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Neurotoxicity of Nanomaterials and Nanomedicine 1st
Edition Xinguo Jiang Digital Instant Download
Author(s): Xinguo Jiang, Huile Gao
ISBN(s): 9780128046203, 0128046201
Edition: 1
File Details: PDF, 9.35 MB
Year: 2017
Language: english

Neurotoxicity of
Nanomaterials
and Nanomedicine
Edited by
Xinguo Jiang
School of Pharmacy, Fudan University, Shanghai, China
Huile Gao
West China School of Pharmacy, Sichuan University, Chengdu, China
AMSTERDAM • BOSTON • HEIDELBERG • LONDON
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xiii
List of Contributors
F. Brandão Portuguese National Institute of Health, Porto, Portugal; University of
Porto, Porto, Portugal
H. Chen Shanghai Jiao Tong University School of Medicine, Shanghai, China
C. Costa Portuguese National Institute of Health, Porto, Portugal; University of Porto,
Porto, Portugal
N. Fernández-Bertólez Universidade da Coruña, A Coruña, Spain
S.J.S. Flora Defence Research and Developmental Establishment, Gwalior, India
F. Gao East China University of Science and Technology, Shanghai, China
H. Gao Sichuan University, Chengdu, China
X. Gao Shanghai Jiao Tong University School of Medicine, Shanghai, China
X. Gu Shanghai Jiao Tong University School of Medicine, Shanghai, China
M. He East China University of Science and Technology, Shanghai, China
Q. He Sichuan University, Chengdu, China
K. Ikeda The Jikei University School of Medicine, Tokyo, Japan
X. Jiang Fudan University, Shanghai, China
D. Ju Fudan University, Shanghai, China
G. Kiliç Karolinska Institutet, Stockholm, Sweden
B. Laffon Universidade da Coruña, A Coruña, Spain
J. Li Lancaster University, Lancaster, United Kingdom
Y. Liu Sichuan University, Chengdu, China
Y. Li Fudan University, Shanghai, China; University of Pennsylvania, Philadelphia,
PA, United States
K. Lou East China University of Science and Technology, Shanghai, China
Y. Manome The Jikei University School of Medicine, Tokyo, Japan
F.L. Martin Lancaster University, Lancaster, United Kingdom; University of Central
Lancashire, Preston, United Kingdom
G. Mi Northeastern University, Boston, MA, United States
E. Pásaro Universidade da Coruña, A Coruña, Spain
L.Q. Shao Southern Medical University, Guangzhou, China
D. Shi Northeastern University, Boston, MA, United States

xiv List of Contributors
B. Song Southern Medical University, Guangzhou, China; Guizhou Provincial People’s
Hospital, Guiyang, China
L. Strużyńska Mossakowski Medical Research Centre, Polish Academy of Sciences,
Warsaw, Poland
T. Tachibana The Jikei University School of Medicine, Tokyo, Japan
J.P. Teixeira Portuguese National Institute of Health, Porto, Portugal; University of
Porto, Porto, Portugal
V. Valdiglesias Universidade da Coruña, A Coruña, Spain
T.J. Webster Northeastern University, Boston, MA, United States; King Abdulaziz
University, Jeddah, Saudi Arabia
C. Zhong East China University of Science and Technology, Shanghai, China

xv
Biography
Xinguo Jiang, BS
Professor, Key Laboratory of Smart Drug
Delivery (Ministry of Education), School
of Pharmacy, Fudan University, Shanghai,
China.
Prof. Xinguo Jiang obtained BS in Phar-
macy from Shanghai First Medical College
in July 1982. Then he worked in the Depart-
ment of Pharmaceutics in Fudan University
(originally Shanghai First Medical College)
since October 1986. Between January and
July 1996, he was a guest professor in the
Department of Pharmacy in Nagasaki University (Japan). He also served as
the vice editor for Chinese Journal of Clinical Pharmacy and as editorial
board member for eight other journals including Acta Pharmaceutica Sinica
and Chinese Pharmaceutical Journal. Prof. Jiang’s research interests focus
on the development of novel drug delivery systems especially for brain-
targeting drug delivery. Having served as the Principal Scientist, Prof. Jiang
received a research grant from the State Plan for Development of Basic
Research in Key Areas. He also has won eight research grants from National
Natural Science Foundation of China and five research grants from Shanghai
government. He has accomplished over 70 R&D projects on novel drug
delivery systems under cooperation with pharmaceutical companies. Prof.
Jiang has published over 120 research papers in peer-reviewed journals and
has 15 patents. He has developed three marked formulations. He served as
guest editor and edited two theme issues for Pharmaceutical Research and
Current Pharmaceutical Biotechnology. He also wrote several book chapters
and edited three books (in Chinese).
Huile Gao, PhD
Associate Professor, Key Laboratory of Drug Targeting and Drug Delivery
Systems, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan,
China.

xvi Biography
Dr. Huile Gao received his PhD in Phar-
maceutics from School of Pharmacy, Fudan
University, in 2013 under the supervision of
Prof. Xinguo Jiang. Then he joined the West
China School of Pharmacy, Sichuan Univer-
sity, as Instructor in July 2013 and was pro-
moted toAssociate Professor in July 2014. Dr.
Gao’s research interests focus on the design,
synthesis, characterization, and evaluation of
stimuli-responsive nanomaterials for drug and
imaging probe delivery to improve treatment
and diagnosis of human diseases especially
tumor and brain diseases. He has published
over 50 peer-reviewed articles. His research
is supported by the National Natural Science Foundation of China (81373337,
81402866), Excellent Young Scientist Foundation of Sichuan University
(2015SCU04A14), and four other grants. He has been given the Excellent Doc-
toral Dissertation of Shanghai award and the Young Excellent Pharmaceutics
Scientist award, both in 2015.

xvii
Preface
Development of nanomaterials and nanomedicines is an impressive endeavor
by researchers from chemistry, physics, engineering, biology, and medicine to
improve the quality of our life. Many kinds of nanomaterials and nanomedicines
are approved for human use or are under evaluation. The extensive application
considerably elevates the exposure of nanomaterials and toxicity potential to
human beings. Even as we enjoy the benefit from nanomaterials and nanomedi-
cines, the toxicity potential should not be ignored.
The central nervous system (CNS) is the most important part of the human
body, and should be paid serious attention when we talk about toxicity. The
blood–brain barrier (BBB) has contributed to the protection of the CNS from
harm by toxicants. Knowledge about BBB and the interaction between BBB
and compounds has greatly expanded in the past several decades especially
the past few years. The depth of knowledge about BBB enables researchers
to develop nanomaterials and nanomedicines for delivering drugs or imaging
probes to brain that display engaging potential for CNS disorders. However,
neurotoxicity is emerging as a critical concern. The knowledge about neurotox-
icity urgently needs to expand.
The chapters in this book were written by active researchers who dedicate
their effort to enlarge the brain application of nanomaterials, develop brain
nanomedicines, and improve the understanding of interaction of nanomateri-
als and the CNS. We appreciate these authors for sharing their knowledge and
insights about this topic, which provide all of us, especially who work toward
nanomaterials and nanomedicines, with an overview of the field and spark to
think more about our research.
The early chapters provide an overview of the application of nanomateri-
als and nanomedicines in brain. The main routes by which nanomaterials enter
brain are described. Then the excretion routes are discussed, although there are
few studies related to this important topic.
A general review about neurotoxicity is provided in Chapter 4, with emphasis
on the neurotoxicity mechanism. Then contributors describe in detail the appli-
cation and neurotoxicity of many kinds of nanomaterials (Chapters 5–12) that
are widely used, including titanium dioxide nanoparticles, iron oxide nanopar-
ticles, silver nanoparticles, gold nanoparticles, manganese-containing nanopar-
ticles, silica nanoparticles, carbon nanotubes, and cationic polymers. These
kinds of nanoparticles represent the most commonly used nanomaterials in this
field. Finally, an overview about neurotoxicity is provided with discussion of

xviii Preface
potential strategies to reduce the neurotoxicity of nanomaterials and nanomedi-
cines. Researchers will benefit from this knowledge to design novel nanomateri-
als and nanomedicines with minimum neurotoxicity.
The editors greatly thank the individual chapter contributors for kindly shar-
ing their knowledge and ideas. It is a great pleasure to collaborate with them
to develop this book. We admire the outstanding work they contributed so that
researchers from nanomaterials and nanomedicines can benefit from this book
and make greater success in their own work.
Xinguo Jiang
Huile Gao
April 2016

xix
Introduction and Overview
H. Gao1, X. Jiang2
1Sichuan University, Chengdu, China; 2Fudan University, Shanghai, China
Nanoparticles (NPs) are generally described as particles of size about 0.1–100nm,
but particles that are several hundred nanometers in size are also called NPs. Thus in
this book, we expand the definition of NPs to all particles around 0.1–1000nm. The
materials of NPs are called nanomaterials. One of the most important applications
of NPs is delivering drugs and imaging probes to human body for disease diagnosis
and treatment. These NPs are called nanomedicines.
Accompanied with the development of chemistry, biology, and materials
science, many kinds of nanomaterials are synthesized with impressive charac-
teristics. Nanomedicines are also extensively designed for both peripheral dis-
eases and central nervous system (CNS) disorders. Despite great achievements,
the toxicity of nanomaterials has been emerging as an increasingly important
concern. The CNS is the most important part of human being, thus the toxicity
to CNS, named neurotoxicity, should be paid particular attention.
In this book, the application and neurotoxicity of nanomaterials and nano-
medicines are reviewed and discussed. The book includes the following:
l
The application of nanomaterials and nanomedicines in brain targeting drug
delivery
l
The routes by which nanomaterials and nanomedicines enter into brain
l
The excretion of nanomaterials and nanomedicines from brain
l
The neurotoxicity of many kinds of nanomaterials, including titanium dioxide
nanoparticles, iron oxide nanoparticles, silver nanoparticles, gold nanoparti-
cles, manganese-containing nanoparticles, silica nanoparticles, carbon nano-
tubes, and cationic polymers
l
The general mechanism of neurotoxicity and strategies to reduce the neuro-
toxicity.
HOW DO NANOMATERIALS AND NANOMEDICINES ENTER
INTO AND GET EXCRETED FROM BRAIN?
In the CNS, the blood–brain barrier (BBB) considerably restricts the brain dis-
tribution of nanomaterials and nanomedicines. In healthy condition, the BBB
protects the CNS from harm by toxicants in blood. But in CNS disorders, the

xx Introduction and Overview
BBB also restricts the brain access of drugs, making CNS disorders the most
difficult diseases to treat. Many researchers dedicate their efforts to enhance
brain drug delivery using various methods. In these methods, nanomaterials
play a critical role. In Chapter 1, we discuss the general application of nanoma-
terials and nanomedicines in brain targeting drug delivery and then in Chapter 2,
Dr. Liu and Dr. He further summarize the routes that the nanomaterials enter
brain, including penetrating the BBB through receptor-mediated endocytosis,
transporter-mediated endocytosis, adsorptive-mediated endocytosis, bypass-
ing BBB through intranasal delivery, inhibiting the function of BBB by inhibi-
tion of efflux pumps, and disturbing the structure of BBB. The distribution of
nanomaterials and nanomedicines in brain is influenced by many factors, such
as size, shape, surface charge, and ligand modification of NPs; administration
routes; chronobiology; and disease condition, which is reviewed by Dr. Gao in
Chapter 3. After entering into brain, the nanomaterials could be degraded or
excreted from brain, which is affected by the deformability, biodegradability,
size, shape, and ligand modification of the nanomaterials and nanomedicines.
The conscious state and disease condition also affect this procedure, which is
discussed in Chapter 3.
WHAT IS THE NEUROTOXICITY OF NANOMATERIALS?
Because nanomaterials could enter into brain through various routes, the contact
of nanomaterials and nanomedicines with CNS may cause some neurotoxicity.
The common neurotoxicity includes oxidative stress, inducing cell apoptosis
and autophagy, immune response and inflammation, activating specific signaling
pathway, affecting BBB function, and so on, which are reviewed in Chapter 4.
Many kinds of nanomaterials have been developed with potential for CNS
exposure, among which the widely used nanomaterials are selected for detailed
description, such as metal NPs, carbon nanotubes, and cationic polymers. The
application and neurotoxicity of these nanomaterials are reviewed in Chapters
5–12. The potential mechanism and influence factors are also reviewed, such as
size, shape, crystal type, charge, surface property, release of ions, and admin-
istration route. Because neurotoxicity is a critical concern in the application of
nanomaterials and nanomedicines, strategies to reduce neurotoxicity are impor-
tant for researchers. Based on the reasons involved in the neurotoxicity, we con-
clude several strategies in Chapter 13, including reducing brain exposure and
decreasing inherent toxicity of nanomaterials and nanomedicines.
CONCLUSION
This book is prepared with the purpose of benefiting nanomaterial and nano-
medicine researchers in the following areas:
l
Fundamental knowledge about nanomaterials and nanomedicines application
in CNS disorders

Introduction and Overview xxi
l
Routes by which nanomaterials and nanomedicines enter into and get excreted
from brain
l
Common neurotoxicity of nanomaterials and the influence factors
l
Mechanism of neurotoxicity and strategies to reduce neurotoxicity.
The valuable insights shared by chapter authors are intended to expand the
fundamental knowledge about brain application of nanomaterials and nanomed-
icines and the corresponding neurotoxicity. Researchers from all related fields
may further develop nanomaterials and nanomedicines with lower neurotoxicity
for more satisfying application in humans.

1
Neurotoxicity of Nanomaterials and Nanomedicine. http://dx.doi.org/10.1016/B978-0-12-804598-5.00001-5
Copyright © 2017 Elsevier Inc. All rights reserved.
Chapter 1
The Medical Applications of
Nanomaterials in the Central
Nervous System
H. Gao1, X. Jiang2
1Sichuan University, Chengdu, China; 2Fudan University, Shanghai, China
1. INTRODUCTION
The development of nanotechnology has been influencing many aspects of
human life. Various nanomaterials have been developed to address critical
requirements including disease diagnosis and therapy, energy, and environ-
mental protection. Especially in medicine, the application of nanomaterials
has gained increasing attention from not only academics but also industry.
The central nervous system (CNS) is one of the most important systems in
the human body. To protect and keep a stable microenvironment for the nor-
mal activities of neurons, several barriers play a key role in guarding the brain
parenchyma against invading substances or organisms (Neuwelt et al., 2008;
Tuladhar et al., 2015). Over a hundred years ago, Goldman proved the existence
of a physiological barrier that separated the brain from the circulation system
Chapter Outline
1. Introduction 1
2.
Small Chemical Drugs Delivery 2
2.1 Natural Nanomaterials 3
2.2
Anionic and Neutral Polymers 5
2.3 Dendrimers 7
2.4 Metal Nanoparticles 7
2.5 Carbon-Based Inorganic
Nanomaterials8
3.
Peptide and Protein Delivery 10
3.1 Natural Nanomaterials 10
3.2 Polymers 11
4. Gene Delivery 14
4.1 Lipid Nanomaterials 14
4.2 Cationic Polymers 15
4.3 Dendrimers 17
4.4 Other Materials 19
5.
Nanomaterials as Imaging Probe 20
5.1
Iron Oxide Nanoparticles 20
5.2 Quantum Dots 21
5.3 Carbon Dots 21
6.
Conclusion and Perspective 22
References23

2 Neurotoxicity of Nanomaterials and Nanomedicine
using trypan blue. Till 1976, the modern concept of the blood–brain barrier
(BBB) was proposed by Hugh Davson (1976). A series of research confirmed
that a barrier system did exist between brain, cerebrospinal fluid, and blood
aiming at limiting the exchange of substances (Zlokovic et al., 1990; Zloković
et al., 1987). This system is a dynamic structure that adjusts and regulates the
balance between blood and brain to maintain the normal function of the CNS
(Abbott, 2005).
Owing to the aging population, the incidence of CNS disorders increases
gradually, such as brain tumor, Alzheimer disease (AD), Parkinson disease
(PD), and stroke. Because most of the CNS disorders gravely decrease the
life quality of patients, they have been considered as the most serious threats
to humans. Unfortunately, in contrast to peripheral diseases, the diagnosis
and treatment of CNS disorders are restricted by the BBB (Wohlfart et al.,
2012). The BBB is a tight barrier that is constituted by several kinds of cells,
such as brain microvessel endothelial cells, astrocytes, microglial cells, and
pericytes (Begley, 2004). The BBB has a high transendothelial electrical
resistance, which considerably restricts the diffusion and transportation of
molecules from blood to brain. Actually, almost 98% of small molecules
(500 Da) and 100% of large molecules are not able to penetrate through
the BBB (Pardridge, 2007). Generally, the integrity of the BBB protects
the brain from harm by toxins and other substances, which is important for
keeping the normal function of brain. Unfortunately, the BBB also restricts
the access of drugs used to treat diseases involving the brain. Therefore, it
is important to enhance brain delivery of drugs to improve the diagnosis and
treatment of CNS disorders.
Nanomaterials are widely used as carriers of drugs and probes because they
can act as Trojan horse to deliver the drugs and probes to certain tissues and
cells after effective disguise (Gao et al., 2013; Gao and Jiang, 2015). Many
kinds of nanomaterials have been utilized for CNS disorders. In this chapter, we
focus on the application of various nanomaterials in delivering different kinds
of drugs and probes to treat CNS disorders.
2.
SMALL CHEMICAL DRUGS DELIVERY
Small chemical drugs are still the most commonly used in disease treatment.
Except certain lipophilic drugs, such as temozolomide and l-dopa, most of the
chemical drugs could not penetrate the BBB. Although some researchers argued
the BBB is disrupted in some conditions, such as brain tumor, the BBB was
indeed complete in at least the filtrated region and the diseased brain tissue is
still hard to be accessed by drugs (Gao et al., 2013). For example, the distribution
of lapatinib in brain metastasis is only 19% as that in lung metastasis (Taskar
et al., 2012). To address this issue, nanomaterials are often used to deliver the
chemical drugs into brain. Owing to the small size and good stability, the chemi-
cal drugs could be encapsulated into or anchored onto most nanomaterials.

The Medical Applications of Nanomaterials Chapter | 1 3
2.1 Natural Nanomaterials
Natural nanomaterials, such as lipid and natural proteins, are widely used
for constructing drug delivery systems because of their safety. Several kinds
of natural nanomaterials-based/derived nanodrugs are available clinically,
such as doxorubicin (DOX)-loaded liposomes (Doxil), daunorobicin-loaded
liposomes (DaunoXome), and paclitaxel (PTX)-loaded albumin nanoparticles
(NPs) (Abraxane) (Weissig et al., 2014). However, these nanodrugs were not
decorated with specific ligand, thus they could be used for the treatment of
peripheral diseases rather than CNS disorders because of the restriction by
BBB. Decorating with BBB-specific ligands could improve the distribution in
brain (Gao et al., 2013), thus many studies developed various brain targeting
drug delivery systems based on the natural nanomaterials.
Liposomes, consisting of lipid and cholesterol, are the most commonly used
drug delivery systems not only because of their safety but also because of their
wide application in almost all kinds of drugs. For chemical drugs, both hydro-
philic and hydrophobic drugs could be loaded into liposomes because they
have an aqueous solution core and a hydrophobic membrane. There are many
kinds of active targeting ligand-modified liposomes to deliver small molecules
to the brain (Lai et al., 2013). Transferrin (Tf) receptor is highly expressed on
the BBB, thus the corresponding ligand, Tf, was modified onto liposomes to
deliver 5-florouracil to brain tumor (Soni et al., 2008). The Tf-liposomes caused
17-fold higher 5-florouracil brain delivery compared with free 5-florouracil.
Modification with two ligands can further elevate the BBB penetration and
disease targeting. Ying et al. (2010) comodified p-aminophenyl-α-d-manno-
pyranoside (MAN) and Tf onto liposomes. MAN is a mannose analog that
has a high affinity for BBB overexpressed glucose transporter 1, which can
facilitate the penetration through BBB of the constructed systems. Tf receptors
are highly expressed on BBB and glioma cells, which could further enhance
the BBB transportation and glioma targeting of liposomes. In combination,
the dual-modified liposomes showed higher BBB model penetration and C6 gli-
oma cells uptake compared with MAN and Tf solo-modified liposomes. Except
the dual modification, it is promising to combine the motifs of different ligands
into one, which could combine the different functions from two ligands (Gao
et al., 2014b). Liu et al. (2014) decorated liposomes with R8-RGD, a tandem
peptide of octaarginine and RGD peptide, to deliver DOX into brain tumor,
which may benefit from the active targeting effect of RGD and cell penetrat-
ing effect of octaarginine. Results showed the uptake of R8-RGD-liposomes
by both brain endothelial cells and brain tumor cells was much higher than
that of unmodified liposomes. In vivo, R8-RGD-liposomes showed consider-
ably higher accumulation in brain tumor than that of unmodified liposomes.
As a result, DOX-loaded R8-RGD-liposomes could considerably prolong the
median survival time of brain tumor–bearing mice from 26 to 48days. Replacing
traditional cell penetrating peptide octaarginine with tumor microenvironment

activatable TH peptide also showed efficient brain tumor targeting accompanied
with long blood circulation time (Shi et al., 2015). More importantly, the blood
circulation time was extended because the activatable cell penetrating peptide
TH was negative in neutral pH.
Owing to the safety of liposomes, several active targeting ligand-modi-
fied liposomes were under preclinical and clinical evaluation (van der Meel
et al., 2013). Glutathione (GSH) can penetrate through the BBB mediated
by GSH transporter, thus GSH-liposomes were developed as a brain target-
ing drug delivery platform (To-BBB technology). In rats receiving 7 mg/kg
of either DOX-loaded GSH-liposomes (2B3-101) or PEGylated liposomal
DOX, the brain-to-blood ratio of DOX was 4.8-fold higher after administra-
tion of 2B3-101 than that of PEGylated liposomal DOX (Birngruber et al.,
2014). In the mice model, 2B3-101 successfully prolonged the survival of
mice (van der Meel et al., 2013), suggesting this nanomedicine was useful in
brain tumor treatment. At present, it is under phase I/II clinical evaluation,
and some positive data have been obtained, which showed that 2B3-101 is
well tolerated.
As albumin is an endogenous protein, albumin-based NPs are impres-
sive systems for drug delivery because of their good biocompatibility, and
Abraxane has been approved by the US Food and Drug Administration in
2007 (Fu et al., 2009). The encapsulation of drugs mainly depends on the
highly affinity between the drugs and albumin. Our group prepared docetaxel-
loaded albumin NPs with a drug-loading capacity of 7.5% (Gao et al., 2015).
The NPs could effectively distribute to brain tumor mainly attributing to the
weak enhanced permeability and retention (EPR) effect of brain tumor and the
interaction between albumin and the secreted protein, acidic and rich in cyste-
ine, which is highly expressed on many kinds of tumor cells (Fu et al., 2009).
Similarly, lapatinib-loaded albumin NPs (LTNPs) effectively target to glioma.
The concentration achieved in the glioma was about 0.08%ID/g tissue, which
was 25-fold higher than the commercial tablet (Fig. 1.1) (Gao et al., 2014a).
In addition, the glioma/normal brain ratio was as high as 30, demonstrating
the LTNPs could selectively target to glioma. Regarding the superiority of
albumin-based NPs, there are several albumin nanodrugs under evaluation,
including docetaxel, lapatinib, and pirarubicin (Gao et al., 2014a, 2015; Zhou
et al., 2013).
To further enhance the targeting delivery efficiency, albumin NPs could be
modified with targeting ligands. Su et al. (2014) decorated lactoferrin (Lf) onto
albumin NPs to deliver DOX into brain tumor. The Lf decoration considerably
increased the uptake by both brain capillary endothelial cells and C6 glioma
cells. Consequently, the Lf-decorated albumin NPs delivered about three times
higher DOX into tumor-bearing brain compared with unmodified albumin NPs.
Dual ligand modification may further improve the targeting efficiency. A kind
of RGD and KALA peptide dual-modified albumin NPs was constructed to
deliver DOX (Chen et al., 2015a). In this system, RGD could recognize integrin

receptors on U87 glioma cells and thus mediate the active targeting of the system,
whereas KALA peptide, a kind of cell-penetrating peptide, further elevated the
internalization of particles. After internalization, the particles would distribute
in endosomes with low pH. At such a low pH value (about 5), the negative
charge of albumin decreased significantly because the endosome pH was near
the isoionic point of albumin (pI=4.7). The low charge density of albumin
decreased the electronic interaction between albumin and cationic KALA peptide,
leading to the disassembly of the particles and release of DOX. Consequently,
the DOX-loaded RGD and KALA dual-modified albumin NPs showed high
toxicity to U87 cells. The half inhibitory concentration (IC50) of the dual target-
ing system was 2.6μg/mL, which was significantly lower than that of free DOX
(9.4μg/mL).
2.2
Anionic and Neutral Polymers
Biodegradable polymers are the most commonly used nanomaterials, such as poly
(ethylene glycol)-block-poly(epsiloncaprolactone) (PEG-PCL), poly(ethylene
FIGURE 1.1 Pharmacokinetics and glioma distribution of lapatinib-loaded albumin NPs (LTNPs)
and the commercial tablet (Tykerb). (A) Lapatinib concentrations in normal brain and glioma of
LTNPs and Tykerb group at 2 and 8h (B) AUC0–∞of LTNPs and Tykerb group. (C) Concentration in
brain and glioma deducted AUC0–∞ of LTNPs and Tykerb group. (D) Glioma/brain ratio of LTNPs
and Tykerb group, n=5. Reprinted from Gao, H., Wang, Y., Chen, C., Chen, J., Wei, Y., Cao, S.,
Jiang, X., 2014a. Incorporation of lapatinib into core-shell nanoparticles improves both the solu-
bility and anti-glioma effects of the drug. Int. J. Pharm. 461 (1–2), 478–488 with permission of the
copyright holder, Elsevier, Amsterdam.

glycol)-block-poly(lactic acid) (PEG-PLA), and poly(ethylene glycol)-block-
poly(lactide-co-glycolide) (PEG-PLGA), mainly because of the safety and con-
trollable properties of these polymers. PEG-PLA and PEG-PLGA have been
approved for injection, and a PTX-loaded PEG-PLA-based micelle has been
approved in 2001 for breast cancer and pancreatic cancer treatment (Weissig
et al., 2014). Although no nanomedicine has been approved for the treatment of
CNS disorders, PEG-PLA and PEG-PLGA still attracted many researchers’ atten-
tion, making them the most widely used nanomaterials in CNS disorders.
There are several studies that suggested unmodified PLGA NPs could distrib-
ute into brain after oral administration, but no mechanism was reported (Semete
et al., 2010). In most studies, specific ligand modification was required to pen-
etrate the BBB and target to the diseased cells. Several peptides, such as tLyp-1
(Hu et al., 2013), iNGR (Kang et al., 2014), APTEDB peptide (Gu et al., 2014),
EGFP-EGF1 (Zhang et al., 2014b), and CLT1 peptide (Zhang et al., 2014a), were
used to modify PEG-PLA NPs and then deliver various chemical drugs into brain.
All these studies showed promising treatment effect, demonstrating that ligand
modification is an effective method for improving brain targeting delivery. For
example, ALMP peptide-modified PEG-PLA NPs delivered approximately two-
fold higher PTX to brain tumor than unmodified PEG-PLA NPs, resulting in
13.5days (39.1%) longer median survival time of brain tumor–bearing mice (Gu
et al., 2013). In addition, the drug encapsulation efficiency could be considerably
elevated using the nanoemulsion templating method to prepare the brain target-
ing delivery system. For example, PLGA NPs prepared using nanoemulsion tem-
plating showed an encapsulation efficiency higher than 90% (Fornaguera et al.,
2015), which is useful for improving the brain drug delivery efficiency.
PEG-PCL is another kind of biodegradable polymer that has been exten-
sively used in recent years. Our laboratory used PEG-PCL to construct NPs of
size about 150nm, which could load both hydrophobic and hydrophilic drugs.
Similarly, PEG-PCL NPs are also modified with specific ligands for brain tar-
geting drug delivery. For example, we modified PEG-PCL NPs with both TGN
peptide and AS1411 aptamer to penetrate the BBB and then target to brain
tumor cells (Gao et al., 2012). Using near infrared dye as a probe, it was shown
that the dual-modified PEG-PCL NPs could specifically accumulate in brain
tumor site with high tumor/normal brain ratio. After loading with docetaxel, a
common chemotherapeutic drug, the dual-modified NPs prolonged the median
survival time of brain tumor–bearing mice from 17 to 32days. More impor-
tantly, the PEG-PCL NPs did not display obvious side effects to most normal
tissues after administering several times.
Other kinds of biodegradable polymers are also used in brain targeting
delivery of chemical drugs in a similar way, such as poly(butyl cyanoacrylate)
(PBCA), poly(isohexyl cyanoacrylate), and poly(alkyl cyanoacrylates) (Kreuter,
2014). For example, RGD-modified (PEG)-b-poly-(l-glutamic acid) micelles
were capable of delivering platinum to brain tumor with rapid accumulation and
high permeability from vessels into the tumor parenchyma (Miura et al., 2013).

2.3 Dendrimers
Different from other kinds of polymers, dendrimers are well defined with pre-
cise size, shape, surface groups, and architectures. There are several kinds of
dendrimers, such as poly(amidoamine) (PAMAM), poly(etherhydroxylamine),
and poly(propyleneimine) (PPI), which are all exploited extensively for drug
and gene delivery (Menjoge et al., 2010). PAMAM is the first commercial den-
drimer. Because of the fruitful amino groups on the surface, PAMAM often
directly conjugates with drugs through linkers. Zhu et al. (2010) conjugated
DOX onto PAMAM through cis-aconitic anhydride, and 1 molecule of PAMAM
could be loaded with 14 molecules of DOX. Zhang et al. (2011) further modified
the DOX-PAMAM with RGD for brain tumor targeting delivery because RGD
can interact with integrin receptors that overexpressed on both brain tumor cells
and neovasculatures. The distribution of RGD-modified DOX-PAMAM in brain
tumor was 21.6-fold and 1.3-fold higher than that of free drug and unmodified
DOX-PAMAM, respectively. Consequently, the RGD-modified DOX-PAMAM
significantly prolonged the median survival time of brain tumor–bearing mice.
Dual targeting strategy could further improve the drug delivery efficiency due
to the complex microenvironment of brain tumor (Gao et al., 2013). Tf and
wheat germ agglutinin (WGA) dual-modified PAMAM was constructed to
deliver DOX because these two ligands could both enhance the BBB penetra-
tion and elevate brain tumor cell uptake (He et al., 2010). The transportation
ratio across BBB of the dual targeting system achieved 13.5% of DOX after 2h
incubation, which was significantly higher than that of Tf-modified PAMAM
(7%) and WGA-modified PAMAM (8%). Regarding the multidrug resistance
proteins are responsible for exocytosis drugs by BBB and tumor cells, tamoxi-
fen, an estrogen receptor antagonist that could inhibit the multidrug resistance
proteins thus improve the BBB penetration, was comodified with Tf onto DOX-
PAMAM (Li et al., 2012). The transportation ratio across the BBB model of this
dual-modified system was 6.1%, which was higher than single-ligand-modified
DOX-PAMAM. As a result, in the BBB model and brain tumor cell coculture
system, the dual-modified DOX-PAMAM led to 31% apoptosis of brain tumor
cells, whereas the number for Tf-modified DOX-PAMAM was only 24%.
Dendrigraft poly-lysine (DGL) is a kind of dendrimer that is similar to
PAMAM. Because of the lower toxicity compared with PAMAM, DGL has
gained increasing attention in drug delivery. Although there are several studies
that evaluated the chemical drug delivery efficiency of DGL (Hu et al., 2015a,b),
no study has evaluated the delivery to treat CNS disorders. Most related studies
focused on gene delivery, which would be discussed in the next section.
2.4 Metal Nanoparticles
Several kinds of metal-based NPs were established for biological application,
such as gold NPs (AuNPs), silver NPs, iron NPs, copper NPs, quantum dots

(QDs), upconversion NPs, and metal organic framework. These nanomateri-
als showed distinguished properties compared with natural materials and tra-
ditional polymers, and some preliminary studies were performed to evaluate
the potential of these nanomaterials in brain targeting delivery. However, the
toxicity of these materials is a major barrier in biological application. In this
section, we focus on the application of AuNPs. Other metal NPs showed similar
application as AuNPs in brain targeting delivery.
The common application of AuNPs is delivery of drugs to brain tumor.
Our group decorated AuNPs with angiopep-2, a ligand for low-density
lipoprotein-related protein, which overexpressed on both BBB and brain tumor
cells (Demeule et al., 2008; Ruan et al., 2015b). The model drug, DOX, was
anchored onto the AuNP surface through hydrozone, a pH-sensitive linker. The
drug-loading capacity was as high as 9.7%, which was higher than for many
other kinds of NPs. Owing to the hydrozone between AuNPs and DOX, the
release of DOX was obviously pH sensitive. The 48-h cumulative release in pH
7.4 was 21.9%, whereas the number in pH 5.0 was elevated to 88.3%. Combin-
ing BBB and brain tumor targeting of anigopep-2 and tumor-specific release
of DOX, DOX-loaded angiopep-2-modified AuNPs significantly prolonged the
median survival time of brain tumor–bearing mice from 19 to 55days. The Tf
peptide-modified AuNPs also could elevate the delivery of photodynamic pro-
drug Pc4 into brain tumor, which was sixfold higher than that of unmodified
AuNPs (Dixit et al., 2015). However, due to the heterogenous microenviron-
ment, the targeting delivery efficiency of NPs with fixed size was still modest
because high tumor retention requires large particle size, whereas high tumor
penetration requires small size (Cabra et al., 2011; Kibria et al., 2013). To sat-
isfy the controversial requirement of tumor retention and penetration, our group
fabricated AuNPs with gelatin NPs (Ruan et al., 2015a), because the gelatin
could be degraded by tumor overexpressed matrix metalloproteinase-2 (MMP-
2), which resulting size reduction from large to small (Wong et al., 2011). After
24-h incubation with MMP-2, the size of fabricated NPs considerably reduced
from 188.2 to 55.9nm. Thus this kind of NPs showed better tumor penetration
and retention, resulting in higher brain tumor accumulation of DOX.
2.5
Carbon-Based Inorganic Nanomaterials
There are several kinds of carbon-based inorganic nanomaterials involved
in the diagnosis and treatment of brain diseases. Carbon nanotubes (CNTs)
received much attention because they could easily load drugs such as DOX
and small interfering RNA (siRNA) onto the polyaromatic surface of nano-
tubes through π-π stacking (Wang and Al-Jamal, 2015). The needle-like shape
of CNTs provides them a unique mechanism to facilitate membrane penetra-
tion and cell internalization (Wong et al., 2013). There was direct evidence
that CNTs could penetrate through in vitro microvascular cerebral endothelial

monolayers (Shityakov et al., 2015). In vivo, acetylcholine-loaded CNTs
without further modification successfully reverse the kainic acid-induced AD
symptom, suggesting CNTs could directly penetrate through the BBB (Yang
et al., 2010). Our group modified oxidized multiwalled CNTs (OMWNTs)
with anogiopep-2 to construct brain tumor targeting delivery systems (Ren
et al., 2012). The DOX loading efficiency of this system was as high as 80%.
In vitro, the DOX-loaded angiopep-2-modified OMWNTs showed signifi-
cantly higher cytotoxicity (IC50 was 2.98μg/mL against C6 glioma cells)
than the unmodified OMWNTs (IC50 was 88.98μg/mL). In vivo, angiopep-
2-modified OMWNTs accumulated much more in brain tumor than unmodi-
fied OMWNTs. As a result, the median survival time of brain tumor–bearing
mice prolonged to 43days after treatment by DOX-loaded angiopep-2-mod-
ified OMWNTs, which was significantly better than free DOX (33.5days)
and DOX-loaded unmodified OMWNTs (36days). This study clearly demon-
strated that CNTs could be used for brain tumor targeting delivery.
Graphene is a two-dimensional nanomaterial with a single layer. The large
surface of graphene makes it easy to load or chemically conjugate various
drugs with high loading capacity (Zhang et al., 2012). To improve biocom-
patibility, graphene is often coated with PEG. Chowdhury et al. (2015) con-
jugated lucanthone onto PEGylated graphene. It was shown that the uptake
by glioma cells was much higher than that of control cells, suggesting the
PEGylated graphene could deliver drugs into glioma cells. Polyacrylic acid
(PAA) was also used to improve the solubility and biocompatibility of gra-
phene oxide. Then the PAA-modified graphene oxide was conjugated with
1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a chemotherapeutic drug, to
treat brain tumor because this drug itself could penetrate the BBB (Lu et al.,
2012). A drug-loading capacity of 19.8% could be achieved, and 70% of the
drug activity was retained after conjugation onto the graphene oxide. In vitro
antitumor study demonstrated that PAA-modified graphene oxide signifi-
cantly decreased the IC50 of BCNU.
Carbon dots (CDs) are also suitable for drug delivery and cancer treatment
because of their small size and potential photothermo effect. Graphene QDs
showed ability in inhibition of β-amyloid aggregation (Liu et al., 2015). As
the dots may penetrate the BBB without modification (Qian et al., 2014a), the
graphene QDs may be used for AD treatment. Our group decorated angiopep-
2-modified CDs with DOX using a disulfide bond to deliver drugs into brain
tumor cells (Chen et al., 2015b). The angiopep-2 could effectively mediate
the internalization of the system by C6 glioma cells; then the DOX is released
into the cells due to the high concentration of GSH in C6 cells (Ballatori et al.,
2009). The DOX-loaded angiopep-2-modified CDs showed higher C6 cellular
uptake and cytotoxicity compared with unmodified CDs and free DOX, sug-
gesting that angiopep-2-modified CDs could serve as a drug delivery system for
brain tumor. However, no in vivo study was reported.

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The Project Gutenberg eBook of Frances Mary
Buss and her work for education

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Title: Frances Mary Buss and her work for education
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*** START OF THE PROJECT GUTENBERG EBOOK FRANCES MARY
BUSS AND HER WORK FOR EDUCATION ***

The cover image was created by the transcriber and is placed in
the public domain.

Photo. by Russell and Sons.
Yours always [** Illegible]
Frances M. Buss

FRANCES MARY BUSS
AND HER WORK FOR EDUCATION
BY
ANNIE E. RIDLEY
“We work in hope”
The School Motto
WITH PORTRAITS AND OTHER ILLUSTRATIONS

LONDON
LONGMANS, GREEN, CO.
AND NEW YORK
1895
All rights reserved

PREFACE
In a life written by a friend for friends there must
of necessity be more of the intimacy of private
friendship than in a record written dispassionately for
an unknown public. The world in general knows
Frances Mary Buss as a public worker—capable,
energetic, successful. By her friends she was loved
as one of the most womanly of women—true, and
tender, and loyal. Her work, to which all women of
this generation owe so much, must assume
prominence in the story of her life; but what is most
desired is to show her as she was to her friends.
My warmest thanks are here offered to all who
have so freely and so kindly helped me in this labour
of love: first, to Miss Buss’ own family and personal
friends, and to old pupils; to Mrs. Bryant, D.Sc., and
the members of the staff in both schools; and, for
many valuable educational details, to Miss Emily
Davies, Miss Beale, Mrs. William Grey, Miss Shirreff,
Miss Mary Gurney, Miss Agnes J. Ward, Miss Hughes,
and Dr. and Mrs. Fitch.

CONTENTS
CHAPTER PAGE
Introductory—Then
and Now
1
BOOK I.
EARLY LIFE.
I. Childhood 25
II. Girlhood 41
III. Influence 58
IV. Helpfulness 73
BOOK II.
PUBLIC WORK.
I. Transition 87
II. “We Work in Hope” 103

III. “The Sisters of the
Boys”
117
IV. Timely Help 131
V. Triumph 146
VI. With her Fellow-
workers
166
VII. Life at Myra Lodge 181
VIII. Early Educational
Ideals
200
IX. Practical Work 215
X. The Head-mistresses’
Association
231
XI. University Education
for Women
252
XII. Training Colleges for
Teachers
273
XIII. General Interests 287
BOOK III.
LATER YEARS.
I. In the Holidays 309
II. Rome 321
III. Social Life 336

IV. Friendships 349
V. Rest 366
VI. “And her Works do
follow her”
379

LIST OF ILLUSTRATIONS
PAGE
Frances M. Buss Frontispiece
Frances M. Buss in 1860 and
1872
87
The Lower School 131
The Great Hall, North London
Collegiate School for Girls
162
The Gymnasium, North London
Collegiate School for Girls
200
North London Collegiate School
for Girls
214
Miss Buss and Dr. Sophie Bryant 273

ERRATA.
Page 1, line 2, for “July 29” read “July
18.”
Page 29, line 12, for “lighted” read
“lifted.”
Page 39, line 25, for “to play” read “for
play.”
Page 111, line 27, for “lady on” read “lady
in.”
Transcriber’s Note:
These corrections have been applied
to this electronic version of the book
—Oct. 25, 2019.

INTRODUCTORY.
THEN AND NOW.
“Educate women, and you educate the teachers of men; if
the child is father to the man, the woman forms the man in
educating the child. The cause of female education is then,
even in the most selfish sense, the cause of mankind at
large.”—C. G. Nicolay.
Gracious speech can seldom have been more truthful
than when the Prince of Wales said, on July 18,
1879, that few of their many public functions had
afforded the Princess and himself more gratification
than the opening of the great hall, given by the
Clothworkers’ Company to the North London
Collegiate School for Girls, a ceremony putting the
final touch to the work of so many years.
It would not be easy to find a more attractive sight
than this spacious building, filled with its five
hundred happy young girls, either on “Founder’s
Day,” when, decked in the school flower, we see
them in that April mood in which

“The heart with rapture fills,
And dances with the daffodils;”
or when, on Prize-day, in the glory of summer roses,
their jubilant young voices ring out in the favourite
school-song, as, with fearless and confident eyes,
they look “Forty years on!” while their elders, looking
back down that long vista, think of the difference
they can remember between Then and Now.
It was in this hall, on the prize-day of 1892, that
the chairman, Mr. Fearon, drew a remarkable
contrast between the present days of light for girls’
education, and the dark days of the first Schools
Inquiry Commission of 1864, of which he had been a
member. Then, it was still possible for the
Commissioners to gravely ask if girls were capable of
learning Latin and mathematics? Now, as he pointed
out, this question might be answered by the results
of this one year for this one school—eighteen passes,
with two honours, on the University Examinations—
to say nothing of the recent success at Cambridge,
where a woman took a place above the Senior
Wrangler.
As a member of the Commission of 1864, and,
later, of the Endowed Schools Commission, Mr.
Fearon was glad to claim some part in the making of

this first public school for girls, of which he felt that
“if ever there was an institution of which they might
be proud, the success of which was calculated to stir
the pulses, excite the emulation and enthusiasm of
others, and give intense satisfaction to all who took
part in it, either as founder, well-wishers, or friends,
it was the North London Collegiate School for Girls.”
Then, from the brilliant hall, with its “rose-bud
garden of girls,” the scene changed to the dark
November day—November 30, 1865, a date to keep
in mind—when, struggling through the November
fog, Emily Davies and Frances Mary Buss made their
way to the dull committee-room in Victoria Street,
where the Commissioners awaited their coming.
The members of the Commission were Lord
Taunton, Lord Lyttelton, Lord Stanley, Sir Stafford
Northcote, the Dean of Chichester, the Rev. A. W.
Thorold, Mr. Acland, Mr. Baines, Mr. Forster, Mr. Erle,
and Dr. Storrar. To these, as Assistant-
Commissioners, were added Messrs. D. B. Fearon, H.
A. Giffard, C. H. Staunton, T. H. Green, J. L.
Hammond, J. G. Fitch, J. Bryce, and H. M. Bompas.
The work of this Commission lasted from 1864 to
1869, and, later, many of the same gentlemen were
appointed on the Endowed Schools Commission, and
may be said to have carried on the same work, since

they here applied the remedy to ills previously
discovered by their researches. There are few of
these names which will not be held in lasting honour
by all thoughtful women who know how much is due
for steady help in every cause most concerning their
welfare.
It has, nevertheless, taken thirty years—since that
same November 30, 1865—to give women a place
side by side with men, on a Royal Commission,
when, in 1894, Mrs. Bryant, D.Sc., took the seat Miss
Buss was no longer able to fill on the second Royal
Commission of Inquiry into Secondary Education. It
is not difficult to imagine the feeling of satisfaction
with which Miss Buss saw her “brilliant young fellow-
worker,” as she delighted to call her, taking this proud
position.
Further to mark the contrast between 1865 and
1894, we may take a passage in a letter from Miss
Buss to Miss Davies, dated December 5, 1865, whilst
still waiting for the Commissioners’ Report, in which
she says—
“When will the evidence come, I wonder? I am so curious
to know what I said, and what you said too. It is very odd,
but the mist which surrounds that interview does not clear.
“They were indeed kind, and more than kind, as you say.
As for Mr. Acland, he is what the ‘Home and Colonial’

consider you to be!
“I can’t get over my astonishment at their civility; and it is
such fun to be told to ‘take a chair,’ as if we were the ‘party’
whom servants are so fond of announcing.”
This is the one side. Wherever it was possible to
see “fun” Miss Buss would see it. But there was
another side too, revealed in a little remark made by
Mr. Fearon to Mrs. Bryant, when the prize-giving was
over at which he gave his reminiscences of that
November day: “We were all so much struck by their
perfect womanliness. Why, there were tears in Miss
Buss’ eyes!”
And small wonder if this were so! In 1865—thirty
years ago—it was an event to cause a heart-thrill
when a woman was summoned, not to meekly
receive information, but actually to give it; not to
listen, but to speak, and before so important a body.
It is quite conceivable that as they paused on the
threshold these two ladies may have felt far more
than a merely imaginative flash of sympathy with
brave women of old, who had faced sterner tribunals
to pay forfeit with life itself for the holding of new
and strange doctrines.
To say that great events may hang on smallest
incidents is a mere truism, trite as true. But we

cannot doubt that a real turning point in the history
of the English people was reached in the first official
recognition of the equal share of women in the task
of training the young. From this date what was
before impossible became fact, and education takes
rank as a true science.
It is of special interest in our own day, when the
jarring note of antagonism between men and women
is too often struck, to look back and remember the
help given by men to the higher education of
women. We note that the two most definite starting
points of the new educational movement are to be
found in the very innermost sanctum, in the
strongest stronghold of masculine rights and
privileges—the Universities and the House of
Commons.
When, in 1863, the University of Cambridge
opened its Local Examinations for girls, and when, in
1864, the House of Commons gave authority to a
Royal Commission to extend its inquiry into the state
of the education of girls, the new era was practically
inaugurated. Henceforth women became free to do
whatever they had power to do.
Nor was this the first help given by men to the
better education of girls. In 1848—the great year of
revolution—the professors of King’s College had

opened the classes which speedily developed into
Queen’s College, the forerunner of Bedford and
Cheltenham Colleges. In 1850 the Rev. David Laing,
who had been associated with the Queen’s College
movement, gave his valuable help in the expansion
of Miss Buss’ first small school on similar lines into
the North London Collegiate School for Ladies. In
1865 this school stood so high that Miss Buss was
asked by the Commissioners to give her views of
education generally. This summons was doubtless
the result of the report of the Assistant
Commissioners who conducted the inquiry.
It was mainly due to the efforts of Miss Davies and
Miss Bostock that girls’ schools were included in this
inquiry. These ladies sent up a widely signed
memorial from persons who had been interested in
the extension to girls of the Local Examinations. Mr.
Roby, the secretary, early in 1865, responded
favourably to this appeal, pointing out that, as so
many girls were privately educated, the limits of
investigation in their case were much narrower than
those for boys, and also pointing out that the
numbers and value of endowments for girls were
also restricted. But, “subject to these limitations,” he
added, “the Commissioners were willing to embrace
in their inquiry the education of both sexes alike.”

He stated also that the Commissioners expected to
derive much important information from the evidence
of persons of special experience and knowledge in
the various matters connected with their inquiry.
Among these witnesses they were ready to include
such persons as may be recommended to them as
best qualified to express opinions on the subject of
this memorial.
In November, 1865, Miss Davies and Miss Buss
were called to give their evidence. Miss Beale
followed in April, 1866, and, during that same year,
information on the education and the employment of
women was given by six other ladies—Miss
Wolstenholme, Miss Porter, Miss Kyberd, Miss Martin,
Miss Smith, and Miss Gertrude King.
In 1870 a valuable summary of this evidence was
compiled by Miss Beale from the twenty large
volumes issued by the Commissioners. It is from this
smaller blue-book that the following extracts are
taken, the evidence of Miss Davies, Miss Buss, and
Miss Beale being selected as characteristic of the
views of the whole.
Read in the light of the recent University honours
gained by women, many of the questions and
answers of these examinations will have a curious
interest for the “modern girl.”

When Lord Taunton put the question to Miss Buss:
—
“‘Your girls come up to you extremely ignorant,’ there is
evident conviction in her brief reply: ‘Extremely ignorant!’
“‘Do they seem to be very little taught at all?’—‘In all the
essentials, hardly ever. They seldom know any arithmetic, for
instance. We have a large number of girls, of thirteen,
fourteen, and fifteen, come to us who can scarcely do the
simplest sum in arithmetic.’
“‘Have you taken any interest in the movement which has
been made to induce the University of Cambridge to institute
examinations and confer honorary distinctions on
girls?’—‘Yes; twenty-five of our pupils went up to the
experimental examination.’
“‘Do you anticipate any beneficial results from the steps
which the University of Cambridge has been induced to
adopt?’—‘Yes; I am quite sure that great good has been
done already. An immense stimulus has been given,
especially to English and arithmetic. The girls have
something to work for, some hope, something to aim at, and
the teachers also.’
“‘As far as you are able to judge, do you think the class of
school-mistresses is as good as it ought to be?’—‘The class
of teachers generally is not.’
“‘In your opinion, should the education of a girl differ
essentially from that of a boy in the same rank of life, with
regard to the subjects which are to be taught?’—‘I think not,
but it is rather difficult to ascertain what is the proper
education for a boy.’
“‘You believe there is not such a distinction between the
mental powers of the two classes as to require any wide

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