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Engineering of
Nanobiomaterials
Applications of
Nanobiomaterials
Engineering of
Nanobiomaterials
Applications of
Nanobiomaterials
Edited by
Alexandru Mihai Grumezescu
Department of Science and Engineering of Oxide Materials and
Nanomaterials, Faculty of Applied Chemistry and Materials Science,
University Politehnica of Bucharest, Romania
Department of Biomaterials and Medical Devices, Faculty of Medical

Engineering, University Politehnica of Bucharest, Romania
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List of contributors
N. Başaran Mutlu Ağardan

Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern
University, Boston, MA, USA; Department of Pharmaceutical Technology, Gazi
University Faculty of Pharmacy, Ankara, Turkey
Udita Agrawal
Department of Pharmaceutical Sciences, Dr. H. S. Gour Vishwavidyalaya,
Sagar, Madhya Pradesh, India
Kandasubramanian Balasubramanian
Department of Materials Engineering, Defence Institute of Advanced
Technology, Ministry of Defence, Girinagar, Pune, India
Eva Baldikova
Department of Nanobiotechnology, Institute of Nanobiology and Structural
Biology of GCRC, Ceske Budejovice, Czech Republic
Ana M.S. Cardoso
CNC Center for Neuroscience and Cell Biology, University of Coimbra,
Coimbra, Portugal
Mustafa Doğan
Department of Electrical and Electronics Engineering, Baskent University,
Ankara, Turkey
Surbhi Dubey
Maryam Ghaffari
Biomaterials Group, Amirkabir University of Technology, Tehran, Iran
Dhanaraj Gopi
Department of Chemistry, Periyar University, Salem, Tamilnadu, India; Centre
for Nanoscience and Nanotechnology, Periyar University, Salem, Tamilnadu,
India
Sias Grobler
University of the Western Cape, Oral and Dental Research Institute, Faculty of
Dentistry, Private Bag X1, Tygerberg, South Africa
Xuesong Han
School of Mechanical Engineering, Tianjin University, Tianjin, China
xv
xvi List of contributors
John G. Hardy
Lancaster University, Department of Chemistry and Materials Science Institute,
Lancaster, England
Vladislav G. Il’ves
Institute of Electrophysics, Ural Branch of the Russian Academy of Sciences,
Yekaterinburg, Russia; Ural Federal University, Yekaterinburg, Russia
Pravin Jagadale
Department of Applied Science and Technology (DISAT) Politecnico di Torino,
Torino, Italy
Hyo-Eon Jin
Physical Biosciences Division, Lawrence Berkeley National Laboratory
Berkeley, CA, USA; Department of Bioengineering, University of California,
Berkeley, CA, USA
Anjali Joshi
Centre for Nanoscience and Nanotechnology, U.I.E.A.S.T, Panjab University,
Chandigarh, India
Amália S. Jurado
Coimbra, Portugal; Department of Life Sciences, University of Coimbra,
Coimbra, Portugal
Okan Karatay
Department of Electrical and Electronics Engineering, Baskent University,
Ankara, Turkey
Louis Kavitha
Department of Physics, School of Basic and Applied Sciences, Central
University of Tamil Nadu, Thiruvarur, Tamilnadu, India
Seung-Wuk Lee
Physical Biosciences Division, Lawrence Berkeley National Laboratory
Berkeley, CA, USA; Department of Bioengineering, University of California,
Berkeley, CA, USA
M. Luı́sa do Vale
UCIBIO/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of
Science, University of Porto, Porto, Portugal
Zdenka Maderova
Eduardo F. Marques
Centro de Investigação em Quı́mica, Department of Chemistry and
Biochemistry, Faculty of Science, University of Porto, Porto, Portugal
List of contributors xvii
David K. Mills
School of Biological Sciences and the Center for Biomedical Engineering and
Rehabilitation Science (CBERS), Louisiana Tech University, Ruston, LA, USA
Nishi Mody
Masoud Mozafari
Bioengineering Research Group, Nanotechnology and Advanced Materials
Department, Materials and Energy Research Center (MERC), Tehran, Iran
Sina Moztarzadeh
Goldie oza
Department of Electrical Engineering (SEES), CINVESTAV-IPN, Mexico City, DF,
Mexico
Maria C. Pedroso de Lima
Coimbra, Portugal
Tamara Perchyonok
Research Development and Innovation, VTPCHEM PTY LTD, Gold Coast,
QLD, Australia
Kristyna Pospiskova
Regional Centre of Advanced Technologies and Materials, Palacky University,
Olomouc, Czech Republic
Fuzhan Rahmanian
Durairajan Rajeswari
Department of Chemistry, Periyar University, Salem, Tamilnadu, India;
Department of Physics, Periyar University, Salem, Tamilnadu, India
Arash Ramedani
Institute for Nanoscience & Nanotechnology (INST), Sharif University of
Technology, Tehran, Iran
Subramanian Ramya
Department of Chemistry, Periyar University, Salem, Tamilnadu, India
Manisekaran Ravichandran
Program on Nanoscience and Nanotechnology, CINVESTAV-IPN, Mexico City,
DF, Mexico
Vanessa Reher
School of Dentistry and Oral Health, Griffith University, Australia
xviii List of contributors
Ivo Safarik
Biology of GCRC, Ceske Budejovice, Czech Republic; Regional Centre of
Advanced Technologies and Materials, Palacky University, Olomouc, Czech
Republic
Mirka Safarikova
Rajeev Sharma
Sandra G. Silva
Centro de Investigação em Quı́mica, Department of Chemistry and
Biochemistry, Faculty of Science, University of Porto, Porto, Portugal
Narinder Singh
Dr SS Bhatnagar University Institute of Chemical Engineering & Technology,
Panjab University, Chandigarh, India
Sergey Yu. Sokovnin
Institute of Electrophysics, Ural Branch of the Russian Academy of Sciences,
Yekaterinburg, Russia; Ural Federal University, Yekaterinburg, Russia
Steven Tom
Department of Materials Science and Engineering, University of California,
Berkeley, CA, USA; Physical Biosciences Division, Lawrence Berkeley National
Laboratory Berkeley, CA, USA
Vladimir P. Torchilin
Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern
University, Boston, MA, USA; Department of Biochemistry, King Abdulaziz
University, Jeddah, Saudi Arabia
Subramaniam Velumani
Department of Electrical Engineering (SEES), CINVESTAV-IPN, Mexico City, DF,
Mexico; Program on Nanoscience and Nanotechnology, CINVESTAV-IPN,
Mexico City, DF, Mexico
Gaurav Verma
Dr SS Bhatnagar University Institute of Chemical Engineering & Technology,
Panjab University, Chandigarh, India; Centre for Nanoscience and
Nanotechnology, U.I.E.A.S.T, Panjab University, Chandigarh, India;
Department of Chemical Engineering, Massachusetts Institute of Technology,
Cambridge, MA, USA
List of contributors xix
Dr. Suresh P. Vyas

Ramdayal Yadav
Department of Materials Engineering, Defence Institute of Advanced
Technology, Ministry of Defence, Girinagar, Pune, India
Abolfazl Yazdanpanah
Michael G. Zuev
Ural Federal University, Yekaterinburg, Russia; Institute of Solid State
Chemistry, Ural Branch of the Russian Academy of Sciences, Yekaterinburg,
Russia
Preface of the series
The era of nanosized materials is now considered the center of the evolution of
future tools and emerging technologies with wide applications in industry,
research, health, and beyond. Despite recent scientific progress, biological appli-
cations of nanomaterials are far from being depleted and current knowledge is
limited by the poor access to significant data, but also by widespread and usually
unfounded speculation. Although exhaustive, the current literature is difficult to
reach and understand because of the specificity and strict focuses of researchers
investigating different applications of nanomaterials.
In this context, the scientific series entitled “Applications of Nanobiomaterials”
was motivated by the desire of the Editor, Alexandru Mihai Grumezescu, and
others to bring together comprehensive, up-to-date and relevant findings on the
field of biological applications of nanostructure materials, to promote the knowl-
edge and expand our vision regarding future perspectives. Even though the
approached domain is quite specific and research-oriented, this multivolume set is
easily intelligible for a wide audience including: under-graduate and post-graduate
students, engineers, researchers, academic staff, pharmaceutical companies, bio-
medical sector, and industrial biotechnologies. However, some basic knowledge of
the field of materials science (nanobiomaterials, pharmaceutical industry, products
for medicinal treatments, nanoarchitectonics for delivery of biological active mole-
cules and release, bone implants and stomatology) and engineering is a requisite
for understanding technical aspects.
The selected authors of each chapter are outstanding specialists in the field of
nanobiomaterials, who have made impressive contributions in a specific area of
research or applied area within the scope of this book.
Each of the 11 volumes of the series contains 15 chapters, addressing the most
relevant and recent matters on the field of the volume.
The first volume, Fabrication and Self-Assembly of Nanobiomaterials, intro-
duces the reader to the amazing field of nanostructured materials and offers inter-
esting information regarding the fabrication and assembly of these nanosized
structures. In Volume II, entitled Engineering of Nanobiomaterials, readers can
easily find the most commonly investigated methods and approaches for obtaining
tailored nanomaterials for a particular application, especially those with a great
deal of significance in the biomedical field. In the following step, readers will dis-
cover the importance and the ways of modifying the surface of nanostructured
materials to obtain bioactive materials, by reading Volume III, Surface Chemistry
of Nanobiomaterials. Starting with Volume IV Nanobiomaterials in Hard Tissue
Engineering and Volume V Nanobiomaterials in Soft Tissue Engineering the bio-
medical applications of engineered nanomaterials are revealed and discussed,
focusing on one of the most impacted fields, tissue engineering. Volume VI,
Nanobiomaterials in Antimicrobial Therapy, highlights the potential of different
xxi
xxii Preface of the series
nanostructured materials to be utilized in the development of novel efficient

antimicrobial approaches to fight the global crisis of antibiotic inefficiency and
emerging infectious diseases caused by resistant pathogens. Volume VII moves
on to another key biomedical domain—cancer therapy. This volume,
Nanobiomaterials in Cancer Therapy, describes current issues of cancer therapy
and discusses the most relevant findings regarding the impact of nanobiomaterials
in cancer management. Medical Imaging represents the focus of Volume VIII,
while Volume IX deals with applications of Nanobiomaterials in Drug Delivery.
Volume X, entitled Nanobiomaterials in Galenic Formulations and Cosmetics,
refers to the perspectives highlighted by the utilization of nanosized functional
biomaterials in the development of improved drugs and active principles for differ-
ent biomedical industries. Finally, Volume XI is dedicated to the impact of
Nanobiomaterials in Dentistry, which currently represents one of the most investi-
gated and controversial domains related to the biomedical applications of
nanostructured materials.
Due to their specific organization, each volume can be treated individually or
as a part of this comprehensive series, which aims to bring a significant contribu-
tion to the field of research and biomedical applications of nanosized engineered
materials.
Ecaterina Andronescu
Department of Science and Engineering of Oxide Materials and Nanomaterials
Faculty of Applied Chemistry and Materials Science
University Politehnica of Bucharest, Bucharest, Romania
Preface
ABOUT THE SERIES (VOLUMES I XI)

The increased fabrication of nanosized materials with applications in the biomedi-
cal field by using biomimetic and bio-inspired processes and formulations, has
recently led to a new concept, named nanobiotechnology. This complex research
and applicative field brings together significant knowledge from physical, chemi-
cal, biological, and technological sciences.
Medical applications of nanobiomaterials range from the development of ade-
quate scaffolds for tissue engineering to therapeutic nanostructures, such as tar-
geted drug delivery systems. The purpose of this multivolume set entitled
Applications of Nanobiomaterials is to offer a broad, updated, and interdisciplin-
ary point of view regarding the application of these “materials of the future medi-
cine,” starting with their fabrication, specific engineering and characterization and
ending with the most investigated applications such as tissue engineering, antimi-
crobial, and cancer therapies, and the development of different medical and cos-
metic use products. These books brings together the work of outstanding
contributors who have significantly enhanced the basic knowledge and applicative
concepts of this research field in their respective disciplines.
The multivolume set entitled Applications of Nanobiomaterials contains 165
chapters, organized into 11 volumes which are ready to present a novel and up-
to-date approach related to this intriguing domain developed in the last years.
Each chapter was carefully composed and illustrated to highlight the relevance of
nanobiomaterials on most biomedical fields, revealing the most recent applica-
tions on a specific domain. The whole set represents a great material for the aca-
demic community, starting with undergraduate and postgraduate students,
researchers, engineers, and medical doctors, but also pharmaceutical companies
and innovative biotechnological settings.
These 11 volumes cover almost all aspects related to the applications of nano-
biomaterials and are named as follows:
Volume I: Fabrication and Self-Assembly of Nanobiomaterials
Volume II: Engineering of Nanobiomaterials
Volume III: Surface Chemistry of Nanobiomaterials
Volume IV: Nanobiomaterials in Hard Tissue Engineering
Volume V: Nanobiomaterials in Soft Tissue Engineering
Volume VI: Nanobiomaterials in Antimicrobial Therapy
Volume VII: Nanobiomaterials in Cancer Therapy
Volume VIII: Nanobiomaterials in Medical Imaging
Volume IX: NanobBiomaterials in Drug Delivery
Volume X: Nanobiomaterials in Galenic Formulations and Cosmetics
Volume XI: Nanobiomaterials in Dentistry
xxiii
xxiv Preface
ABOUT THIS BOOK

Volume II, Engineering of Nanobiomaterials, provides an up-to-date approach
about the engineering and distinct applications of the most utilized nanobiomater-
ials designed from organic or inorganic raw materials.
Engineered nanobiomaterials are currently offering promising alternatives in
many biomedical applications, such as antibacterial therapy, biosensors, cancer
therapy, stimuli-responsive drug release, drug delivery, gene therapy, and visual
prostheses.
The great number of nanotechnology applications on the biomedical field is
the motivation behind this volume, to summarize current research findings con-
cerning the engineering of nanobiomaterials. Volume II contains 15 chapters, pre-
pared by outstanding international researchers from Canada, the United States of
America, Germany, Poland, Ukraine, Israel, India, and China.
In Chapter 1, entitled Engineering of stimuli-sensitive nanopreparations to
overcome physiological barriers and cancer multidrug resistance, Ağardan et al.,
present the advantages of nanopreparations (liposomes, micelles, and polymeric
nanoparticles) with functional moieties to facilitate prolonged circulation, target-
ability, enhanced intracellular penetration, and stimuli-sensitivity. The microenvi-
ronment of the tumors (reduced pH, increased local temperature, and altered
redox status) is a guideline for the design of stimuli-sensitive drug-delivery sys-
tems. The authors also discuss the most important causes of ineffective che-
motheraphy and multidrug resistance.
Sokovnin et al., in Chapter 2, entitled Production of complex metal oxide
nanopowders using pulsed electron beam in low-pressure gas for biomaterials
application, give an overview about nanopowders of a pure and metal doped
oxide produced by a pulsed electron beam evaporation method in low-pressure
gas for biomaterials application.
Chapter 3, Bioabsorbable engineered nanobiomaterials for antibacterial ther-
apy, presents the current knowledge of nanofiber fabrication techniques for the
development of technical and medical textiles which exhibit antimicrobial proper-
ties and are tailored for stimuli-responsive drug release.
In the Chapter 4, Organic electronic materials for gene delivery, the authors
discuss the potential of organic electronic materials (i.e., fullerenes, graphenes,
and conjugated polymers) to be utilized as nonviral gene delivery vectors and as
novel theranostic devices. These represent an exciting new class of nonviral vec-
tors that are at the frontier of novel approaches towards gene therapy.
Safarik et al., in Chapter 5, Magnetic modification of cells, focus their atten-
tion on the presentation of available procedures used to prepare magnetically
responsive cells from originally diamagnetic precursors. Immunomagnetic techni-
ques have become widely used tools in cell biology, medicine, and microbiology.
The unique properties of magnetically responsive cells enable their selective mag-
netic separation, MRI imaging, cancer treatment, etc. Cell labeling methods using
Preface xxv
magnetic particles have been widely developed, usually showing no adverse effect
on cell proliferation and functionalities while conferring magnetic properties to
various cell types.
In Chapter 6, Aptamers as functional bionanomaterials for sensor applica-
tions, Tom et al., present an up-to-date review focused on the development of
aptamers as recognition elements. The authors also describe their incorporation
into materials and sensor devices, with the ultimate goal of detecting various
chemical and biological targets with high sensitivity and selectivity.
Cardoso et al., in Chapter 7, entitled Gene delivery mediated by gemini surfac-
tants: structure activity relationships, describe the structural characteristics of gem-
ini surfactants that are correlated with their biological impact on cells, in terms of
adverse effects produced and with capacity to deliver and promote the expression of
nucleic acids. Examples from the literature illustrate the ability of these complexes
to circumvent biological barriers associated with the different steps leading to gene
expression, with emphasis on membrane translocation and endosomal escape.
Chapter 8, Nanobiomaterials for bionic eye: vision of the future, discusses the
current role of nanobiomaterials in visual prosthesis progress and touches on the
future possibilities of this technology.
Perchyonok et al., in Chapter 9, Bioactive-functionalized interpenetrating
network hydrogel (BIOF-IPN), reveal the advances in basic material science,
biotechnology, and designer functional materials. It has the specific aim of
exploiting molecular mechanistics, understanding of conventional free radicals
towards finding, and harnessing a broad range of biologically relevant processes
such as bio-adhesion, biocompatibility, biorepair, and topical drug delivery. The
advantage of the novel intelligent designed functional material—BIOF-INP—is
its amalgamation of molecular design, mechanism, bioanalytical advancement,
and molecular biology. Furthermore, it presents the ability to easily refocus the
aim of the problem, making its applications only limited by the imagination.
Singh et al., in Chapter 10, Engineered nanomaterials for biomedicine:
advancements and hazards, describe the ways in which the interaction of nanoma-
terials with biomolecules can be controlled for beneficial biomedical applications.
This chapter highlights different types of engineered nanomaterials currently used
in biomedical applications and provides a critical overview of the recent advance-
ments and their potential hazards and drawbacks.
Han et al., in Chapter 11, Mechanism of nanomachining semiconductor and
ceramic blades for surgical applications, investigate the mechanisms of ductile
machining ceramic/silicon using DEM/MD method.
Chapter 12, Design and implementation of an electrospinning system, aims
to provide a brief introduction to the electrospinning process for obtaining nanofi-
bers by using personalized, up-to-date novel modeling techniques. Moreover,
the feasibility of suppressing the bending instability due to the complicated
oscillations of a polymer jet was investigated with experimental observations and
mathematical models are also developed.
xxvi Preface
Sharma et al., in Chapter 13, Engineered nanoparticles as a precise delivery

system in cancer therapeutics, summarize the recent advancement of nanoparticle
engineering for tumor-targeted therapies, including theranostic applications, clini-
cal trials, and recent patents.
Oza et al., in Chapter 14, Inorganic nanoflotillas as engineered particles for
drug and gene delivery, highlight the techniques used for nanocrystalline synthe-
sis, advanced processing by polymers, such as antibodies, attachment of drug/
genes, and delivery of such engineered nanoparticles at the desired site. They pos-
sess capabilities of integrating different functionalities like provision of effective
contrast for imaging modalities, synaptic delivery, and thermal therapies. This
chapter is an endeavor towards comprehension of complex nanostructures which
are emerging as a future avenue for nanomedicine.
Gopi et al., in Chapter 15, Chemical and green routes for the synthesis of multi-
functional pure and substituted nanohydroxyapatite for biomedical applications,
discuss the synthesis methods of pure and substituted nano-hydroxyapatite through
various chemical and green routes for multidirectional biomedical applications.
Alexandru Mihai Grumezescu

Department of Science and Engineering
of Oxide Materials and Nanomaterials,
University Politehnica of Bucharest,
Romania
Department of Biomaterials and Medical Devices,
Faculty of Medical Engineering,
University Politehnica of Bucharest,
Romania
http://grumezescu.com/
CHAPTER
Engineering of
stimuli-sensitive
nanopreparations to
overcome physiological
1
barriers and cancer
multidrug resistance
N. Başaran Mutlu Ağardan1,2 and Vladimir P. Torchilin1,3

1
Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston,
MA, USA 2Department of Pharmaceutical Technology, Gazi University Faculty of Pharmacy,
Ankara, Turkey 3Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia
1.1 INTRODUCTION
Cancer is a major health problem worldwide in terms of mortality and morbidity.
The main therapeutic approach in clinics for the treatment of both localized and
metastatic tumors is chemotherapy. Although chemotherapy is the most common
approach, the crucial problem is that anticancer drugs often lack specificity and
selectivity for cancer cells. Since the cancer therapeutics are highly hydrophobic
and cytotoxic, they fail in the treatment because of a lack of effectiveness and
side effects. In addition to the toxicity that is generally observed in rapidly divid-
ing cells in the body (such as hair, spleen, liver), many widely used chemothera-
peutics include solvents (such as castor oil and polysorbate 80) to provide drug
solubility which is a key factor for systemic/intravenous administration. These
solvents are known to be directly involved with adverse effects. Currently,
conventional chemotherapeutics are substantially limited by (i) systemic cytotox-
icity, (ii) insufficient ability to bypass biological barriers, (iii) poor biodistribution
and nonspecific delivery, and (iv) development of drug resistance.
Nanotechnology, although not a new concept, has gained significant momentum
in the past few decades, especially in the area of cancer research. Briefly, the
expected features of an effective nanoparticulate system are selective accumulation
Engineering of Nanobiomaterials. DOI: http://dx.doi.org/10.1016/B978-0-323-41532-3.00001-4

© 2016 Elsevier Inc. All rights reserved.
1
2 CHAPTER 1 Engineering of stimuli-sensitive nanopreparations
in the target tissue/organ and an ability to penetrate target cells with loaded drug.
Although nanoparticulate drug delivery systems have several advantages over
conventional therapeutics such as increasing drug stability in vivo and blood circu-
lation time, it has been established that only a small fraction of an administered
dose reaches the tumor site for its intended effect. The primary reasons for an
inability to reach the target site selectively are physiological and cellular barriers.
They are the main protective mechanisms which limit access to organs/tissues.
Additionally, the failure of conventional chemotheraphy is often directly associated
with multidrug resistance (MDR), which is most frequently caused by insufficient
drug concentration at the tumor site. When tumors are exposed to nonoptimal
amounts of drug, they often develop resistance. Higher doses of drug are then
needed to elicit a therapeutic response.
Tumor cells have some unique properties and a microenviroment which is
perhaps more heterogeneous than the other cells of the body. Stimuli-sensitive
drug delivery systems can be engineered based on the specific properties of the
tumor microenvironment, including reduced pH, increased local temperature,
altered redox status, and enzyme activities. This chapter focuses on the
development of stimuli-sensitive nanopreparations with the ability to overcome
physiological barriers and cancer MDR.
1.2 BARRIERS IN DRUG DELIVERY

The key factor for a successful drug delivery system is reaching the target area
selectively with the loaded drug. Therefore, the drug delivery system has to be
stable in blood and be transported across the barriers to reach target cells. The
body has developed many offensive and defensive mechanisms to remove foreign
materials such as bacteria, viruses, medical devices, and drugs. Hence, compre-
hension of the barriers of the body is crucial for engineering of nanoparticulate
drug delivery systems. The barriers can be classified into two main parts as:
physiological and cellular barriers.
1.2.1 PHYSIOLOGICAL BARRIERS

1.2.1.1 The mononuclear phagocyte system—opsonization
Stability of the drug delivery system in the systemic circulation is the first neces-
sity. Blood is a dynamic fluid which contains many proteins (albumin, fibrinogen,
complement system proteins, etc.), enzymes, and immune cells. When nanoparti-
cles enter the systemic circulation, the plasma proteins can bind unselectively and
reversibly on their surface. This adsorption process, “opsonization,” determines
the fate of the drug carriers’ pharmocokinetics and pharmacological effects. The
opsonization process permits macrophages of the mononuclear phagocytic system
(MPS) (also known as the reticuloendothelial sytem or RES) to readily recognize
1.2 Barriers in Drug Delivery 3
and eliminate the drug carrier before it reaches its target site (Owens and Peppas,
2006; Serpe, 2006). Once nanoparticles are coated with plasma proteins (opso-
nized), the macrophages of the liver (Kupffer cells) and spleen rapidly take up
these particles.
The physiochemical characteristics of nanoparticles such as shape, size,
charge, and surface chemistry are determinative for opsonization and clearence
(Kiwada, 1997; Dobrovolskaia et al., 2008; Albanese et al., 2012). To be effec-
tive, the nanoparticulate drug delivery systems must be camouflaged so as to be
unrecognized by the MPS and to avoid phagocytosis by macrophages.
The most common approach to avoid MPS effects and obtain prolonged circula-
tion times by minimizing clearence is by coating nanoparticulate systems with
hydrophilic polymers such as poly(ethylene glycol) (Gref et al., 1995; Storm et al.,
1995). This type of polymer forms dense “conformational clouds” which deny
surface interaction of drug delivery systems (i.e., liposomes, nanoparticles, poly-
meric micelles, dendrimers, quantum dots) with macromolecules (Torchilin and
Trubetskoy, 1995), although, it has been noted that repetitive administration of
pegylated nanoparticles may cause immunogenic responses where the production of
antibodies can promote the blood clearance of nanoparticles. This is known as the
accelerated blood clearance (ABC) phenomenon and is demonstrated for clinically
used pegylated liposomes (Ishida et al., 2006; Abu Lila et al., 2013).
1.2.1.2 Tumor vasculature and nanoparticle extravasation

There are three main subcompartments for healthy and neoplastic tissues: vascular,
interstitial, and cellular (Jain, 1987). After escaping from the MPS, a nanoparticu-
late system has to pass through the vascular endothelial layer to reach the interstitial
compartment. The most important factors that affect the flow of particles through
the vasculature are the rate of blood flow and vascular morphology. In normal
tissues, there is a balanced array of proangiogenic and antiangiogenic molecules,
which provides for an efficient and regular network of blood vessels to supply the
metabolic demands of the tissue. It is known that, in comparision to normal tissues,
blood vessel systems of tumor tissues are highly different and irregular (Cairns
et al., 2006; Baxter and Jain, 1990). Until they reach a diameter of 12 mm,
tumors can use the vasculature of their host tissues to provide their nutrient and
oxygen supplies by passive diffusion (Nishida et al., 2006). In time, cancerous
tissues grow along with their metabolic demands. At this point, tumors orchestrate
the building of their own vasculature system by recruiting surrounding mature
blood vessels which sprout new blood vessel capillaries for themselves. This angio-
genic process is a very important factor in the progress of cancer and is determina-
tive for metastasis (Kerbel, 2000). Tumors express high levels of endogenous
angiogenic factors including cytokines, vascular endothelial growth factor (VEGF),
and transforming growth factor (TGF)-α, which activate surrounding cells for initi-
ation and maintenance of enhanced angiogenesis (Weis and Cheresh, 2011).
The main structural abnormalities of the tumor vasculature, referred to as
“vascular chaos,” can be divided into three main types. First, they have an
1.3 Stimuli-Sensitive Nanopreparations 15
cyclization by two-electron reduction, either chemically or enzymatically. Paclitaxel

was loaded into these polymeric nanoparticles and a triggered release of paclitaxel
was observed by sodium dithionite-mediated reduction (Cho et al., 2012).
1.3.3 ENZYME-SENSITIVE NANOPREPARATIONS

In the past few decades, many biomedical research efforts have been made to
understand the molecular events that occur during carcinogenesis and the signal-
ing pathways participating in cancer progression. The interactions between tumor
cells and the tumor microenvironment play a pivotal role in this process.
Overexpression of certain enzymes is found to be associated with MDR. Thus,
enzyme-sensitive drug delivery to tumors is recognized as a promising strategy
(Gillet and Gottesman, 2010).
ECM remodeling proteinases, such as matrix metalloproteinases (MMPs), are
the main mediators of the changes in the microenvironment which exist during can-
cer progression. MMP activity, especially MMP-2 and MMP-9, contributes to
tumor growth and differentiation, the multistep processes of tumor angiogenesis,
invasion, and metastasis including proteolytic degradation of the ECM, alteration of
the cellcell and cellECM interaction, migration, and angiogenesis (Egeblad and
Werb, 2002; Folgueras et al., 2004; Kessenbrock et al., 2010; Gialeli et al., 2011).
The alterations in certain local enzymes’ expression and composition (such as
MMPs) can be considered biomarkers for cancer diagnosis and prognosis.
Additionally, these alterations provide an opportunity to engineer drug delivery sys-
tems that release their drug payloads via enzyme-triggered mechanisms at the
tumor site. Yamada and coworkers designed two different nanopreparations by con-
jugating paclitaxel at different sites (the 20 - and 7-hydroxyl groups to glutamine’s
C-terminus) to an octapeptide Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln known to be selec-
tively and efficiently hydrolyzed by MMP2 at tumors. The concentrations needed
to arrest the cell cycle in the G2/M phase were 100-fold higher with free paclitaxel
compared to PTX-20 AcG. PTX is known to be highly hydrophobic, and its cyto-
toxic effect is limited by its poor solubility. The cause of the increased activity of
PTX-AcG was suggested to be due to the increased solubility of paclitaxel with the
octapeptide. In in vivo results, the mice treated with PTX-AcG had more and larger
areas of necrosis and fewer proliferating cells in tumor sections than mice treated
with paclitaxel, indicating the binding and activation of the conjugate by MMP2 at
the tumor sites. This suggested that the development of drug resistance, the spread
of metastases, and the side effects resulting from prolonged exposure of the patient
to the PTX may be reduced by a high-impact first-line therapy with targeted
delivery of PTX (Yamada et al., 2010). A self-assembling, MMP2-sensitive, TATp-
modified micellar nanopreparation composed of the paclitaxel prodrug (PEG2000-
peptide-PTX) and two other polymers, TATp-PEG1000-phosphoethanolamine (PE)
(a cell-penetrating enhancer) and PEG1000-PE (a nanocarrier building block) was
formulated in an aqueous environment with high paclitaxel loading by Zhu and his
group. PTX was located in the hydrophobic “core,” covered and protected by a
Another random document with
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mention of “legislatures” implies no “grant.” On the contrary it is a
command to these “legislatures,” representing the members of the
union of states. The command comes from the superiors of the
states, the “conventions” of the whole American people.
It is not the only command which the “conventions” of that one
people made to the states and their “legislatures.” How absurd to
imply from that command that it is a “grant” of power to those
commanded governments, giving them omnipotence over every
human freedom of the American people who made the command!
We know what Madison told the Americans in the “conventions,”
when he asked them to make his Fifth Article. He told them that it
was a “mode of procedure” in which either the general government
or the state governments could originate, by proposal, the
introduction of changes into the Constitution which is both national
and federal. He pointedly did not tell those Americans that the Fifth
Article is a “grant” of any ability to the state governments to make
national Articles and he pointedly did not tell them that it is a “grant”
of ability to anyone to make any Articles.
Why then was it necessary for the leading brief, in support of the
Eighteenth Amendment, to add to Madison’s explanation of his own
Fifth Article (the explanation that it was a “mode of procedure”) the
absurd statement that it was a “grant” from the “conventions” to the
“conventions” and the state legislatures of power to make
Amendments? Why then was it necessary that this brief, speaking of
the Fifth Article, should say: “The people thus ordained the mode of
Amendment,” exactly what Madison said, “and in their own interest
they established this power of Amendment”—exactly what Madison
pointedly omitted to state to the Americans he asked to make the
Fifth Article?
The answer is simple. Without adding to the Madison statement
what he pointedly omitted to state, without stating the addition as
axiomatic, Hughes could not even begin any argument for the
Eighteenth Amendment.
The statement which Hughes adds to that of Madison is a
statement which flatly contradicts everything we have heard in the
“conventions.” It flatly contradicts everything the Americans did from
1775 on. It flatly contradicts the Tenth Amendment declaration that
the Fifth Article gives no power whatever to the states or their
governments. The added statement is sheer “nonsense,” assumed
and asserted as axiomatic fact.
And, during the last five years, how has every argument against
the Eighteenth Amendment met the “nonsense” of the assumption
that the Fifth Article is a “grant?” In no way at all, except by
assuming and asserting the same “nonsense,” and by then
undertaking to prove another absurdity, namely, that the Fifth Article
does not relate to the making of fundamental changes because the
imaginary “grant” is limited in extent and does not include power to
take away from the importance of the respective political entities
which are the states.
Let no American citizen make any mistake as to this one fact. In
no argument either for or against the Eighteenth Amendment has
there been any challenge to the sheer assumption that the Fifth
Article is a “grant” of ability to make changes in the Constitution
which is both federal and national. On the contrary, in every
argument, the foundation of everything asserted and urged is that
very assumption.
In every argument against the Eighteenth Amendment, possible
changes in the Constitution (which is both federal and national) have
been divided into two classes, but not into the federal class and the
national class. It has been invariably contended that the first class
include those which can be made under the imaginary “grant” of
power in the Fifth Article and in the mode of procedure therein
prescribed. On the other hand, it has been invariably contended that
the other class includes those which cannot be made under that
imaginary “grant” or in any constitutional procedure because they
take away from the citizens of a state their right to govern
themselves.
All arguments alike, whether for or against the Eighteenth
Amendment, have wholly ignored the fact that the citizens of
America, for the protection of the individual liberty of the one
American people, in that character, established the Constitution
and made it the supreme law over the citizens of the respective
states and the states themselves and the state governments and the
league of the states, which the citizens of America continued as
subordinate to their nation of men.
For this reason probably, no argument, on either side, has ever
recognized the identity of the “conventions” of the Seventh Article
with the “conventions” of the Fifth Article. For this reason probably,
no argument has ever recognized the identity of both “conventions”
with the most important factor and reservee in the Tenth
Amendment, “the people” of America, as distinguished from the
lesser reservees, the peoples or citizens of each state, “the states
respectively.”
It is this very failure to recognize this identity which has forced the
opponents of the new Amendment into the “nonsense” of assuming
and asserting, with their adversaries, that the Fifth Article is a “grant”
to the “conventions” and the state “legislatures.” If there had not
been this failure, everyone would have recognized that the
“conventions,” which made the Constitution, neither could nor did
“grant” to themselves, the “conventions” named in the Fifth Article,
any or all of the very power which they were then exercising. The
“nonsense” of the concept of such a “grant” is patent once there is
recognized the identity between the “conventions” with the most
important reservee of the Tenth Amendment, the one American
people of Marshall.
We all know that, for five years, that identity has never been
known or mentioned. The failure to know or to mention it has been
emphasized by the occasional references to “conventions” which
have been made. In one or two arguments, there has been passing
attempt to support the “nonsense,” that the Fifth Article is a “grant,”
but a “grant” limited in extent, by a suggestion that the Eighteenth
Amendment could be “grafted” on the Constitution entirely outside of
any mode of procedure mentioned in the Constitution. The
suggestion has been that it could be “grafted” on the Constitution by
“conventions” of the citizens of each state, provided that the citizens
of every state gave their consent. In these suggestions, we
ourselves, the citizens of America, the whole American people of
Marshall, have figured not at all.
We, who are the citizens of America, must now realize the vital
importance to our personal liberty of our own knowledge that we are
citizens of America as well as citizens of some particular state.
Wilson pointed out to the Americans in the Pennsylvania convention
the dual capacity of the American, if the new Constitution were
adopted. We remember his statement that “it was necessary to
observe the two-fold relation in which the people would stand—first
as citizens of the general government and, secondly, as citizens of
their particular state. The general government was meant for them in
the first capacity; the state governments in the second. Both
governments were derived from the people; both meant for the
people; both therefore ought to be regulated on the same principles.”
And we remember the one most important American principle, that
every government in America must get, directly from its own citizens,
every power to interfere with their individual freedom.
We cannot help contrasting the accurate statement of Wilson, “in
this Constitution the citizens of America appear dispensing a portion
of their power,” with what must be the modern statement, if the
Eighteenth Amendment is in the Constitution, namely, “in this
Constitution the state governments appear dispensing to themselves
and to the national government another portion of the power of the
citizens of America.”
And, if that modern statement is “nonsense,” what else but
“nonsense” are the arguments which rely upon its truth or which do
not point out its absurdity?
What action of our public leaders, even in this year 1923, does not
disclose that they still have the Tory concept that states and their
governments, both of which are political entities, can exercise or
grant power which the Tenth Amendment expressly declares that the
American citizens reserved exclusively to themselves, and which the
Supreme Court, even as late as 1907, clearly held “could be
exercised only by them or upon further grant from them?” No
discerning American has failed to note that the Senate still clings to
the delusion of 1917, that states and their citizens and their
governments have anything whatever to do with the national part of
the Constitution of the citizens of America. In the newspapers, on
January 30, 1923, under the heading, “Favor New Defense for
Constitution,” appeared a dispatch from Washington. It told how the
senators on the Judiciary Sub-Committee had agreed to report
favorably a proposal again to amend the Constitution by changing
the language of the Fifth Article. And the main element of the
proposed change is to provide that any state may require that
ratification by its legislature be subject to confirmation by popular
vote of the citizens of that state.
The citizens of each state make their own Constitution. In it, they
give to their own government what ability they please to interfere
with their own individual freedom. What have the citizens of any
State, what have the citizens of every state, in their capacity as state
citizens, to do with grants of power to the American government to
interfere with the individual liberty of the American citizens? Have not
the American citizens, in every state, protection against grants of
such power to the one government of the American people except by
the citizens of America themselves, in that character? Is there
anything in the Fifth Article, as it was written by Madison and made
by the one American people, which permits any state governments—
which have no power even over their own respective citizens except
by grant from them—to exercise or create new government power to
interfere with the liberty of the citizens of the distinct and supreme
nation, America?
Why persistently and insistently ignore the basic American legal
principle that every state government must get its own power over its
own citizens from them and that the only government of the
American citizens must get its every national (as distinguished from
federal) power directly from the citizens of America, assembled in the
“conventions” named in the Fifth Article?
Is there any doubt that Madison, who wrote the Fifth Article, knew
whom its word “conventions” described? When he asked the one
American people to make the entire Constitution, this is what he told
them about the Seventh Article, in which the same word
“conventions” was used: “This Article speaks for itself. The express
authority of the people alone could give due validity to the
Constitution.” If the Seventh Article “speaks for itself” and points out
that “the people alone” are to make the Constitution, with its grants
of national power in the First Article, what word in that Seventh
Article identifies the makers of the Constitution, which Madison and
all Americans know was made by the one people of America? Is
there any word in it except the one word “conventions” to describe
the people or citizens of America? And if that one word “conventions”
makes the Article speak for itself and tell us that the American
citizens themselves made the whole Constitution, does not the word
“conventions” in the Fifth Article speak just as plainly for itself and tell
us that it also describes and identifies the one people of America, the
citizens of America?
Why then tinker with the Fifth Article and repeat the monumental
error on which the existence of the Eighteenth Amendment is
assumed? Why propose an Amendment to the Fifth Article, which
Amendment will itself assume that the Fifth Article already is a
“grant” to the state legislatures of ability to give away from the
citizens of America their exclusive power to say to what extent and in
what matters their one American government may interfere with their
individual freedom in their character as American citizens?
Why not be sane and admit that the Fifth Article is not a “grant” to
the legislatures of state citizens? It is settled fact that each such
legislature, like every legislature in America, must get its every
power to govern its own citizens from its own citizens. That is why
the Fourth Article guarantee of “a Republican Form of Government”
to every state has taught us (pp. 250-1) the absurdity of the thought
that the Fifth Article enables state governments outside Rhode Island
to give its government power to interfere with the individual freedom
of citizens of Rhode Island. And there is a further and more
monumental absurdity, in this same respect, when we contrast this
Fourth Article guarantee with the assumption that the Fifth Article is
a “grant” to the state legislatures. One of the great purposes for
which the whole American people made themselves one nation of
men was that the strength of such a great nation might be used to
secure to the Americans in every state the ability to govern
themselves without any interference from outside the state, in all
matters except those in which the citizens of America took from them
the ability to govern themselves. That is why the citizens of America
wrote that guarantee into the Fourth Article as a command to their
inferiors, the states and the state governments. Having thus secured
“a Republican Form of Government” to the Americans in every state
by the command of the Fourth Article, is it conceivable that the same
whole American people, immediately thereafter and in the Fifth
Article, created for the citizens of America a government which has
not even the semblance of “a Republican Form of Government”?
That is the concept on which the existence of the Eighteenth
Amendment depends. It is not in the Constitution unless,
immediately after the guarantee of the Fourth Article and in the Fifth
Article, the whole people of America said: “We have just insisted that
the Americans in each state must be governed by a government
which gets its power directly from them. For ourselves, however, as
the whole American people, we are content to let two thirds of
Congress and the legislatures of three fourths of the states interfere
with our individual freedom, in all matters whatsoever. For that
reason, we make this grant to those legislatures. For ourselves, as
one people, we have no desire for a Republican Form of
Government.”
Does not the claim that the Americans did say this in their Fifth
Article entitle us more justly than Henry to exclaim: “I suppose that I
am mad, or that my countrymen are so!” (3 Ell. Deb. 446.)
We know, with certainty, that the Eighteenth Amendment is not in
our Constitution, and we know that the real and invincible challenge
to its existence has never been made. What will be the epitaph of the
audacious attempt of government to dictate to Americans as
“subjects,” when the challenge is presented to the Supreme Court?
No patriotic American can have the slightest doubt. No man, familiar
with its history and traditions, can fail to know the answer of that
Court to the question, “Citizen or Subject?”
It is not unknown that there is growing up in America, even among
many public leaders and lawyers, an unfounded concept that the
Supreme Court was created by the American citizens to make law.
Such concept is quite in accord with the concept—indeed it is part of
the concept—that government can create and constitute new
government of men. But the entire history and tradition of the
Supreme Court flatly denies the existence of any such concept in the
mind of the Court itself. Even in the National Prohibition Cases, the
Court quickly displayed the American concept of the relation of men
to all governments in America. When the lawyers had finished their
incessant talk about the imaginary Fifth Article “grant” which would
make all American citizens “subjects” of some governments of state
citizens, had the Tory concept of such a grant made the slightest
impression upon the mind of the Court? We all know that in the
decisions, which merely negatived four unsound challenges to the
Amendment, the first statement of the Court was a reference to the
power “reserved” in the Fifth Article.
And we know how, in the same litigations, the Court wholly ignored
the absurd claim, even when advanced by a former justice of the
Court, that, when governments had attempted to put anything into
our Constitution, so long as the attempt did not involve changing the
number of senators from a state, the Court was without power to
review the action of governments or to protect the American citizen
against usurpation by government.
The Constitution is not only the same in words, but the
same in meaning, and delegates the same powers to the
government, and reserves and secures the same rights and
privileges to the citizen, and as long as it continues to exist in
its present form, it speaks not only in the same words, but
with the same meaning and intent with which it spoke when it
came from the hands of its framers and was voted on and
adopted by the people of the United States. Any other rule of
construction would abrogate the judicial character of the
Court, and make it the mere reflex of the popular opinion or
passion of the day. This Court was not created by the
Constitution for such purposes. Higher and graver trusts have
been confided to it, and it must not falter in the path of duty.
(Scott v. Sandford, 19 How. 393, at p. 426.)
The high power has been conferred upon this Court of
passing judgment upon the acts of the state sovereignties and
of the legislative and executive branches of the federal
government, of determining whether they are beyond the
limits of power marked out for them respectively by the
Constitution of the United States. (Luther v. Borden, 1849, 7
How. 1 at p. 47.)
The Court will never be called upon to exercise a higher or graver
trust than to answer the question “Citizen or Subject?”, when the real
challenge is made to the new attempted constitution of government
of men entirely by government. The Court is not unaware that the
whole American people established their Constitution for the one
purpose of protecting individual liberty.
The simple, classical, precise, yet comprehensive language
in which it is couched, leaves, at most, but very little latitude
for construction; and when its intent and meaning is
discovered, nothing remains but to execute the will of those
who made it, in the best manner to effect the purposes
intended. The great and paramount purpose was to unite this
mass of wealth and power, for the protection of the humblest
individual; his rights, civil and political, his interests and
prosperity, are the sole end; the rest are nothing but the
means. (Justice Johnson, Gibbons v. Ogden, 9 Wheat. 1, at
p. 223.)
Nor will anyone familiar with the unbroken tradition of the Supreme
Court listen, with aught but mingled incredulity and indignation, to the
suggestion that the Court itself has not always understood that it is
itself but a part of the limited government of the one American
people, created by that people as one means to that sole end.
“It is emphatically the province and duty of the Judiciary
Department to say what the law is.”
This is the clear statement of Marshall in Marbury v. Madison, 1
Cranch. 137, declaring unconstitutional a section of an act of
Congress, which had been passed at the first session in 1789. The
entire Bench and Bar of America, including the Supreme Court, for
fourteen years, had practiced on the assumption that the section was
constitutional. Yet in 1803, the Supreme Court declared it to be
unconstitutional. Nothing could more clearly establish the knowledge
of the Supreme Court that no continued thought (even by the Court
itself), that any command of legislatures is valid, will ever blind the
Court to its bounden duty to announce the fact that the command
was made without authority from the people, when that fact is once
made clear to the Court.
Exactly the same attitude was taken by the Court in relation to an
income tax and a federal limitation on a national power given to
impose direct taxation.
When that federal limitation was imposed it was aimed only at
taxation on land and at what were then known as “poll” or
“capitation” taxes. In the days of the “conventions” where we have
sat, all other kinds of taxation were deemed to be indirect taxation.
In the very early days of the Supreme Court, this knowledge of the
“convention” days was echoed in decisions which, on that ground,
held that certain taxes, which today might be regarded as direct
taxation, were not within the federal limitation as to apportionment of
direct taxes among the states. Among those taxes, those imposed
without apportionment, were a tax on carriages and receipts of
insurance companies and on the inheritance of real estate. Even as
late as the days of the Civil War, when a tax was imposed upon
incomes and without apportionment among states, the Supreme
Court held that such tax was not a direct tax within the meaning of
“direct tax” to those who imposed the federal limitation.
Nevertheless, when the income tax law of 1894 had been enacted,
its opponents again carried to the Supreme Court the claim that it
violated the federal limitation on the power of direct taxation,
because it did not apportion the tax among the states. And the
Supreme Court, by a divided vote and on the ground that a tax on
the income from land was a tax on the land itself and consequently a
direct tax, held the Income Tax Law of 1894 to be void. It was by
reason of this decision that the Sixteenth Amendment was proposed
and adopted, making the federal change in the Constitution that lifted
the federal limitation from the national power of direct taxation
insofar as a tax on incomes was concerned.
In these decisions, as in the many others which have followed the
same clear American concept of duty and power, the Supreme Court
has always known and followed the reason stated by Hamilton for its
existence as part of the limited government of the one American
people.
In Federalist, Nos. 78 and 81, appealing to the Americans to make
the Constitution, Hamilton points out that the Constitution does not
authorize the Supreme Court to exercise its will to make the law
what the Court thinks it ought to be, but does impose upon the Court
the duty of exercising its judgment to ascertain what the law has
been made by those competent to make it. And then he points out
that the Supreme Court, in this Constitution of a self-governing
people, is made the great bulwark of the people against legislative
encroachment upon the rights or powers of the people reserved to
themselves.
This knowledge of Hamilton has been the knowledge of the
Supreme Court from its institution. It has been reiterated and
explained and expounded in that Court from the days of Marshall to
our own day. It has become part and parcel of the great traditions of
that Court, which are the foundation of the great respect which the
average American citizen pays to its decisions and its authority as
his own great protection against usurpation of power by other
departments of his various governments.
And so the average American citizen will look forward with
certainty to the decision of that Court when the real challenge is
made to the existence of the Eighteenth Amendment by an American
who does know and assert the plain facts which mean that either
there is no Eighteenth Amendment or there never has been an
American citizen. It is simple fact that the existence of the Eighteenth
Amendment, that government-made constitution of government of
men, is absolutely incompatible with the existence of a citizen of
America. It is simple fact that the Fifth Article did not grant to state
governments or to any governments the ability to make Articles like
the First Article or the Eighteenth Amendment, or else the Fifth
Article made all Americans “subjects” of a part of the state
governments, with omnipotent ability in those governments to
legislate for Americans “in all matters whatsoever.”
And it is simple fact that the Supreme Court must and will—when
the real challenge is at last made—decide that the Eighteenth
Amendment is not in the national part of the American Constitution
because it was made by governments and not by the “conventions”
of the Fifth Article. Otherwise, in the face of history, in the face of the
record of the “conventions” of the American citizens, and in the face
of all that the Supreme Court has hitherto decided, the Court must
decide that the American citizen has never existed. The possibility
that there should be such a decision is absolutely beyond
conception.
What the decision will be was long ago foreshadowed and forecast
by Daniel Webster. It would almost seem as if Webster had heard
the Sheppard claim that the states made the Constitution and that
the states had then agreed between themselves that the
governments of thirty-six of the states, in combination, could
command the American citizen in any matter of his individual
freedom. It would almost seem as if Webster had heard Hughes
deny, while his associate lawyers for the Eighteenth Amendment still
asserted with Sheppard, that the Constitution was a compact
between states and then had heard them all insist that the Fifth
Article was a “grant” which made thirty-six governments of state
citizens an omnipotent Parliament over all citizens of America.
“When the gentleman says, the Constitution is a compact between
the states, he uses language exactly applicable to the old
Confederation. He speaks as if he were in Congress before 1789.
He describes fully that old state of things then existing. The
Confederation was, in strictness, a compact; the states, as states,
were parties to it. We had no other general government. But that was
found insufficient, and inadequate to the public exigencies. The
people were not satisfied with it, and undertook to establish a better.
They undertook to form a general government which would stand on
a new basis—not a confederacy, not a league, not a compact
between states, but a constitution; a popular government, founded in
popular election, directly responsible to the people themselves, and
divided into branches, with prescribed limits of power, and
prescribed duties. They ordained such a government; they gave it
the name of a constitution; and therein they established a distribution
of powers between this, their general government, and their several
state governments. When they shall have become dissatisfied with
this distribution, they can alter it. Their own power over their own
instrument remains. But until they shall alter it, it must stand as their
will, and is equally binding on the general government and on the
states.” (Webster’s concluding remarks in the reply to Hayne, 4 Ell.
Deb. 518.)
Is not the same doctrine certain from the Court which knew the
whole Constitution so well that it decided, in the important case of
Barron v. Mayor of Baltimore, supra, p. 376, that the entire
Constitution gave no power of any kind to the state governments? Is
not the same doctrine certain from the Court which held:
The powers the people have given to the General
Government are named in the Constitution, and all not there
named, either expressly or by implication, are reserved to the
people, and can be exercised only by them, or upon further
grant from them. (Turner v. Williams, 194 U. S. 279 at 296.)
When the real challenge to the Eighteenth Amendment is
presented before that Court, it will be necessary for the defenders of
the Amendment to abandon the disguise in which they attempt to
conceal the real nature of their Tory concept. No one of them has
been bold enough to state in words the real claim about the Fifth
Article. That real claim is that the Article is a “grant” and that the
“grant” gives to thirty-six governments of state citizens unrestricted
ability to interfere with the freedom of the American citizen on every
subject enumerated in the First Article and on every subject not
enumerated in the First Article. That is not the way any defender of
the Amendment states his claim. It is always stated that those thirty-
six governments can change the Constitution by putting into it
anything which the American citizens, assembled in their
“conventions,” can put into it. Our education with the Americans in
the “conventions” has taught us that both statements are exactly the
same statement. If the thirty-six state governments can make the
command to the American citizens which is embodied in the First
Section of the Eighteenth Amendment, by putting that command into
the national part of our Constitution, any thirty-six state legislatures
can make any command to the American citizens on any subject
enumerated or not enumerated in the First Article. The claim, that the
Fifth Article “grants” to the thirty-six state governments the right to
put the command in the Constitution, is identical with the claim that
the Fifth Article “grants” to the state governments the right to make
the command to the citizens of America. A legislative command to
human beings, interfering with their individual freedom, is a
legislative command by whatever name it may be called. Mere
omission to call a legislative command by the usual names, an “Act”
or “Statute,” cannot alter its essential nature.
From June 21st, 1788, the birthday of the American nation of men,
there has been but one possible answer to the question which is the
title of this book. That one answer was known to everyone in the
“conventions” which made the Fifth Article. The Americans in those
conventions all knew that they were becoming “citizens” of America,
not “subjects” of any governments. They knew that they were
dispensing part of the power of the American citizens to Congress in
the First Article; and that the rest of that power they were reserving
to themselves. They knew that they were giving no power whatever
to the state governments with whom they never deal except to
command those governments.
That is why Pendleton, in the Virginia convention, made his
statement of fact in the oratorical form of a question, because the
one answer to the question was known and “felt and acknowledged
by all.” His statement of fact, made in the oratorical form of a
question, is, in substance, exactly the title of this book:
“Who but the people can delegate powers?... What have the state
governments to do with it?” (3 Ell. Deb. 37.)
APPENDICES
APPENDIX I
THE ORIGINAL CONSTITUTION OF THE UNITED STATES
We the People of the United States, in Order to form a more

perfect Union, establish Justice, insure domestic Tranquility, provide
for the common defence, promote the general Welfare, and secure
the Blessings of Liberty to ourselves and our Posterity, do ordain and
establish this Constitution for the United States of America.
Article. I.
Section, 1. All legislative Powers herein granted shall be vested in

a Congress of the United States, which shall consist of a Senate and
House of Representatives.
Section. 2. The House of Representatives shall be composed of
Members chosen every second Year by the People of the several
States, and the Electors in each State shall have the Qualifications
requisite for Electors of the most numerous Branch of the State
Legislature.
No Person shall be a Representative who shall not have attained
to the Age of twenty five Years, and been seven Years a Citizen of
the United States, and who shall not, when elected, be an Inhabitant
of that State in which he shall be chosen.
Representatives and direct Taxes shall be apportioned among the
several States which may be included within this Union, according to
their respective Numbers, which shall be determined by adding to
the whole Number of free Persons, including those bound to Service
for a Term of Years, and excluding Indians not taxed, three fifths of
all other Persons. The actual Enumeration shall be made within
three Years after the first Meeting of the Congress of the United
States, and within every subsequent Term of ten Years, in such
Manner as they shall by Law direct. The Number of Representatives
shall not exceed one for every thirty Thousand, but each State shall
have at Least one Representative; and until such enumeration shall
be made, the State of New Hampshire shall be entitled to chuse
three, Massachusetts eight, Rhode-Island and Providence
Plantations one, Connecticut five, New-York six, New Jersey four,
Pennsylvania eight, Delaware one, Maryland six, Virginia ten, North
Carolina five, South Carolina five, and Georgia three.
When vacancies happen in the Representation from any State, the
Executive Authority thereof shall issue Writs of Election to fill such
Vacancies.
The House of Representatives shall chuse their Speaker and other
Officers; and shall have the sole Power of Impeachment.
Section. 3. The Senate of the United States shall be composed of
two Senators from each State, chosen by the Legislature thereof, for
six Years; and each Senator shall have one Vote.
Immediately after they shall be assembled in Consequence of the
first Election, they shall be divided as equally as may be into three
Classes. The Seats of the Senators of the first Class shall be
vacated at the Expiration of the second Year, of the second Class at
the Expiration of the fourth Year, and of the third Class at the
Expiration of the sixth Year, so that one third may be chosen every
second Year; and if Vacancies happen by Resignation, or otherwise,
during the Recess of the Legislature of any State, the Executive
thereof may make temporary Appointments until the next Meeting of
the Legislature, which shall then fill such Vacancies.
No Person shall be a Senator who shall not have attained to the
Age of thirty Years, and been nine Years a Citizen of the United
States, and who shall not, when elected, be an Inhabitant of that
State for which he shall be chosen.
The Vice President of the United States shall be President of the
Senate, but shall have no Vote, unless they be equally divided.
The Senate shall chuse their other Officers, and also a President
pro tempore, in the Absence of the Vice President, or when he shall
exercise the Office of President of the United States.
The Senate shall have the sole Power to try all Impeachments.
When sitting for that Purpose, they shall be on Oath or Affirmation.
When the President of the United States is tried the Chief Justice shall
preside: And no Person shall be convicted without the Concurrence
of two thirds of the Members present.
Judgment in Cases of Impeachment shall not extend further than
to removal from Office, and disqualification to hold and enjoy any
Office of honor, Trust or Profit under the United States: but the Party
convicted shall nevertheless be liable and subject to Indictment,
Trial, Judgment and Punishment, according to Law.
Section. 4. The Times, Places and Manner of holding Elections for
Senators and Representatives, shall be prescribed in each State by
the Legislature thereof; but the Congress may at any time by Law
make or alter such Regulations, except as to the Places of chusing
Senators.
The Congress shall assemble at least once in every Year, and
such Meeting shall be on the first Monday in December, unless they
shall by Law appoint a different Day.
Section. 5. Each House shall be the Judge of the Elections,
Returns and Qualifications of its own Members, and a Majority of
each shall constitute a Quorum to do Business; but a smaller
Number may adjourn from day to day, and may be authorized to
compel the Attendance of absent Members, in such Manner, and
under such Penalties as each House may provide.
Each House may determine the Rules of its Proceedings, punish
its Members for disorderly Behaviour, and, with the Concurrence of
two thirds, expel a Member.
Each House shall keep a Journal of its Proceedings, and from time
to time publish the same, excepting such Parts as may in their
Judgment require Secrecy; and the Yeas and Nays of the Members
of either House on any question shall, at the Desire of one fifth of
those Present, be entered on the Journal.
Neither House, during the Session of Congress, shall, without the
Consent of the other, adjourn for more than three days, nor to any
other Place than that in which the two Houses shall be sitting.
Section. 6. The Senators and Representatives shall receive a
Compensation for their Services, to be ascertained by Law, and paid
out of the Treasury of the United States. They shall in all Cases,
except Treason, Felony and Breach of the Peace, be privileged from
Arrest during their Attendance at the Session of their respective
Houses, and in going to and returning from the same; and for any
Speech or Debate in either House, they shall not be questioned in
any other Place.
No Senator or Representative shall, during the Time for which he
was elected, be appointed to any civil Office under the Authority of
the United States, which shall have been created, or the
Emoluments whereof shall have been encreased during such time;
and no Person holding any Office under the United States, shall be a
Member of either House during his Continuance in Office.
Section. 7. All Bills for raising Revenue shall originate in the House
of Representatives; but the Senate may propose or concur with
Amendments as on other Bills.
Every Bill which shall have passed the House of Representatives
and the Senate, shall, before it become a Law, be presented to the
President of the United States; If he approve he shall sign it, but if
not he shall return it, with his Objections to that House in which it
shall have originated, who shall enter the Objections at large on their
Journal, and proceed to reconsider it. If after such Reconsideration
two thirds of that House shall agree to pass the Bill, it shall be sent,
together with the Objections, to the other House, by which it shall
likewise be reconsidered, and if approved by two thirds of that
House, it shall become a Law. But in all such Cases the Votes of
both Houses shall be determined by yeas and Nays, and the Names
of the Persons voting for and against the Bill shall be entered on the
Journal of each House respectively. If any Bill shall not be returned
by the President within ten Days (Sundays excepted) after it shall
have been presented to him, the Same shall be a Law, in like
Manner as if he had signed it, unless the Congress by their
Adjournment prevent its Return, in which Case it shall not be a Law.
Every Order, Resolution, or Vote to which the Concurrence of the
Senate and House of Representatives may be necessary (except on
a question of Adjournment) shall be presented to the President of the
United States; and before the Same shall take Effect, shall be
approved by him, or being disapproved by him, shall be repassed by
two thirds of the Senate and House of Representatives, according to
the Rules and Limitations prescribed in the Case of a Bill.
Section. 8. The Congress shall have Power To lay and collect
Taxes, Duties, Imposts and Excises, to pay the Debts and provide for
the common Defence and general Welfare of the United States; but
all Duties, Imposts and Excises shall be uniform throughout the
United States;
To borrow Money on the credit of the United States;
To regulate Commerce with foreign Nations, and among the
several States, and with the Indian Tribes;
To establish an uniform Rule of Naturalization, and uniform Laws
on the subject of Bankruptcies throughout the United States;
To coin Money, regulate the Value thereof, and of foreign Coin,
and fix the Standard of Weights and Measures;
To provide for the Punishment of counterfeiting the Securities and
current Coin of the United States;
To establish Post Offices and post Roads;
To promote the Progress of Science and useful Arts, by securing
for limited Times to Authors and Inventors the exclusive Right to their
respective Writings and Discoveries;
To constitute Tribunals inferior to the supreme Court;
To define and punish Piracies and Felonies committed on the high
Seas, and Offences against the Law of Nations;
To declare War, grant Letters of Marque and Reprisal, and make
Rules concerning Captures on Land and Water;
To raise and support Armies, but no Appropriation of Money to that
Use shall be for a longer Term than two Years;
To provide and maintain a Navy;
To make Rules for the Government and Regulation of the land and
naval Forces;
To provide for calling forth the Militia to execute the Laws of the
Union, suppress Insurrections and repel Invasions;
To provide for organizing, arming, and disciplining, the Militia, and
for governing such Part of them as may be employed in the Service
of the United States, reserving to the States respectively, the
Appointment of the Officers, and the Authority of training the Militia
according to the discipline prescribed by Congress;
To exercise exclusive Legislation in all Cases whatsoever, over
such District (not exceeding ten Miles square) as may, by Cession of
particular States, and the Acceptance of Congress, become the Seat
of the Government of the United States, and to exercise like
Authority over all Places purchased by the Consent of the
Legislature of the State in which the Same shall be, for the Erection
of Forts, Magazines, Arsenals, dock-Yards, and other needful
Buildings;—And
To make all Laws which shall be necessary and proper for carrying
into Execution the foregoing Powers, and all other Powers vested by
this Constitution in the Government of the United States, or in any
Department or Officer thereof.
Section. 9. The Migration or Importation of such Persons as any of
the States now existing shall think proper to admit, shall not be
prohibited by the Congress prior to the Year one thousand eight
hundred and eight, but a Tax or duty may be imposed on such
Importation, not exceeding ten dollars for each Person.

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