
And weds them there for life; our social cups
Smile, as we smile; open, and unreserved.
We speak our inmost souls; good humour, mirth,

BOOK IV THE CHASE v. 506-530.

 Soft complaisance, and wit from malice free,
Smooth every brow, and glow on every cheek.
O happiness sincere! what wretch would groan
Beneath the galling load of power, or walk
Upon the slippery pavements of the great,
Who thus could reign, unenvied and secure?
Ye guardian powers, who make mankind your care,
Give me to know wise nature’s hidden depths,
Trace each mysterious cause, with judgment read
The expanded volume, and, submiss, adore
That great creative will, who, at a word,
Spoke forth the wonderous scene. But if my soul
To this gross clay confined, flutters on earth
With less ambitious wing; unskill’d to range
From orb to orb, where Newton leads the way;
And, view with piercing eyes, the grand machine;
Worlds above worlds, subservient to his voice;
Who, veil’d in clouded majesty, alone
Gives light to all; bids the great system move,
And changeful seasons, in their turns, advance,
Unmoved, unchanged himself: yet this, at least,
Grant me propitious, an inglorious life,
Calm and serene, nor lost in false pursuits
Of wealth or honours; but enough to raise
My drooping friends, preventing modest want

BOOK IV THE CHASE v. 531-536.

That dares not ask. And if, to crown my joys,

Ye grant me health, that, ruddy in my cheeks,
Blooms in my life’s decline; fields, woods, and streams,
Each towering hill, each humble vale below,
Shall hear my cheering voice; my hounds shall wake
The lazy morn, and glad the horizon round.
Printed by W. Bulmer and Co.
Cleveland-row, St. James’s.
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