Nanoparticles and Brain Tumor Treatment

111 Pages·2012·0.742 MB·English

by  Gerardo Caruso, Maria Caffo, Giuseppe Raudino

Nanoparticles
and Brain Tumor
Treatment
Gerardo Caruso, M.D.,
Maria Caffo Ph.D, M.D.,
Giuseppe Raudino, M.D., and
Francesco Tomasello, M.D.
© 2012, ASME, 3 Park Avenue, New York, NY 10016, USA (www.asme.org)
All rights reserved. Printed in the United States of America. Except as permitted under
the United States Copyright Act of 1976, no part of this publication may be reproduced
or distributed in any form or by any means, or stored in a database or retrieval system,
without the prior written permission of the publisher.
Co-published by Momentum Press, LLC, 222 E. 46th Street, #203, New York,
NY 10017, USA (www.momentumpress.net)
INFORMATION CONTAINED IN THIS WORK HAS BEEN OBTAINED
BY THE AMERICAN SOCIETY OF MECHANICAL ENGINEERS FROM
SOURCES BELIEVED TO BE RELIABLE. HOWEVER, NEITHER ASME
NOR ITS AUTHORS OR EDITORS GUARANTEE THE ACCURACY
OR COMPLETENESS OF ANY INFORMATION PUBLISHED IN THIS
WORK. NEITHER ASME NOR ITS AUTHORS AND EDITORS SHALL
BE RESPONSIBLE FOR ANY ERRORS, OMISSIONS, OR DAMAGES
ARISING OUT OF THE USE OF THIS INFORMATION. THE WORK IS
PUBLISHED WITH THE UNDERSTANDING THAT ASME AND ITS
AUTHORS AND EDITORS ARE SUPPLYING INFORMATION BUT ARE
NOT ATTEMPTING TO RENDER ENGINEERING OR OTHER PROFES-
SIONAL SERVICES. IF SUCH ENGINEERING OR PROFESSIONAL
SERVICES ARE REQUIRED, THE ASSISTANCE OF AN APPROPRIATE
PROFESSIONAL SHOULD BE SOUGHT.
ASME shall not be responsible for statements or opinions advanced in papers or . . .
printed in its publications (B7.1.3). Statement from the Bylaws.
For authorization to photocopy material for internal or personal use under those
circumstances not falling within the fair use provisions of the Copyright Act, contact
the Copyright Clearance Center (CCC), 222 Rosewood Drive, Danvers, MA 01923,
tel: [phone], www.copyright.com.
Requests for special permission or bulk reproduction should be addressed to the ASME
Publishing Department, or submitted online at: http://www.asme.org/kb/books/
book-proposal-guidelines/permissions.
ASME Press books are available at special quantity discounts to use as premiums or
for use in corporate training programs. For more information, contact Special Sales at
[email protected].
A catalog record is available from the Library of Congress.
(Print) ISBN: 978-0-7918-6003-8
ASME Order No.: 860038
(Electronic) ISBN: 978-1-60650-408-6
Series Editors’ Preface
Biomedical and Nanomedical Technologies (B&NT)
This concise monograph series focuses on the implementation of various
engineering principles in the conception, design, development, analysis and
operation of biomedical, biotechnological and nanotechnology systems and
applications. The primary objective of the series is to compile the latest re-
search topics in biomedical and nanomedical technologies, specifically de-
vices and materials.
Each volume comprises a collection of invited manuscripts, written in
an accessible manner and of a concise and manageable length. These timely
collections will provide an invaluable resource for initial enquiries about
technologies, encapsulating the latest developments and applications with
reference sources for further detailed information. The content and format
have been specifically designed to stimulate further advances and applica-
tions of these technologies by reaching out to the non-specialist across a
broad audience.
Contributions to Biomedical and Nanomedical Technologies will inspire
interest in further research and development using these technologies and
encourage other potential applications. This will foster the advancement of
biomedical and nanomedical applications, ultimately improving healthcare
delivery.
Editor:
Ahmed Al-Jumaily, PhD, Professor of Biomechanical Engineering &
Director of the Institute of Biomedical Technologies, Auckland University
of Technology.
Associate Editors:
Waqar Ahmed, PhD, Chair, Nanotechnology and Advanced Manufac-
turing, and Head, Institute of Nanotechnology and Bioengineering, School
of Computing, Engineering & Physical Sciences, University of Central
Lancashire, UK.
Christopher H.M. Jenkins, PhD, PE, Professor and Head, Mechanical &
Industrial Engineering Department, Montana State University.

Contents
1. Introduction 1
2. Glioma biology 4
2.1 Invasion and angiogenesis 4
3. Blood-brain barrier 9
3.1 Blood-brain barrier physiology 9
3.2 Blood-brain barrier transport systems 11
4. Nanomedicine and nanotechnology 14
4.1 Nanoparticle drug delivery 19
4.1.1 Nanoparticle distribution 20
4.1.2 Nanoparticle functionalization 21
4.1.3 Nanoparticle targeting 23
4.2 Nanomedicine and cancer 25
4.3 Nanomedicine and toxicity 30
5. Nanoparticle technologies 33
5.1 Polymeric and polymer-drug conjugate nanoparticles 33
5.2 Micelle nanoparticles 35
5.3 Liposomes 37
5.4 Gold and silver nanoparticles 39
5.5 Metal oxide 41
5.6 Magnetic nanoparticles 42
5.7 Carbon nanotubes 43
5.8 Fullerenes 44
5.9 Peptides nanoparticles 45
5.10 Silica nanoparticles 46
5.11 Quantum dots 48
5.12 Dendrimers 49
6. Nanomedicine applications in brain tumors 51
6.1 Brain tumor drug targeting 55
6.1.1 Systemic approaches 55
6.1.2 Physiological approaches 56
6.1.2.1 Receptor-mediated transcytosis 57
6.1.2.2 Adsorptive-mediated transcytosis 58
6.1.2.3 Efflux pump inhibition 60
6.1.2.4 Cell-mediated drug transport 61
6.1.3 Direct CNS approaches 61
6.1.3.1 Intracerebral routes 65
6.1.4 Drug modifications and prodrugs 66
7. Experimental studies 69
8. Conclusions 77
References 81

Abstract
Despite progresses in surgery, radiotherapy, and in chemotherapy, an effec-
tive curative treatment of gliomas does not yet exist. Mortality is still close
to 100% and the average survival of patients with GBM is less than 1 year.
The efficacy of current anti-cancer strategies in brain tumors is limited by
the lack of specific therapies against malignant cells. Besides, the delivery
of the drugs to brain tumors is limited by the presence of the blood brain
barrier. The oncogenesis of gliomas is characterized by several biological
processes and genetic alterations, involved in the neoplastic transformation.
The modulation of gene expression to more levels, such as DNA, mRNA,
proteins and transduction signal pathways, may be the most effective mo-
dality to down-regulate or silence some specific gene functions. Gliomas are
characterized by extensive microvascular proliferation and a higher degree
of vasculature. In malignant gliomas targeted therapies efficacy is low. In
this complex field, it seems to be very important to improve specific selective
drugs delivery systems. Drugs, antisense oligonucleotides, small interference
RNAs, engineered monoclonal antibodies and other therapeutic molecules
may diffuse into CNS overcoming the BBB. Nanotechnology could be used
both to improve the treatment efficacy and to reduce the adverse side effects.
Nanotechnology-based approaches to targeted delivery of drugs across the
BBB may potentially be engineered to carry out specific functions as needed.
Moreover, nanoparticles show tumor-specific targeting and long blood cir-
culation time, with consequent low-short-term toxicity. Nanotechnology
deals with structures and devices that are emerging as a new field of re-
search at the interface of science, engineering and medicine. Nanomedicine,
the application of nanotechnology to healthcare, holds great promise for
revolutionizing medical treatments, imaging, faster diagnosis, drug delivery
and tissue regeneration. This technology has enabled the development of
nanoscale device that can be conjugated with several functional molecules
including tumor-specific ligands, antibodies, anticancer drugs, and imag-
ing probes. Nanoparticle systems are, also emerging as potential vectors for
brain delivery, able to overcome the difficulties of the classical strategies. By
using nanotechnology it is possible to deliver the drug to the targeted tis-
sue across the BBB, release the drug at the controlled rate, and avoid from
degradation processes. At the same time, it is also necessary to retain the
drug stability and ensure that early degradation of drugs from the nano-
carriers does not take place. Large amounts of small molecules, such as
contrast agents or drugs, can be loaded into NPs via a variety of chemical
methods including encapsulation, adsorption, and covalent linkage. Most
targeting molecules can be added to the surface of NPs to improve targeting
through a concept defined as surface-mediated multivalent affinity effects.
viii Nanoparticles and Brain Tumor Treatment
The future challenges may be the possibility to modify the cell genome and
induce it to a reversion to the wild-type conditions and the enhancing of im-
mune system anti-tumor capacity. Recent advances in molecular, biological
and genetic diagnostic techniques have begun to explore cerebral glioma-
associated biomarkers and their implications for gliomas development and
progression. Realization of targeted therapies depends on expression of the
targeted molecules, which can also provide as specific biomarkers. The de-
velopment of multifunctional NPs may contribute to the achievement of
targeted therapy in glioma treatment.
1. Introduction
Gliomas are the most common primary brain tumors in adults, with a
worldwide incidence of approximately 7 out of 100,000 individuals per year.
Although brain tumors constitute only a small proportion of overall human
malignancies, they carry high rates of morbidity and mortality. Mortality
is still close to 100% and the average survival of patients with glioblastoma
multiforme (GBM) is less than 1 year when classical treatment is used.
Recent progress in multimodal treatment of this disease has led to only a
slight increase in average survival up to 15–18 months. The effectiveness of
the actual chemotherapeutic approach and multimodal targeted therapies
remains modest in gliomas.
Gliomas are brain tumors with histological, immunohistochemical and
ultra structural features of glial differentiation. Approximately 50% of pri-
mary brain tumors are gliomas, arising from astrocytes, oligodendrocytes,
or their precursors and ependymal cells. Gliomas are classified from I to
IV according to the World Health Association (WHO) malignancy scale.
Grade I gliomas are benign with a slow proliferation rate and include py-
locitic astrocytoma most common in pediatric age. Grade II gliomas are
characterized by a high degree of cellular differentiation and grow diffusely
into the normal brain parenchyma and are prone to malignant progression.
They include astrocytoma, oligodendroglioma and oligoastrocytoma. Grade
III lesions include anaplastic astrocytoma, anaplastic oligoastrocytoma and
anaplastic oligodendroglioma. These tumors show a higher cellular density
and a notable presence of atypia and mitotic cells. Grade IV tumors are the
most malignant and also the most frequent gliomas and include glioblas-
toma and gliosarcoma. These tumors presented microvascular proliferations
and pseudopalisading necrosis.
Conventional brain tumor treatments include surgery, radiation therapy
and chemotherapy. Surgical treatment is invasive but represents the first
approach for the vast majority of brain tumors due to difficulties arising
in early stage detection. However, after surgical resection, the residual pool
of invasive cells rises to recurrent tumor which, in 96% of cases arise ad-
jacent to the resection margins [1]. Aggressive treatment modalities have
extended the median survival from 4 months to 1 year, but the survival is
often associated with significant impairment in the quality of life. Radiation
therapy and chemotherapy are non-invasive options often used as adjuvant
therapy, but may also be effective for curing early-stage tumors. In patients
with recurrent GBM, the 6-months progression-free survival is only 21%
after treatment with temozolomide [2]. Adjuvant radiotherapy gives limited
benefits and causes debilitation side effects which reduce its efficacy [3]. The
effectiveness of systemic chemotherapy is limited by toxic effects on healthy
cells, generally resulting in morbidity or mortality of the patient. Moreover,
the presence of the BBB limits the passage of a wide variety of anticancer