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CHAPTER
15
Beyond the BloodBrain Barrier:
Facing New Challenges and Prospects
of Nanotechnology-Mediated Targeted
Delivery to the Brain
Mukesh Kumar
1
, Piyoosh Sharma
2
, Rahul Maheshwari
3
,
Muktika Tekade
4
, Sushant K. Shrivastava
2
and
Rakesh K. Tekade
3
1
Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong,
Hong Kong
2
Department of Pharmaceutical Engineering & Technology, Indian Institute of
Technology (Banaras Hindu University), Varanasi, India
3
National Institute of Pharmaceutical
Education and Research (NIPER)- Ahmedabad, Gandhinagar, Gujarat, India
4
TIT College of
Pharmacy, Bhopal, Madhya Pradesh, India
OUTLINE
15.1 Introduction: Brain Tumor 398
15.2 Role of the BloodBrain Barrier
and Mechanism of Transport 401
15.3 Hurdles in Drug Delivery to the
Brain 404
15.4 Approaches in Delivering Drugs
to the Brain 405
15.4.1 Invasive Approach 406
15.4.2 Pharmacological Approach 407
15.4.3 Biological or Physiological
Approach 408
15.5 Nanotechnology and the
BloodBrain Barrier 409
15.6 Nanodevices for Brain Tumor
Targeting and Delivery 410
15.6.1 Liposomal Formulations 410
15.6.2 Polymeric Nanocarriers 412
15.6.3 Magnetic Nanoparticles 413
15.6.4 Dendrimeric Nanocarriers 414
397
Nanotechnology-based Targeted Drug Delivery Systems for Brain Tumors
DOI: https://doi.org/10.1016/B978-0-12-812218-1.00015-4 ©2018 Elsevier Inc. All rights reserved.
15.6.5 Carbon Nanotubes 416
15.6.6 Gold Nanoparticles 417
15.6.7 Viral Nanoparticles 418
15.6.8 Nucleic Acids-Based
Nanotechnology 418
15.7 Nanotechnology for Brain Tumor
Imaging 419
15.8 Challenges and Safety Considerations
of Nanotechnologies Used for
Brain-Targeted Delivery 421
15.9 Future Perspectives and
Conclusion 422
Acknowledgments 422
References 423
Further Reading 437
15.1 INTRODUCTION: BRAIN TUMOR
Cancer is one of the leading causes of mortality worldwide, with approximately 8.8 million
deaths in 2015 (Ferlay et al., 2013). Primary brain tumors are one of the most prevalent CNS
tumors, accounting for 8590% of cases and affecting all age groups (Mehta, Vogelbaum,
Chang, & Patel, 2011).Braincancerisaverycommonformofsolidmalignancyinchildrenand
adolescents (birth to 19 years), and it has surpassed leukemia as the leading cause of cancer
death (Adams et al., 2012; Siegel, Miller, & Jemal, 2016). According to a report of the cancer sta-
tistics for 2016, brain tumor is the second leading cause of cancer death in young males below
39 years of age and young females below 20 years of age (Adams et al., 2012; Siegel et al., 2016).
Brain tumors are classified by the WHO based on tumor morphology, cytogenetics, molecular
genetics, and immunologic markers into various types (Mehta et al., 2011). Based on tumor his-
tology and slow-growing and fast-growing properties, brain tumors are graded by their rate of
malignancy (Kleihues, Burger, & Scheithauer, 1993)(Table 15.1). The 2016 WHO classification
of brain tumors and their grading is summarized in Table 15.2 (Louis et al., 2016).
Recently, the American Cancer Society estimated 23,800 new cases and 16,700 deaths
from brain tumors and other nervous system tumors in the United States in the year 2017.
Brain tumors may be either noncancerous (benign) or cancerous (malignant). Of all the
brain tumors, glioblastoma is the most fatal and frequent malignant brain tumor (Adams
et al., 2012; Ellor, Pagano-Young, & Avgeropoulos, 2014). Glioblastomas and anaplastic
astrocytomas account for 38% of brain tumors and are the most common (Mehta et al.,
2011; Nagane, 2011; Tzeng & Green, 2013). Meningiomas and other mesenchymal tumors
account for 27% of brain tumors and are the second most common brain tumors (Mehta
et al., 2011). Glioblastoma or glioblastoma multiforme (GBM), one of the astrocytic grade
IV tumors, is a mitotically active, highly vascularized, and necrosis-prone tumor (Ellor
et al., 2014). Exposure to ionizing radiation, vinyl chloride, EpsteinBarr virus infection,
and HIV infection are risk factors for brain tumors (Perkins & Liu, 2016; McNeill, 2016;
Mehta et al., 2011; Schabet, 1999). Also, cellular phone use, radio frequency exposure, and
electromagnetic radiation have also been found to be risk factors for brain cancer (Group,
2010; Kheifets, Sussman, & Preston-Martin, 1999; Schu
¨z et al., 2006).
398 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
Interestingly, individuals with asthma and other allergic disorders such as hayfever,
eczema, and food allergies have a lower risk of brain cancer (Amirian et al., 2016; Wigertz
et al., 2007). However, the underlying mechanism of association between environmental,
occupational exposure and brain cancer risk is not entirely understood (da Silva, 2016). The
symptoms of brain tumors depend on the tumor type and anatomical regions of the lesions.
For example, meningioma, which is a very common intracranial brain tumor, originates in
the dura mater and is often asymptomatic (Aizer & Alexander, 2017; Vernooij et al., 2007),
while GBM, which is the most common intraparenchymal tumor of the CNS, is symptom-
atic. The general symptoms of brain tumor are headache, nausea, seizures, anorexia, nausea,
vomiting, lack of concentration, and mood disorders (Aizer & Alexander, 2017; Mehta et al.,
2011). Although the symptoms may correlate with the affected brain region, lesions in the
frontal lobe cause mood changes, lesions in the temporal lesions cause aphasia, while
cerebellar lesions cause ataxia and gait disturbances (Aizer & Alexander, 2017).
The ability of drugs to cross the bloodbrain barrier (BBB) and potentially target tumor
cells are a prerequisite for brain drug delivery that is unlikely to occur with most drugs
(Crawford, Rosch, & Putnam, 2016). Nanotechnology-based targeted drug delivery
systems are based on nanometer-size materials and devices which are used for biologic
applications and medicine (Lalu et al., 2017; Tekade, Maheshwari, Soni, Tekade, &
Chougule, 2017a; Tekade, Maheshwari, Soni, & Tekade, 2017b). Nanotechnology-based
drugs are designed in such a way that they cross the BBB and interact with tissue and cells
at the molecular level. Liposome, dendrimers, solid lipid nanoparticles and polymeric
nanoparticles are the majorly explored nanotechnology based platforms in recent years
TABLE 15.1 WHO Tumor Grading System Based on Histology and Proliferation Potential
WHO
Grade Criteria
I•The tumor cell has a low proliferative potential, and looks similar to a normal cell
•The proliferation is slower than grades II, III, and IV tumor cells
•There is a possibility of cure by surgical resection alone
II •The tumor cell has a higher proliferative potential than grade I tumor cells with less mitotic
activity
•Proliferation and metastasis are slower than grade III and IV tumor cells
•The possibility of recurrence after surgery and becoming a higher-grade tumor is greater than
grade I tumor cells
III •The tumor cell has a higher proliferation potential than grade I and II tumor cells and looks very
different from normal cells
•Marked histopathological changes with an increased mitotic activity and highly metastatic in
nature
•Treated with aggressive adjuvant chemotherapy
IV •The tumor cell has a high proliferation potential with postoperative progression and fatal
outcomes
•The tumor cells are mitotically active and necrosis-prone
•Grade IV tumors cannot be cured, however, they are treated with aggressive adjuvant
chemotherapy
39915.1 INTRODUCTION: BRAIN TUMOR
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
(Maheshwari et al., 2012, 2015a; Soni et al., 2016b, 2017; Tekade et al., 2017a, 2017b;
Tekade, Maheshwari, Tekade, & Chougule, 2017c). Also, these drugs reach the brain tumor
and can be administered systemically, i.e., intravenous with minimal systemic side effects
(Crawford et al., 2016). Successful drug delivery in the case of brain tumor is very chal-
lenging, and requires multidisciplinary approaches comprising of engineering, chemistry,
cell biology, physiology, pharmacology, and medicine (Silva, 2007). In this chapter, we
TABLE 15.2 Drug Transporter Expressed in the Brain and Involved in Multidrug Resistance in Brain Cancer
SN Transporter Short Description Anticancer Drug
1. P-glycoprotein
(MDR1;
ABCB1)
This is a prototypic energy- and
Na
1
-dependent transporter involved in the
multidrug resistance of cancer cells. ABCB1
or multidrug resistance 1 (MDR1) gene is
responsible for the expression of
P-glycoprotein
Doxorubicin, Daunorubicin, Docetaxel,
Epirubicin, Etoposide, Idarubicin,
Methotrexate, Mitoxantrone, Paclitaxel,
Teniposide, Vinblastine, Vincristine
2 MRP1
(ABCC1)
The ABCC1 gene encodes multidrug
resistance-associated protein 1 (MRP1) in
humans. The ABCC1 transporter protein is
especially prevalent in neuroblastoma
(Munoz, Henderson, Haber, & Norris, 2007)
Daunorubicin, Doxorubicin, Epirubicin,
Etoposide, Melphalan, Methotrexate,
Teniposide, Vinblastine, Vincristine
3. MRP2
(ABCC2)
Multidrug resistance-associated protein 2
(MRP2), also known as canalicular
multispecific organic anion transporter
1 (cMOAT), is encoded by the ABCC2 gene
in humans
Cisplatin, Doxorubicin, Epirubicin,
Etoposide, Flavopiridol, Methotrexate,
Vincristine
4. MRP3
(ABCC3)
Multidrug resistance-associated protein
3 (MRP3) is a member of the superfamily of
ATP-binding cassette (ABC) transporters
and is encoded by the ABCC3 gene in
humans
Etoposide, Methotrexate, Teniposide
5. MRP4
(ABCC4)
The ABCC4 gene encodes multidrug
resistance-associated protein 4 (MRP4) in
humans
Methotrexate, 6-Mercaptopurine,
Thioguanine, Topotecan
6. MRP5
(ABCC5)
Multidrug resistance-associated protein
5 (MRP5) is encoded by the ABCC5 gene
in humans
6-Mercaptopurine, Thioguanine
7. MRP6
(ABCC6)
Multidrug resistance-associated protein
6 (MRP6), also known as multispecific
organic anion transporter E, is encoded
by the ABCC6 gene in human
Actinomycin D, Cisplatin, Daunorubicin,
Doxorubicin, Etoposide, Teniposide, BCRP
8. BCRP
(ABCG2)
Breast cancer resistance protein (BCRP) is
the second member of the G subfamily of
the large ATP-binding cassette transporter
superfamily (ABCG2). It is encoded by the
ABCG2 gene in humans
Doxorubicin, Bisantrene, Irinotecan,
Methotrexate, Mitoxantrone, Topotecan
400 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
have summarized the role of the bloodbrain barrier and various nanotechnologies used
for targeting drugs for the treatment of brain tumor. Herein, we also briefly discussed the
hurdles, challenges, and safety considerations in using nanotechnologies for brain tumors.
15.2 ROLE OF THE BLOODBRAIN BARRIER AND MECHANISM
OF TRANSPORT
The bloodbrain barrier (BBB) is a most critical barrier that separates brain tissue from
the peripheral circulation (Ballabh, Braun, & Nedergaard, 2004; Saunders, Ek, Habgood, &
Dziegielewska, 2008). The BBB is a complex structure comprising blood vessel endothelial
cells, junction complex (tight junctions and adherence junction), and astrocytes. The endo-
thelial cells of the BBB are different from endothelial cells of the peripheral blood circula-
tion as these cells are devoid of fenestrations, and have a more extensive junction complex
and thin pinocytic vesicular transport system. The endothelial cell tight junction complex
restricts the paracellular flux of polar molecules across the BBB, while small nonpolar
molecules diffuse freely across plasma membranes (Ballabh et al., 2004; Ransohoff, 2016).
This barrier acts as a selective gate for the entry of molecules into the brain, and it limits
the diffusion of potentially harmful substances into the brain. It also has a critical role in
the transportation of essential nutrients such as glucose, amino acids and larger molecules
such as insulin, leptin, and iron transferrin into the brain and removal of metabolites and
harmful substances from the brain via specific receptors and transporters (Ransohoff,
2016; Saunders, Habgood, Møllga
˚rd, & Dziegielewska, 2016). The tight junctions (TJ) and
adherence junctions (AJ) are the building blocks of the BBB. The TJ comprises of integral
membrane proteins such as claudin, occludin, junction adhesion molecules, and various
cytoplasmic accessory proteins, while AJ comprises of a cadherin, catenin, alpha-actinin,
and vinculin. Occludin and claudins form a complex of proteins spanning the intercellular
cleft with junctional adhesion molecules and several cytoplasmic scaffolding and regula-
tory proteins (Wolburg & Lippoldt, 2002; Wolburg, Noell, Mack, Wolburg-Buchholz, &
Fallier-Becker, 2009). The adherens junctions hold the cells together, giving the tissue
structural support via a complex formation of cadherin and scaffolding proteins alpha-,
beta-, and gamma-catenin. These are crucial for the integrity of tight junctions, and disrup-
tion of AJs leads to disruption of the BBB (Wolburg & Lippoldt, 2002). Astrocytes play a
significant role in the induction and maintenance of TJ and for polarized expression of
transporters in the luminal and abluminal endothelial membranes (Cheslow & Alvarez,
2016; Ronaldson & Davis, 2016; Wolburg et al., 2009).
Chemotherapeutic agents have limited efficacy in the treatment of brain tumors due to
the impediment to delivery across the intact BBB and brain-to-blood efflux of drugs.
Moreover, WHO grade III and IV brain tumor patients have a disrupted BBB. Early studies
have demonstrated a correlation between the reduction of TJ and tumor differentiation and
experimental evidence has emerged to place TJ in the frontline as the structure that cancer
cells must overcome in order to metastasize (Bauer, Erly, Moser, Maya, & Nael, 2015;
Liebner et al., 2000; Long, 1970, 1979;Papadopoulos et al., 2001). Glioma-derived factors
such as transforming growth factor beta-2, caveolin-1, reactive oxygen species, matrix metal-
loproteinases, aquaporins, and proinflammatory cytokines are responsible for the
40115.2 ROLE OF THE BLOODBRAIN BARRIER AND MECHANISM OF TRANSPORT
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
degradations of tight TJs (Ishihara et al., 2008; Schneider et al., 2004; Wolburg, Noell, Fallier-
Becker, Mack, & Wolburg-Buchholz, 2012). However, the degraded TJ and leaky BBB do not
result in optimal pharmacokinetics and dynamics of chemotherapeutic agents. Because in
tumor cells increased expression and activity of efflux transporter, drug metabolizing
enzymes and cerebral blood flow dynamics leads to inefficient drug concentrations in the
brain (Neuwelt et al., 1986; Wei et al., 2013). The BBB strictly regulates the brain ion concen-
tration and maintains it optimal for synaptic signaling activity. The concentration is main-
tained in spite of changes that can occur in plasma following exercise or disease conditions
(Hansen, 1985; Hladky & Barrand, 2016; Jeong et al., 2006; Nischwitz, Berthele, & Michalke,
2008). The BBB also regulates the excitatory amino acid glutamate levels in the brain by
keeping the peripheral plasma glutamate pools away from the central glutamate pool
(Abbott, Ro
¨nnba
¨ck, & Hansson, 2006; Bernacki, Dobrowolska, Nierwin
˜ska, & Malecki, 2008).
Moreover, the BBB prevents the entry of plasma proteins such as albumin, prothrombin,
and plasminogen into the brain. The endogenous metabolites or proteins or xenobiotics
which sometimes act as neurotoxins are also expelled from the brain via some energy-
dependent efflux transporters (Abbott, Patabendige, Dolman, Yusof, & Begley, 2010).
Molecules, including nutrients and drugs, can cross the BBB via several mechanisms of
transportation. Lipid-soluble/nonpolar and low-molecular-weight molecules can pass
freely across the BBB and enter the brain along with the concentration gradient (Liu, Tu,
Kelly, Chen, & Smith, 2004). Meanwhile highly polar molecules and high-molecular-
weight molecules which have a tendency to form more than six hydrogen bonds cannot
pass freely cross the BBB (Clark, 2003; Gleeson, 2008). However, lipid solubility and the
molecular weight of molecules are not absolute factors for passive transportation; there are
several drug molecules which do not follow the above rule of passive transportation across
the BBB (Bodor & Buchwald, 2003). Oxygen and carbon dioxide freely move across the
BBB, along with their concentration gradients, while bicarbonate ions which have a nega-
tive charge are poorly permeable to the BBB. This is because molecules that carry a posi-
tive charge have an advantage of interaction with negatively charged cell membrane
components which aids in the passage of these molecules across the BBB.
Solute carriers are another important mechanism for transportation across the BBB.
Highly polar molecules are not able to diffuse across the BBB, and thus there are large
numbers of solute carriers in the BBB (Suhy, Webb, Papp, Geier, & Sadee, 2017; Zhang,
Knipp, Ekins, & Swaan, 2002a; Zhou, Zhu, Wang, & Murray, 2016). These solute carriers
in the BBB facilitate many essential polar nutrients, such as glucose and amino acids, into
the brain. Some of these solute carriers depend on Na
1
gradients such as sodium-
dependent glucose transporter, sodium myoinositol cotransporter, an amino acid trans-
porter of glutamate and aspartate (EAAT1), and nucleosides, nucleotides, and nucleobases
(CNT1) transporter (Abbott et al., 2010; Rose & Verkhrastky, 2016).
ATP-binding cassette transporters (ABC transporters) in the BBB are increasingly recog-
nized as a key factor for the distribution and elimination of drugs from the brain (Chen
et al., 2016; Lo
¨scher & Potschka, 2005a). These transporters are responsible for the much
lower BBB passage of highly lipophilic drugs (Chen et al., 2016). These efflux transporters
are involved in the removal of potentially neurotoxic endogenous or xenobiotic molecules
from the brain and play a crucial role in detoxification of the brain (Dallas, Miller, &
Bendayan, 2006). The most common and extensively studied ABC efflux transporter is
402 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
P-glycoprotein (Pgp). Previous studies have demonstrated a key role of Pgp in the efflux
of a variety of lipid-soluble drugs out of the brain because several drugs are substrates
for these ABC efflux transporters (Begley, 2004; Chen et al., 2016). Other ABC efflux
transporters present in the BBB are the multidrug resistance protein (MRP) family and
breast cancer resistance protein (BCRP) (Fletcher, Williams, Henderson, Norris, & Haber,
2016; Szaka
´cs, Paterson, Ludwig, Booth-Genthe, & Gottesman, 2006).
The polar, larger-molecular-weight molecules, such as peptides, can cross the BBB by
transcytosis. Transcytosis is a type of transcellular transport by which larger-molecular-
weight molecules are transported across the BBB via an endocytic mechanism into the brain
(Goulatis & Shusta, 2017; Jones & Shusta, 2007). Transcytosis is of two types: receptor-
mediated transcytosis and adsorptive-mediated transcytosis (Abbott et al., 2010; Herve
´,
Ghinea, & Scherrmann, 2008). Receptor-mediated transcytosis involves the binding of
macromolecules (ligand) to specific receptors followed by endocytosis of ligandreceptor
complex across the BBB. Examples of receptor-mediated transcytosis are transport of trans-
ferrin, melanotransferrin, insulin, leptin, TNF-alpha, and epidermal growth factor (Fig. 15.1)
FIGURE 15.1 Schematic representation of the various transport process of molecules across the BBB. Adapted
with permission from Fernandes, Soni, & Patravale (2010).
40315.2 ROLE OF THE BLOODBRAIN BARRIER AND MECHANISM OF TRANSPORT
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
(Banks, Niehoff, Martin, & Farrell, 2002; Demeule et al., 2002a; Pan & Kastin, 1999; Pan,
Kastin, & Brennan, 2000; Visser, Voorwinden, Crommelin, Danhof, & de Boer, 2004).
In adsorptive-mediated transcytosis, an interaction between the positive charge on the
macromolecule and cell surface binding sites results in endocytosis of this complex across
the BBB (Sauer, Dunay, Weisgraber, Bienert, & Dathe, 2005). Transport of cationized
albumin and cell-penetrating peptides (Synb5/pAnt-(43-45)) across the BBB are examples
of adsorptive-mediated transcytosis (Drin, Cottin, Blanc, Rees, & Temsamani, 2003;
Pardridge, Triguero, Buciak, & Yang, 1990).
15.3 HURDLES IN DRUG DELIVERY TO THE BRAIN
Globally, approximately 1.5 billion people suffer from some central nervous system dis-
orders at any given time (Brasnjevic, Steinbusch, Schmitz, Martinez-Martinez, & Initiative,
2009). Bloodbrain barrier permeability is a major challenge for the scientist to meet the
high demand from patients for effective treatments. The numbers of people affected by
CNS disorders is a trend that will increase due to the increasing number of older adults
in the general population. If effective treatments fail to meet the demand, the number
of people with CNS disorders will increase to approximately 1.9 billion by 2020
(Pardridge, 2001).
The major hurdle in drug delivery to the brain is the bloodbrain barrier and enzymes
which restrict the entry of drugs into the brain. The bloodbrain barrier, together with
enzymes such as drug-metabolizing enzymes, play an important role in the homeostasis of
the brain by providing a gateway for the selective entry of any substances including drugs
(Pablo Rigalli, Ciriaci, Domingo Mottino, Alicia Catania, & Laura Ruiz, 2016). The BBB
acts as an anatomical and biochemical barrier which protects the brain from the entry of
pathogens and potentially harmful substances.
Brain endothelial cells are different from the microvasculature in the periphery, the endo-
thelial cells of brain capillaries are closely attached and form tight junctions, with limited
fenestrations and pinocytic vesicles. TJ also called zonulae occludes, restrict the passage of
hydrophilic molecules and macromolecules into the brain. Tight junctions with other pro-
teins such as claudins, occludins, and junctional adhesion molecules form a junctional com-
plex which maintains the integrity of endothelial cells (Agarwal, Sane, Oberoi, Ohlfest, &
Elmquist, 2011; Ballabh et al., 2004; Vartanian et al., 2014). Moreover, the endothelial cells
are surrounded by astrocyte foot processes, which further strengthens the BBB. This prop-
erty of the brain makes most of the treatments for CNS disorders such as brain tumor,
Alzheimer disease, Parkinson disease, and mood disorders ineffective and is pushing
researchers to develop novel and effective brain drug delivery systems. Interestingly, in a
report, one scientist reported that only 1% of pharmaceutical companies globally are
involved in brain drug delivery programs (Pardridge, 2005), which shows a considerable
demand for effective treatment for brain-related disorders.
The understanding of BBB physiology in normal/disease conditions and the nature of
various transport receptors at the BBB helps researchers to overcome the failure of effec-
tive brain drug delivery. There are several factors responsible for crossing the BBB to gain
entry into the brain (Upadhyay, 2014). Binding of the drug to a transporter, opening and
404 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
closing of ion channels due to ionic concentration lipophilicity, enzymatic degradation of
drugs, larger-molecular-weight drugs, the presence of functional groups, and the presence
of charged residues of the molecules are factors which decide the BBB permeability of any
drugs (Huttunen & Rautio, 2011; Schaddelee et al., 2003; Seelig, Gottschlich, & Devant,
1994). Though the drug enters the brain and is therapeutically available, it becomes
inactive by the presence of catabolic enzymes in the brain tissue (Foti et al., 2015; Tamai &
Tsuji, 1996). Another major hurdle in drug delivery to the brain is drug resistance
(Lo
¨scher & Potschka, 2005b). In general, lipophilicity is one of the prerequirements for
BBB penetration and to reach targets in the brain. However, several lipophilic drugs have
shown much less BBB permeability than would be predicted by their lipophilicity (Begley,
2004). This is due to the high binding affinity of these drugs to drug efflux transporters
and multidrug resistance protein family which are present at the BBB (de Lange, 2004;
Lingineni, Belekar, Tangadpalliwar, & Garg, 2017; Sun, Dai, Shaik, & Elmquist, 2003).
Particularly in the case of brain tumors, anticancer drugs with a high lipophilicity have
shown remarkably poor efficacy in the treatment of primary or metastatic brain tumors.
Because these drugs have a high affinity towards multidrug ABC transporters such as
Pgp or MRPs (Table 15.2), this makes the drugs less bioavailable to the tumor site
(Bart et al., 2000; Kemper, Boogerd, Thuis, Beijnen, & van Tellingen, 2004; Oberoi et al.,
2016; Wardill et al., 2016).
15.4 APPROACHES IN DELIVERING DRUGS TO THE BRAIN
Effective treatment of neurological disorders, such as brain tumors, psychological disor-
ders, and neurodegenerative disorders depends on successful drug delivery to the brain
(Chen, Dalwadi, & Benson, 2004; Choonara, Kumar, Modi, & Pillay, 2016; Oberoi et al.,
2016). The major challenge for successful drug delivery to the brain is to cross the protec-
tive barriers of the BBB and bloodcerebrospinal fluid (CSF) barrier (BCSFB). The compo-
sitions of the BBB and BCSFB are different, the BBB comprises of the tight junctions of
endothelial cells and the foot processes of astrocytes, while the BCSFB comprises of tight
junctions of choroid plexus cells with intracellular gaps and fenestration (Marques et al.,
2016). Although, the BBB and BCSFB have different physical compositions they both
participate in controlling the selective passage of molecules between the blood and brain
parenchyma or CSF (Dwibhashyam & Nagappa, 2008; Marques et al., 2016).
The circulating molecules in the blood enter the brain or CSF through the endothelial
cells or choroid plexus cells by passive diffusion or active transport or a combination of
both. Passive transport is a process in which molecules get to enter the brain or CSF
freely and is the primary pathway for many therapeutic agents. As a rule of thumb, only
lipid-soluble molecules with a molecular mass under 400600 Da can enter through the
tight junction of the BBB. However, water-soluble molecules and macromolecules with a
mass of ,600 Da may enter into the brain through carrier-mediated transport
(Vykhodtseva, McDannold, & Hynynen, 2008), receptor-mediated transport, or
absorptive-mediated transport (Goulatis & Shusta, 2017; Sai et al., 1998). Essential nutri-
ents such as amino acids, glucose, carboxylic acids, and nucleosides enter into the brain
through these transporters (Daneman & Prat, 2015). The receptor-mediated transporters
40515.4 APPROACHES IN DELIVERING DRUGS TO THE BRAIN
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
involved in the transport of surface receptor ligand-conjugated macromolecules include
transferrin and insulin (Burkhart et al., 2016; Goulatis & Shusta, 2017; May, Bedel, Shen,
Woods, & Liu, 2016).
In active transport, the molecules cross a cell membrane against the concentration gradi-
ent that is guided by cellular energy, i.e., adenosine triphosphate (ATP). Transporters such
as P-glycoprotein, multidrug-resistant protein, multidrug resistance-associated protein,
breast cancer resistance protein, organic anion transporter, and organic cation transporter
help in the active transportation of small hydrophilic molecules (Ro
¨mermann et al., 2013;
Tamai & Tsuji, 2000). As discussed earlier, several factors are responsible for successful
drug delivery across the BBB and the BCSFB. Due to the complexity of the BBB and
BCSFB, the systemic drug concentration is very high in conventional drug administration,
which significantly increases the risk of toxicity. To bypass the BBB and to deliver drugs
into the brain, without any systemic toxicity, three different approaches are currently
used: invasive, pharmacological, and biological or physiological.
15.4.1 Invasive Approach
The invasive approach is a physical-based technique in which peptides and nutrients
which have poor bioavailability in the brain after intravenous or oral administration are
made bioavailable (Gabathuler, 2010; Stepensky, 2016; Wu, Yoon, Wu, & Bodor, 2002).
These techniques include (1) intracerebroventricular infusion, (2) convection-enhanced
delivery, and (3) intracerebral injection or brain implants. In certain cases the BBB is
mechanically breached by applying osmotic shock, MRI-guided focused ultrasound BBB
disruption, and the use of a bradykinin analog to provide open access to the brain
(Dasgupta et al., 2016; Fortin, Gendron, Boudrias, & Garant, 2007; Kinoshita, McDannold,
Jolesz, & Hynynen, 2006; Wang, Frazier, & Brem, 2002).
15.4.1.1 Intracerebroventricular (ICV) Infusion
In ICV infusion, drug is directly injected into the cerebral lateral ventricles resulting in
diffusion of drugs into the brain through the cerebrospinal fluid (Passini & Wolfe, 2001).
The diffusion of the drug in the brain parenchyma from the CSF through the BCSFB is
very low; it is an effective drug delivery method only in the case that the target site is close
to the ventricles. This might be due to an anatomically different membrane barrier and dif-
ferent permeability profiles of the choroid plexus and brain parenchyma (Spector, Keep,
Snodgrass, Smith, & Johanson, 2015). ICV infusion of opioid peptides shows therapeutic
effects only by binding with the receptors, which are located near the ependymal surface
of the brain (Pardridge, 2007).
15.4.1.2 Convection-Enhanced Delivery
Convection-enhanced delivery (CED) is a stereotactically guided drug delivery method
in which the drug is delivered directly into targeted brain parenchymal cells. With the
help of stereotactic apparatus, the catheter(s) are inserted through cranial burr holes into
the brain and drug is actively pumped into the brain parenchyma through the catheter
(Cunningham et al., 2008; DiMeco et al., 2002). This method shares several advantages
406 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
over other invasive methods such as delivery of high-molecular-weight molecule drugs,
wide distribution of the drug, and it does not cause cerebral edema or measurable
increases in intracranial pressure (Bidros & Vogelbaum, 2009; Bobo et al., 1994; Chen,
Lonser, Morrison, Governale, & Oldfield, 1999). However, the precise placement of the
catheter is a critical step for successful drug delivery by CED (Jahangiri et al., 2017;
Vandergrift & Patel, 2006; Zhou, Singh, & Souweidane, 2017).
15.4.1.3 Intracerebral Injection or Brain Implants
Intracerebral injection is the most direct method for drug delivery to the target site. In
this method, intermittent bolus injections are administered locally in the brain, where the
drugs are diffused with minimal systemic exposure and toxicity (Bergonzi et al., 2016;
Greig, 1987). The use of brain implants is another strategy for drug delivery in which
biodegradable material impregnated with drugs is implanted into the brain. These
drug delivery approaches are commonly employed in the treatment of primary brain
tumors, and neurological disorders such as Parkinson disease (Brem & Gabikian, 2001;
Herzog et al., 2007; Lu et al., 2014; Marks et al., 2008).
15.4.2 Pharmacological Approach
The pharmacological approach comprises of techniques by which lipid-insoluble high-
molecular-weight drug molecules are modified and made bioavailable to the active site in
the brain. These techniques include (1) chemical techniques and (2) colloidal drug carrier
techniques.
15.4.2.1 Chemical Techniques
Chemical approaches are based on the modification of the chemical structure of the
drug molecule that improves their physicochemical property, i.e., lipophilicity thus
improves therapeutic activity (Lu et al., 2014). By reducing the relative number of polar
ends in a drug, this molecule increases the lipophilicity of the other molecule. In the same
way, by adding lipid groups to the polar ends of drug molecules better BBB-permeable
drug molecules are made than the original drug molecule. The prodrug method is another
example of chemical approaches in which drug molecules are modified in such a way
that, on systemic administration, it must convert into the active form by metabolic pro-
cesses (Kreuter, 2001; Lu et al., 2014).
15.4.2.2 Colloidal Drug Carrier Techniques
Colloidal drug approaches are based on colloidal drug carriers in which microscopically
dispersed drug particles are suspended in a suspension form (Kreuter, 2001). The most
common colloidal drug carriers are nanoparticles, micelles, liposomes, emulsions, and
dendrimers (Lu et al., 2014). Many of these colloidal drug carriers are effectively trans-
ported across the BBB by various transcellular mechanisms, such as endocytosis and trans-
cytosis, and have demonstrated significant pharmacokinetics and biodistribution in
different brain-related disorders including brain tumor (Batrakova & Kabanov, 2008;
Wong, Wu, & Bendayan, 2012). Targeted drug delivery to brain tumor by the oral route
40715.4 APPROACHES IN DELIVERING DRUGS TO THE BRAIN
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
has been successfully done using polymeric micelles (Bhujbal, de Vos, & Niclou, 2014;
Kabanov, Batrakova, & Miller, 2003).
15.4.3 Biological or Physiological Approach
Biological or physiological approaches are based on the mechanism of transport of an
essential molecule such as glucose, insulin, growth hormone, low-density lipoprotein, etc.,
in the brain. The specific transporter transports these molecules, such as insulin receptors,
transferrin receptors, etc. into the brain. The physiological approaches are (1) cell-
penetrating peptide-mediated drug delivery, (2) receptor-mediated drug delivery, and (3)
adsorptive-mediated drug delivery.
15.4.3.1 Cell-Penetrating Peptide-Mediated Drug Delivery
In this technique, highly basic amino acids with a positive charge are used to enhance
the brain drug delivery (Dissanayake, Denny, Gamage, & Sarojini, 2017; Temsamani &
Vidal, 2004). The interaction of the cell-penetrating peptide with the cell surface is
receptor-independent, and these can transport the drug molecules into the cytoplasm and
to the nucleus (Guidotti, Brambilla, & Rossi, 2017). They can enter into the cell by two
broad mechanisms: energy-independent direct penetration of the plasma membrane and
energy-dependent endocytosis (Fretz et al., 2007; Guidotti et al., 2017; Palm-Apergi, Lo
¨nn,
& Dowdy, 2012). This approach has been extensively studied preclinically and also tested
clinically in cancer patients (Jia et al., 2011; Warso et al., 2013).
15.4.3.2 Receptor-Mediated Drug Delivery
Receptors such as transferrin receptor, LDL receptor, and insulin receptor are highly
expressed on the endothelial cells of the BBB. In this approach, these receptors are targeted
by specific ligands, modified ligands, and antibodies which will transfer the drugs into the
brain (Pardridge, 2003). The antibody against transferrin receptor and insulin receptor
has demonstrated effective drug delivery of drugs via receptor-mediated transcytosis
(Jones & Shusta, 2007; Pinto, Arce, Yameen, & Vilos, 2017; Zhang & Pardridge, 2005).
Furthermore, the diphtheria toxin receptor, as a targeting vector and low-density lipopro-
tein receptor-related protein, is also used for drug delivery to the brain (Demeule et al.,
2008a; Demeule et al., 2008b; Gaillard, Brink, & de Boer, 2005).
15.4.3.3 Adsorptive-Mediated Drug Delivery
This is another approach to drug delivery in which endocytosis and transcytosis of a
drug molecule are different as compared to receptor-mediated endocytosis and transcyto-
sis. A nonspecific mechanism of endocytosis, adsorptive endocytosis delivers the peptides
and proteins from the luminal plasma membrane of the cell. Various peptide vectors have
been developed and studied in adsorptive-mediated drug delivery for brain tumors
(Byeon et al., 2016; Honary & Zahir, 2013; Jain et al., 2015).
408 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
15.5 NANOTECHNOLOGY AND THE BLOODBRAIN BARRIER
The BBB is the primary systemic barrier that restricts the access of drug molecules
to the brain (Deeken & Lo
¨scher, 2007; Pardridge, 1998). The drug molecules cannot pene-
trate the BBB efficiently due to the presence of a microvascular endothelial cellular net-
work in the brain. This network of cells is responsible for effluxing out a large number of
contents from the brain (Abbott et al., 2010; Demeule et al., 2002b). The tumor cells also
have an acidic environment that neutralizes the basic moiety to inactivate it. Apart from
this, the tumor cells could also impede the action of anticancer drugs by altering enzyme
activity and apoptotic regulation (Brigger, Dubernet, & Couvreur, 2002). Many available
anticancer drugs are largely hydrophilic in nature, and the BBB restricts their entry. The
only prospect for entry of these hydrophilic drugs into the brain is by conjugating or load-
ing them with nanodevices, which could provide efficient distribution of drug in the brain
(Be
´duneau, Saulnier, & Benoit, 2007; Ferrari, 2005; Lockman, Mumper, Khan, & Allen,
2002; Pardridge, 2002; Shi, Kantoff, Wooster, & Farokhzad, 2017).
Nanodevices are of various sizes, ranging from small molecules to large macromole-
cules. The potential applications of nanotechnology-mediated drug delivery include site-
specific drug targeting (Amiji, 2007; Koo, Rubinstein, & Onyuksel, 2005; Park et al., 2010)
and varying the pharmacokinetics of the anticancer drug to improve the therapeutic out-
come with reduced off-target effects (Davis & Shin, 2008; Gabizon, Shmeeda, & Barenholz,
2003). A nanotechnology-mediated drug delivery system is an efficient strategy to over-
come the difficulties of tumor cell-mediated resistance and triggering the release of anti-
cancer drugs into a specific tumor cell. Nanodevices provide protection to the anticancer
drug from the acidic environment of the tumor tissue and thereby increase the penetration
of anticancer drugs into tumor cells (Brannon-Peppas & Blanchette, 2012; Brigger et al.,
2002). Nanodevices can be utilized for delivery of prodrugs to the particular site
along with its activator enzyme (Gupta et al., 2009; Linderoth, Peters, Madsen, &
Andresen, 2009).
Nanotechnology provides greater promise for targeting delivery of anticancer drugs to
brain tumors. The primary reason behind the success is that they can be targeted through
both specific and nonspecific mechanisms. The specific targeting strategy is antigen-
dependent and based on the complexation of the nanomaterial with the specific antigen
and its interaction with a particular tumor cell. The nonspecific mechanism depends upon
the efficient delivery of drug molecules into the brain through vascular permeation
provided by BBB cessation due to a brain tumor. Nanoparticles provide better brain
tissue permeability and retention effect that makes nanodevices the ideal system for tar-
geted delivery of anticancer drugs towards brain tumors (Evans & Alexander, 1972;
Orringer et al., 2009; Peer et al., 2007).
The transportation of nanocarrier-complexed drug through the BBB can occur either via
passive diffusion or endocytosis. Passive diffusion is facilitated by larger drug concentra-
tions in the plasma that lead to a higher osmotic gradient in the BBB and thereby increases
the CNS entry of drug molecules. Endocytosis mainly relies on receptor mediation. The
specific receptor in the BBB interacts with the surface of nanoparticles and thus forms an
efficient mechanism for brain targeting (Gabathuler, 2010; Grabrucker et al., 2013; Kreuter,
2002; Wohlfart, Gelperina, & Kreuter, 2012).
40915.5 NANOTECHNOLOGY AND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
15.6 NANODEVICES FOR BRAIN TUMOR TARGETING AND
DELIVERY
15.6.1 Liposomal Formulations
Liposomes are phospholipid bilayer membrane constructs consisting of diverse charac-
teristic groups such as phosphoric residues, hydrophobic chains, and a polar head.
Liposomes have varied physicochemical properties due to different phospholipid compo-
sitions, surficial charges, the size of the liposomal carrier, and the use of preparation meth-
odology (Maheshwari, Tekade, Sharma, & Kumar Tekade, R., 2015b; Sharma, Maheshwari,
Tekade, & Kumar Tekade, 2015). Liposomes are ideal nanodevices for drug delivery appli-
cations. Over the last several decades, liposomal formulations have been studied exten-
sively for the targeted delivery of molecules (Allen & Cullis, 2013; Daraee, Etemadi,
Kouhi, Alimirzalu, & Akbarzadeh, 2016; Lian & Ho, 2001; Torchilin, 2005). The liposomal
formulation provides regulated retentive entrapment and improved uptake of drugs by
targeted cells. The “stealth liposomes,” coated with biocompatible polymers, have been
used widely for targeted drug delivery applications (Allen & Cullis, 2013; Bae & Park,
2011; Gabizon, 2001). Macrophages are unable to recognize the stealth liposomes, and
thereby these types of nanodevices have a longer biological half-life (Cattel, Ceruti, &
Dosio, 2003; Deshpande, Biswas, & Torchilin, 2013; Moghimi & Szebeni, 2003; Silvander,
2002). In the last few years, rapid advancements have been made to utilize liposomal
nanoconstructs in targeted drug delivery for brain tumors.
The therapeutic index of convection-enhanced delivery of liposomes for targeting brain
tumor was investigated. The study showed that convection-enhanced delivery of
gadolinium-colabeled liposomes could be used successfully as visualizing agents of a rat
brain tumor model for in vivo MRI (Saito et al., 2004). Alternatively, immunoliposomes
were also utilized for targeting therapeutic genes for brain delivery in a brain tumor
model (Agarwal et al., 2011). Further, the PEGylated immunoliposomes carrying plasmid
DNA were targeted to mouse transferrin (Tfr) and human insulin receptors. Tfr receptor
targeting improves transport across the tumor vasculature, and insulin receptor targeting
causes transport across plasma and the nuclear membrane of human brain cancer cells
(Zhang, Zhu, & Pardridge, 2002b).
Siegal et al. investigated and compared the biodistribution and clinical efficiency of
doxorubicin (DOX) in free and stealth liposomal encapsulation form. The study was per-
formed for a secondary brain tumor model in Fischer rats. The comparative study con-
firmed the improved drug exposure and therapeutic efficiency with a stealth liposomal
carrier against early small- and large-sized brain tumors (Siegal, Horowitz, & Gabizon,
1995). Gao et al. have developed the dual-targeted DOX-liposomal carrier and anchored it
with folate (Fol) and Tfr. The folate-anchored liposomal system improves BBB penetration,
and Tfr conjugation efficiently targets brain glioma cells (Gao et al., 2013). Gaillard and
coworkers developed glutathione pegylated liposomal doxorubicin for a brain tumor.
Additional glutathione coating enhances the drug delivery of DOX in brain tumor as com-
pared to PEGylated liposomes (Gaillard et al., 2014). The focused ultrasound (FUS) pulse
can also be induced in and around the tumor with the simultaneous intravenous adminis-
tration of a microbubble contrasting agent. The FUS-introduced DOX-cationic liposomes
410 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
were investigated in a C6 glioma model. FUS when combined with microbubble contrast
agent, induced a noninvasive, local, and transient disruption of BBB without affecting
normal tissues. Combining the benefits of BBB opening using FUS and targeting using
cationic liposomes, this strategy can be effectively utilized further for targeting brain
tumor therapy (Lin et al., 2016). The microbubble DOX-liposomes also combined success-
fully with interleukin-4-receptor peptide for targeting in brain tumor therapy (Park et al.,
2016). In another development, DOX liposomes can be adequately anchored with pH-
responsive peptide H
7
K(R
2
)
2
as targeting ligand. This peptide specifically responds to the
acidic environment present in tumor tissue and can be successfully utilized as a targeting
strategy in brain tumor therapy (Zhao et al., 2016).
Multifunctional paclitaxel (PTX) liposomes were developed in several studies to
improve the therapeutic and functional targeting. The PTX liposomal system is anchored
with cyclic RGD peptide and cell penetration R8 peptide (RGD-R8-PTX-lipo). The study
showed that conjugation with RGD and R8 peptide possess multifunctions such as effec-
tive brain accumulation, targeting, and better tumor penetration in glioma-bearing mice
(Liu et al., 2014b). In another strategy for developing a multifunctional PTX liposomal sys-
tem, artemether was used additionally as a regulator of apoptosis and inhibitor of vasculo-
genic mimicry (VM) channels. The VM channels can cause a recurrence of brain glioma.
The liposomal system was developed by conjugating mannose-vitamin E derivative
(MAN) and dequalinium-lipid derivative (DQA) and proven to be an effective strategy for
treatment of brain tumor in in vitro and in vivo models (Li et al., 2014). Further, celecoxib
was also used along with epirubicin liposomes for the treatment of brain tumor and
destruction of VM channels. The results of the study indicate effective targeting using an
epirubicin and celecoxib combination to inhibit tumor VM channels and treat brain tumor
in glioma-bearing nude mice (Ju et al., 2016). A recent experiment also showed that vin-
cristine- and tetrandrine-combined liposomes along with Tfr tethering could increase cel-
lular uptake, inhibit multidrug resistance, and block cancer cell invasion and VM channels
to treat brain tumor (Song et al., 2017).
In an investigation by Yang et al., Angiopep-2 and neuropilin-1 receptor-specific pep-
tides have been anchored on vascular endothelial growth factor (VEGF) siRNA and doce-
taxel (DTX) liposomal systems. The dual peptides improve the binding ability and
internalization into glioma cells by a specific receptor-mediated endocytosis mechanism of
cellular uptake. The dual peptide anchored liposomes were shown to possess a better
targeting strategy for the treatment of brain tumor compared to nonmodified and single
peptide-modified liposomes (Yang, Li, Wang, Dong, & Qi, 2014). The comparative study
of six different peptide-based ligands (Angiopep-2, T7, Peptide-22, Cyclic RGDfK peptide,
D-SP5 cys peptide, and Pep-1) was performed on targeting efficiency of DOX liposomes.
An in vitro cellular uptake study proves that combination of Cyclic RGDfK and Peptide-22
synergistically improves the internalization more than any of the single ligand modifica-
tions. In vivo imaging also confirms higher brain tumor distribution by a Cyclic RGDfK
and Peptide-22 combination than single ligand-modified liposomes (Chen et al., 2017). In a
recent study, DTX-loaded nanoliposomes were developed, and cellular uptake was investi-
gated in C6 glioma cells (Shaw et al., 2017).
41115.6 NANODEVICES FOR BRAIN TUMOR TARGETING AND DELIVERY
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
15.6.2 Polymeric Nanocarriers
The polymeric nanocarrier-mediated drug delivery platform is a very versatile and effi-
cient strategy for modifying the properties of nanoparticles to meet specific requirements
(van Vlerken, Vyas, & Amiji, 2007). The versatile characteristics of the polymer matrices
offer significant advantages over other systems such as easy preparation, surface functio-
nalization, improved payload capacity, and protection (Chacko, Ventura, Zhuang, &
Thayumanavan, 2012; Ryu et al., 2010; Simone, Dziubla, & Muzykantov, 2008). There are
several classes of polymeric materials that could be effectively utilized for drug delivery in
brain tumor therapy, such as synthetic polymers poly(D,L-lactide-co-glycolide) (PLGA)
(Acharya & Sahoo, 2011; Chang et al., 2012), poly(L-lactic acid) (PLL) (del Burgo,
Herna
´ndez, Orive, & Pedraz, 2014; Liu, Xue, Ke, Xie, & Ma, 2014a), poly(phenylene ethy-
nylene) (PPE) (Kulkarni, Surnar, & Jayakannan, 2016), poly(epsilon-caprolactone) (PCL)
(Forrest et al., 2008; Nicolas, Mura, Brambilla, Mackiewicz, & Couvreur, 2013; Zhang et al.,
2012), polyalkylcyanoacrylates (PACA) (Gelperina et al., 2010; Yordanov, 2012), and natu-
ral polymers such as gelatin (Matsumoto et al., 2006), chitosan (Agrawal et al., 2017;
Garcia-Fuentes & Alonso, 2012; Kim, Choi, Kim, & Tae, 2013), hyaluronic acid (Choi,
Saravanakumar, Park, & Park, 2012; Choi et al., 2011), albumin (Comes Franchini et al.,
2010), and heparin (Yu & Zhang, 2009).
The most significant importance of using polymeric nanocarriers is that they sharply
increase the circulation time and decrease the RES accumulation (Klibanov, Maruyama,
Torchilin, & Huang, 1990; Torchilin, 1998). PEGylated liposomal systems have already been
discussed for targeted and effective delivery of DOX (Gabizon & Martin, 1997; Krauze et al.,
2007). Different polymeric nanocarriers could be prepared to apply varied type strategies.
The intravenous administration of DOX coated with Polysorbate-80 reduces tumor mass in
rats (Kreuter, 2001). The study reveals that PEGylated poly(methoxyPEG cyanoacrylate-
co-n-hexadecylcyanoacrylate) (PHDCA) with amphiphilic copolymer can penetrate the
brain to a larger extent than any other nanodevices (Calvo et al., 2001). The hybrid type
of nanoparticles combined with lipid and polymeric material also demonstrated effective
targeted delivery of chemotherapeutics (Dehaini et al., 2016; Zhang et al., 2017a).
The “polymeric wafers” are a new advanced strategy that has now been introduced to
deliver chemotherapeutics locally and bypass the BBB. These polymeric wafers are
implantable devices inserted at the tumor site to discharge and deliver the chemotherapeutic
agents. The polymer utilized in clinical application is polyanhydride poly[1,3-bis(carboxy-
phenoxy) propane- co-sebacic-acid] (PCPP:SA) along with the anticancer drug carmustine
(Brem et al., 1991; Brem et al., 2007; Mangraviti, Gullotti, Tyler, & Brem, 2016).
The major drawback with polymeric nanodevices is that they can be taken up by RES
and distributed in the liver, spleen, and bone marrow, which leads to very low t
1/2
of the
particles in the bloodstream (Le Ray, Vert, Gautier, & Benoit, 1994; Verrecchia et al., 1995).
To overcome this issue, several modifications can be incorporated, such as conjugation of
polymeric nanocarriers with antibodies (Duncan, 2006; Masood, 2016; Reddy et al., 2006),
peptides (Arnold, Czupiel, & Shoichet, 2017; Jiang et al., 2017; Shen et al., 2011; Wang
et al., 2015; Zhang et al., 2016), proteins (Wang et al., 2016), nucleotides (Guo et al., 2011;
Mead et al., 2016), or receptor-specific ligands such as Tfr (Jain et al., 2015), and folic acid
(Wang et al., 2016).
412 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
15.6.3 Magnetic Nanoparticles
Magnetic nanoparticles can be successfully employed as drug delivery vehicles for
effective targeting of therapeutic agents. In this strategy, therapeutic agents can be
attached to the surface or encapsulated inside a complex of polymer and magnetic nano-
particles (Mody et al., 2014b). This therapeutic drug delivery strategy is based on the
application of a magnetic field to localize the specific target in the body. The underlying
mechanism behind this strategy depends upon generated heat from the moving magnetic
nanomaterials using a strong magnetic field. This therapeutic strategy is noninvasive and
safer to target the magnetic nanoparticles to the brain tumor tissues (Silva et al., 2011).
Chen and coworkers have developed doxorubicin (DOX) magnetic nanoparticles, in
which DOX are chemically bonded to ferric oxide nanoparticles and embedded in PEG
functionalized with porous silica (Chen, Zhang, Chen, Zhang, & Zhang, 2010). Magnetic
nanoparticles can also be employed along with focused ultrasound (FUS) to improve drug
targeting synergistically. This synergistic combination increases the local magnetic nano-
particle concentration in the targeted tissue. Liu and coworkers successfully employed this
strategy in the delivery of epirubicin with iron oxide magnetic nanoparticles (Liu et al.,
2010). In another experiment, PEI-modified magnetic nanoparticles were delivered suc-
cessfully into a brain tumor. The study showed a 30-fold increase in targeting by intracaro-
tid administration along with magnetic targeting in comparison to intravenous
administration (Chertok, David, & Yang, 2010). Recently, FUS has also been utilized with
microbubbles to enhance drug targeting in brain tumor. The combination of FUS with
microbubbles increases brain permeability and disrupts the BBB in the condition of a brain
tumor. To utilize the same effect, Fan et al. developed a theranostic complex of superpara-
magnetic iron oxide nanoparticles loaded with microbubbles. The magnetically labeled
system enhanced targeted drug (DOX) deposition in brain glioma cells (Fan et al., 2016).
In a similar experiment, dynamic contrast enhancement (DCE)-based magnetic resonance
imaging was characterized by FUS-induced brain permeability and utilized for targeted
delivery of DOX in 9L gliosarcoma cells of rats (Park, Aryal, Vykhodtseva, Zhang, &
McDannold, 2017).
Some studies have also been proven to be successful in the low-frequency magnetic
field (Golovin, Golovin, Klyachko, Majouga, & Kabanov, 2017a; Golovin, Klyachko,
Majouga, Sokolsky, & Kabanov, 2017b). In such a study, Kim et al. developed magnetic
vortex microdisks for targeting brain tumor. The results showed that mechanical stimulus
generated by microdisk oscillations could selectively target brain tumor cells and kill them
(Kim et al., 2010). In a recent experiment, biogenic nanosized cell-derived microvesicles
have been targeted effectively by magnetic and folate functionalization. In this study,
microvesicles were conjugated with streptavidin-modified iron oxide nanoparticles and
effectively transformed as targeted drug delivery nanovectors for delivery of anticancer
agents in the treatment of brain tumor (Zhang et al., 2017b). The Tfr receptor-binding
peptide T7 mediated drug targeting was also utilized along with the application of an
applied magnetic field. This dual-targeted magnetic PLGA nanoparticle was employed for
delivery of paclitaxel and curcumin. Dual targeting results in a 10-fold increase in cellular
uptake and over fivefold increase in brain targeting in an orthotopic glioma model
(Cui et al., 2016).
41315.6 NANODEVICES FOR BRAIN TUMOR TARGETING AND DELIVERY
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
15.6.4 Dendrimeric Nanocarriers
Dendrimeric structures have unique characteristic properties such as monodispersity
(Mody, Tekade, Mehra, Chopdey, & Jain, 2014a), modifiable surface functionality (Patri,
Kukowska-Latallo, & Baker, 2005), membrane transport efficiency, high drug payload
(Satija, Gupta, & Jain, 2007), biocompatibility, and well-defined molecular structure and
composition (Jain & Asthana, 2007). These unique properties of dendrimers make them
highly suitable nanocarriers for drug targeting. Usually dendrimer architecture consists of
three topological domains: (1) a central core comprising of an atom or a molecule with a
minimum of two identical functional groups; (2) branches, with several interior repeating
units structured geometrically in a sequence of radically aligned layers known as “genera-
tions” ; and (3) terminal groups which determine the surface properties of the dendritic
structure (Kesharwani, Jain, & Jain, 2014a; Kesharwani, Tekade, & Jain, 2015a; Martinho
et al., 2014)(Fig. 15.2). Dendrimeric architectures are prepared using divergent and con-
vergent approaches. In both approaches, dendrimers are synthesized by step-by-step
growth and branching generations. Dendrimers are depicted and classified by their gener-
ation numbers. The central core group represented G0 (generation 0), although following
additions of branching units were termed as higher generations of dendrimers (G1, G2,
G3, etc.). This exponential increase with the addition of each group results in sterically
crowded dendrimers, which leads to geometrical changes in the dendrimeric structures.
With the growth in generations, dendrimers take a globular structure due to increasing
steric hindrance (Kesharwani, Tekade, & Jain, 2014b; Kesharwani, Tekade, & Jain, 2015b).
Several strategies were developed to transport the therapeutic agents across the brain in
a site-specific manner. Amongst all the approaches, dendrimers have emerged as promis-
ing vectors with great potential for delivering drugs into the CNS. Various types of den-
drimers, such as polyamidoamine (PAMAM), poly-L-lysine (PLL), and poly(propylimine)
(PPI) have been explored successfully in the treatment and diagnosis of brain tumors.
Sarin and coworkers have developed a G5 PAMAM dendrimer conjugated with DOX and
in chelation with Gd-DTPA. The results demonstrated significant improvement in target-
ing as compared to free DOX in a rodent malignant glioma model (Sarin et al., 2008, 2009).
A PEGylation strategy is also employed to successfully deliver anticancer agents to the tar-
geted site. He et al. have developed PEGylated PAMAM dendrimers as dual targeting
nanocarriers in brain tumor. They prepared PEGylated G4 PAMAM dendrimers with Tfr
and WGA loaded with DOX. The results demonstrated reduced cytotoxicity and increased
accumulation of DOX in the tumor site due to targeting effects of Tfr and WGA (He et al.,
2011). Li et al. explored the targeting potential of G4 PAMAM dendrimers anchored with
Tfr and encapsulated with tamoxifen in brain gliomas. The results indicated faster drug
release in weakly acidic conditions (Li et al., 2012). Recently, the PEGylated PAMAM den-
drimers were also anchored with various peptides such as angiopep-2 (Xu et al., 2016) and
homing peptides (Pep-1) (Jiang et al., 2016) as an effective targeting strategy in the treat-
ment of brain tumors.
Similarly, PEGylated PLL-based dendrimers loaded with DOX have been effectively uti-
lized for brain tumor targeting. In an experiment by Kaminskas et al., nanocarriers were
linked to an acid-labile 4-(hydrazinosulfonyl) benzoic acid (HSBA) linker that causes the
release of DOX in acidic conditions. The in vivo results in rats bearing Walker 256 tumors
414 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
demonstrated higher uptake in tumor tissue as compared to control tissue of muscle and
heart (pH 5) (Kaminskas et al., 2011). Ligand-anchored poly(propyleneimine) dendrimers
were also evaluated for their brain-targeting potential by Jain and coworkers. They
anchored various ligand molecules, such as sialic acid (S), glucosamine (G), and concanav-
alin A (C) to the surface of poly(propyleneimine) (PPI) dendrimers encapsulated with pac-
litaxel. The results of in vivo pharmacokinetics and biodistribution studies in rats showed
a significantly higher accumulation of paclitaxel in the brain as compared to free pacli-
taxel. The order of targeting potential of various ligands under investigation was found as
sialic acid .glucosamine .concanavalin A (Patel, Gajbhiye, Kesharwani, & Jain, 2016).
Researchers have recently developed a spatially controlled multistage nanocarrier by
FIGURE 15.2 Structured diagram of dendrimers presenting its major domains: (1) core, (2) generations, (3) ter-
minal groups, and (4) internal voids.
41515.6 NANODEVICES FOR BRAIN TUMOR TARGETING AND DELIVERY
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
encapsulating small polyamidoamine (PAMAM) dendrimers (B5 nm) within large gelatin
NPs (B200 nm). This strategy showed the higher stability of nanodevices in the systemic
circulation and enhanced permeation through the tumor vasculature. The PAMAM den-
drimer was released in response to MMP-2 enzymes in the tumor microenvironment and
resulted in higher intracellular uptake and deeper tissue penetration in a tumor model.
The results have also demonstrated effective and targeting delivery of methotrexate with
this system (Fan et al., 2017).
15.6.5 Carbon Nanotubes
In recent years, CNTs have emerged as a potential delivery system for biologically
active molecules to enhance the therapeutic benefits. Currently, functionalized CNT-
mediated selective and specific delivery of biomolecules has gained huge attention as a
potential, promising nano-architecture due to its unique physicochemical properties in the
treatment of various deadly diseases including cancer (Bianco, Kostarelos, & Prato, 2005;
Bottini et al., 2006; Sajid et al., 2016; Zhang, Bai, & Yan, 2010).
Ren et al. employed angiopep-2 surface-modified oxidized-MWCNTs for a dual-
targeting drug delivery system for the treatment of brain glioma. These authors reported
that the ultrahigh surface area of MWCNTs resulted in a loading potential of higher order
to load doxorubicin (DOX). Angiopep-2 is an activatable cell-penetrating peptide with the
ability to selectively bind to the low-density lipoprotein receptor-related protein receptor,
generally overexpressed on the BBB and glioma cells. The outcomes suggested that
MWCNTs had lower cardiotoxicity than DOX alone (Ren et al., 2012). Another example of
using angiopep-2, presented by Kafa et al., has also displayed significant outcomes as a
targeting ligand for brain delivery using MWCNTs. In particular, these authors demon-
strated better results with functionalized MWCNTs in comparison to the nontargeted for-
mulation in each aspect including in vitro and in vivo performance employing primary
porcine brain endothelial cells and primary rat astrocytes, following intravenous adminis-
tration. Enhanced whole-brain uptake, increased uptake in glioma brain cells, and
enhanced brain accumulation were found with angiopep-2-functionalized MWCNTs (Kafa
et al., 2016). It was also reported that functionalization does not significantly affect the
dimension of MWCNTs, indicating the importance of functionalized MWCNT diameter
towards their accumulation at desired sites. Continuing with cancer, Mehra et al., demon-
strated the pharmacokinetic and pharmacodynamic investigations of the cancer-targeting
potential of the DOX-loaded D-α-tocopheryl polyethylene glycol 1000 succinate-decorated
surface-functionalized MWCNT nano-formulation and compared it with pristine
MWCNTs and free doxorubicin solution. The authors concluded that the investigated
MWCNTs’ nano-architect had greater cancer-targeting potential on tumor-bearing Balb/c
mice (Mehra, Verma, Mishra, & Jain, 2014). In a different investigation, Lu et al. employed
MWCNTs and magnetic NPs as a dual approach for treating brain cancer. In this case, the
functionalization was done with poly(acrylic acid) via free radical polymerization linked
with folic acid and DOX was used as the chemotherapeutic agent. Outcomes using
advanced microscopic techniques suggest that DOX-loaded folic acid-conjugated
MWCNTs efficiently accumulated within U-87 cells following the desired release of DOX
416 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
intracellularly and then effectively transported into the nucleus with the MWCNTs left in
the cytoplasm (Lu, Wei, Ma, Yang, & Chen, 2012; McDevitt et al., 2007). Apart from
MWCNTs, McDevitt et al. used SWCNTs modified with rituximab and lintuzumab to
demonstrate the capability to selectively target cancerous cells. Based on pharmacody-
namic studies, the authors claimed higher biodistribution in a murine xenograft model of
lymphoma, suggesting further SWCNTs as a potential delivery platform for selective
delivery (McDevitt et al., 2007).
15.6.6 Gold Nanoparticles
Biologically active enteritis can also be decorated onto the exterior of AuNPs (Wolburg
et al., 2012). The huge exterior area/volume ratio of AuNPs allows their surface to be
encrusted with a variety of molecules like therapeutic agents, site-specific ligand, and anti-
fouling polymers (Catherine, & Olivier, 2017). An interesting pilot study was conducted
using a cell culture technique employing an animal model of glioblastoma multiforme in
which PEG-based gold NPs supported radiation therapy. The dual action gold NPs
enhanced survival of mice with orthotopic GBM tumors. The authors also demonstrated
enhanced extravasation and greater accumulation of gold NPs, indicating that this dual
approach significantly disrupts the BBB and could be leveraged to enhance cancer cell tar-
geting. There findings indicate that pegylated gold NPs can be significantly combined
with radiation therapy for the treatment of cancerous cells (Joh et al., 2013). In another
study, Hainfeld et al. demonstrated the use of gold NPs for high-resolution computed
tomography tumor imaging with radiation therapy using 30 Gy 100 kVp X-rays. The gold
NPs were taken up by tumor cells 19 3time more than the normal brain cells. Also, mice
injected with gold NPs were capable of inducing tumor-free survival for more than a year
in comparison to mice receiving radiation only (Hainfeld, Smilowitz, O’Connor,
Dilmanian, & Slatkin, 2013). Ruan et al., considering the problem of limited accumulation
of drugs and NPs within brain cells, proposed a legumain base approach to enhance the
retention of chemotherapeutics in brain tumors. They devised a nano-platform, gold NPs-
A&C, which was comprised of Ala-Ala-Asn-Cys-Lys-modified gold NPs, and 2-cyano-6-
aminobenzothiazole-modified gold NPs. This approach increased the accumulation of the
gold NPs in glioma cells both in vitro and in vivo due to the blocking of NP exocytosis
and minimizing NP backflow to the bloodstream. The authors also employed DOX as a
chemotherapeutic agent to further improve the efficiency against glioma. The median sur-
vival time for the DOX-linked AuNPs-A&C increased to more than 285% in comparison to
the saline group. They concluded that this approach has potential to elevate NP tumor
accumulation and therefore may have a better clinical outcome (Ruan et al., 2016).
Gromnicova et al. studied the ability of nanosized (4 nm) glucose-modified gold NPs to
penetrate human brain endothelium selectively and subsequently to enter astrocytes. The
transfer rate of these NPs across primary human brain endothelium was not less than
three times faster than across nonbrain endothelia. The authors further reported that
movement of these NPs occurred across the apical and basal plasma membranes through
the cytosol with relatively little vesicular or paracellular migration; antibiotics that inter-
fere with vesicular transport did not block the migration. The transfer rate also relied on
41715.6 NANODEVICES FOR BRAIN TUMOR TARGETING AND DELIVERY
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
surface modification of the NPs and incubation temperature. They claimed that the
glucose-modified NPs traverse the endothelium, move through the extracellular matrix,
and localize in astrocytes, and it was finally concluded that these NPs have the ability to
cross the bloodbrain barrier and deliver the therapeutic goods (Gromnicova et al., 2013).
15.6.7 Viral Nanoparticles
Viral vectors are the most recognizable system for delivering exogenous genetic materi-
als to specific cells, following traversing them to the cell nucleus and thereby activating
the genomic (During, 1997; Handbook; Vile, Tuszynski, & Castleden, 1996). Liu et al. dis-
played RVG29 (rabies virus glycoprotein) as a promising ligand for proficient brain-
targeting gene delivery. For the purpose, RVG29 was treated on PAMAM dendrimer using
bifunctional PEG, then complexed with DNA, yielding multiconstructed NPs. The results
exhibited that a high potential of BBB disruption ability in an in vitro BBB model was
achieved using RVG29 ligand containing formulation, whereas in vivo results demon-
strated higher accumulation and cellular internalization in the brain. This dual-functional
strategy provides a safer and noninvasive mode for gene delivery through the BBB (Liu
et al., 2009).
In another example of gene therapy, Zhang et al. employed an antisense technique with
an artificial virus that uses a receptor-specific monoclonal antibody gene delivery system
to treat a brain tumor. Mice implanted with intracranial U-87 human glial brain tumors
were treated with a nonviral expression plasmid encoding antisense mRNA against the
human epidermal growth factor receptor gene. The plasmid DNA is packaged within the
interior of PEG-functionalized immunoliposomes and administered to the cancerous cells
with MAbs that target the mouse transferrin receptor and the human insulin receptor.
The mouse TRFR MAb enables transport across the tumor vasculature, which is of mouse
brain origin, and the INSR MAb causes transport across the plasma membrane and the
nuclear membrane of the human brain cancer cell. As an outcome, the lifespan of the mice
treated weekly with an intravenous administration of the EGFR antisense gene therapy
packaged within the artificial virus was increased 100% compared with mice treated either
with a luciferase gene or with saline (Zhang et al., 2002b).
Lee et al. tried to achieve better cellular internalization and enhance the bioavailability
employing rabies virus-based silica-modified gold nanorods based on a photothermal
principle to treat brain cancer. The prepared functionalized nanorod was injected and
could induce a hyperthermal effect in response to NIR laser (808 nm) irradiation, based on
localized surface plasmon resonance, to effectively suppress brain tumors of mice.
Together, these results support the assertion that the rabies virus mimetic gold nanorods
are a potential prototype delivery platform for treating brain tumors (Lee et al., 2017a).
15.6.8 Nucleic Acids-Based Nanotechnology
Oligonucleotides annealed with targeted mRNA sequences can be utilized successfully
as a delivery vector to the targeted site. Galectin-1 is a naturally occurring galactose-
binding protein, which is upregulated in the case of GBM. Galectin-1 is involved in cancer
418 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
progression and is a potent immune suppressor in the tumor microvasculature. Recently,
Woensel et al. developed siRNA-tailored chitosan NPs to target Galectin-1 for the treat-
ment of GBM via intranasal delivery. This study was the first of its type and involved con-
centrated chitosan NP suspensions for the delivery of siRNA into brain tumor a few hours
after intranasal administration. These NPs could complex siRNA targeting Galectin-1 to a
high percentage and avoid RNAse degradation. The results indicated that siRNA nano-
formulation significantly depressed the expression of Galectin-1 in both murine and
human GBM cell lines. Sequence-specific RNA-interference displayed a more than 50%
Galectin-1 reduction in tumor-bearing mice. This investigation indicates that the intranasal
pathway is an underexplored transport route for delivering siRNA-based therapies target-
ing Galectin-1 in the treatment of GBM (Van Woensel et al., 2016).
In another application of the siRNA delivery system, Wei et al. investigated the biomed-
ical significance of intravenously administered T7 peptide-based coreshell NPs employ-
ing an siRNA approach against brain tumors. As a methodology, the authors employed
layer-by-layer deposition of protamine, chondroitin sulfate, siRNA, and cationic lipid vesi-
cles followed by T7 peptide modification to construct a site-specific siRNA-based delivery
system. The pharmacokinetic study revealed a higher cellular internalization of fluores-
cence intensity of siRNA in brain microvascular endothelial cells and U87 glioma cells
when tested with T7-siRNA-based liposomal construct and compared with PEG-siRNA
based system. In vivo, the experiment exhibited significant silencing of EGFR protein
expression in the U87 glioma cells after treatment with the T7-siRNA-based liposomal con-
struct. It was also noticed that this construct was advantageous in deep penetration of the
tumor spheroid compared with the non-T7-modified formulation. The authors concluded
that transferrin receptor-mediated coreshell NPs are promising siRNA delivery systems
for selective brain-targeting applications (Wei et al., 2016).
Different to siRNA, Lee et al., demonstrated downregulation of oncogenic miRNA-21
for the treatment of glioblastoma by rescuing tumor suppressors, PTEN and PDCD4. The
authors constructed three-way junction (3WJ)-based RNA NPs artificially collected from
pRNA of bacteriophage phi29 DNA packaging motor and conjugated with folic acid. The
formed nano-construct was shown to be promising in silencing miR-21 expression in glio-
blastoma cells both in vitro and in vivo, with favorable biodistribution. Systemically
injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glio-
blastoma cell apoptosis and tumor growth regression. Overall, the survival rate was also
significantly improved by FA-3WJ-LNA-miR21 RNP. These results are indicative of the
clinical benefit of FA-3WJ RNP-based gene therapy for the successful targeted therapy of
developing and even recurring glioblastoma (Lee et al., 2017b).
15.7 NANOTECHNOLOGY FOR BRAIN TUMOR IMAGING
Magnetic resonance imaging is an excellent example of the utilization of nanotechnol-
ogy for the imaging of brain cancer cells since numerous NPs have been reported as MRI
contrast agents (Babes, Denizot, Tanguy, Le Jeune, & Jallet, 1999; Hyeon, Piao, & Park,
2016; Kim, Lee, Kwak, & Kim, 2005; Na, Song, & Hyeon, 2009; Wei et al., 2017a). Mostly,
NP-based imaging agents have been fabricated with a core of iron oxide crystals with/
41915.7 NANOTECHNOLOGY FOR BRAIN TUMOR IMAGING
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
without a shell of organic material, like PEG. The main advantage of using NPs as the
contrast agent is the extent of information they provide about the stage/level of the tumor
(Wei, Liao, Mahmood, Xu, & Zhou, 2017b). However, gadolinium-based contrast agents
and NP-based contrast agents cause an elevation of tumors by passing through areas of
disrupted BBB, where they change the Mr signal intensity (Boxerman, Schmainda, &
Weisskoff, 2006; Sorensen, Tievsky, Ostergaard, Weisskoff, & Rosen, 1997). As an advan-
tage over gadolinium-based imaging, NP-based contrast agents, for example, ultra-small
superparamagnetic iron oxide NPs are taken up by the phagocytes found at tumor mar-
gins, and thus areas of tumor not seen with gadolinium-enhanced MRI can be detected
using iron oxide-based NPs. Also, iron oxide-based NPs spend a longer time inside the
tumor and more accurately delineate tumor margins. NPs are also capable of being used
for selective molecular tumor targeting (Enochs, Harsh, Hochberg, & Weissleder, 1999; Lee
et al., 2008; Thorek, Chen, Czupryna, & Tsourkas, 2006).
Recently, Cho et al. developed a novel imaging agent using peptide-decorated AuNPs
toward brain glioma stem cell marker CD133 with stimulus responsive ability. The peptide
CBP4 is relatively small and was screened by a phage display method, and showed attach-
ment with the target CD133 in comparison to an antibody. The authors employed AuNPs
as a quencher, and the targeting peptide was linked to AuNPs with greater efficacy. Using
a quenching effect, the peptide-decorated AuNPs displayed signal onoff characters
depending upon the presence of the target. Also, the formed system showed excellent
biocompatibility when localized in the cytosol. The authors concluded that the peptide-
decorated AgNPs could be used as an imaging agent for correct diagnosis of GBM and
have potential to be explored as a drug carrier (Cho et al., 2017).
Timbie et al. designed an Mr image-guided delivery system of cisplatin-incorporated
brain-penetrating NPs to invasive glioma with selective ultrasound to analyze whether
brain-penetrating NPs modified with PEG would be able to be delivered through both the
bloodtumor and BBB to producing therapeutic effectiveness. This is an example of using
an Mr-guided delivery approach for the treatment of brain tumors (Timbie et al., 2017).
Wang et al. used a folic acid-based targeting strategy to deliver fluorescent magnetic
bovine serum albumin-modified NPs to enhance intracellular dual modal imaging in
human glioma U251 cells. The outcomes revealed that the prepared system was not toxic
to cells with better biocompatibility and higher cellular uptake. The formulation was shown
to be effectively internalized for MRI and intracellular visualization after fluorescein iso-
thiocyanate (dye) labeling in the targeted U251 cells. These investigators finally concluded
that the developed formulation effectively enables dual modal imaging without significant
toxicity and a site-specific carrier for the treatment of brain cancer in the future. In an inter-
esting and novel approach, Han et al. employed autocatalytic brain tumor-targeting, in
which half of the portion of nanoparticles was introduced through BBB leakage, receptor-
mediated transcytosis, carrier-mediated transcytosis, and adsorptive-mediated transcytosis
and the remaining portion was introduced when these NPs reached the tumor site and
released BBB modulators which enhanced the permeability of the BBB (Wang et al., 2016).
Thus, the efficiency of NP accumulation in tumors autocatalytically increases with time
and subsequent administrations. The overall conclusion can be drawn from different
investigations that NPs have a promising and meaningful role as imaging or contrast
agents for the detection of progression of various diseases.
420 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
15.8 CHALLENGES AND SAFETY CONSIDERATIONS OF
NANOTECHNOLOGIES USED FOR BRAIN-TARGETED DELIVERY
Nanotechnology approaches comprise of engineered nanomaterials and nanodevices
which interact more specifically with biological systems at molecular levels and are used
in diagnostics as well as therapeutics (Bawa, Audette, & Rubinstein, 2016). The applica-
tions of nanotechnology in basic and clinical neuroscience are developing day by day.
Besides the various advantages of nanotechnology in the understanding of neurobiology,
neuropathophysiology, and intervention at the molecular level, there are numerous chal-
lenges associated with nanotechnology (Howard, 2016; Soni, Garg, Patel, & Yadav, 2016a).
In the field of cancer, early detection of precancerous and neoplastic lesions remains
a major challenge for nanotechnology (Fruscella, Ponzetto, Crema, & Carloni, 2016).
Conventional cancer imaging technologies are not able to detect the precancerous stage
based on lesion anatomy. This is because of low spatial resolution—to increase the spatial
resolution, imaging techniques require a signal-amplifying material conjugate, known as a
contrast agent (Namen & Luke, 2017). Nanoparticles have been used as multifunctional
and molecularly targeted contrast agents for imaging smaller and early-stage cancers
(Fruscella et al., 2016; Harisinghani et al., 2003; Sullivan & Ferrari, 2004).
In the case of multidimensional CNS disorders, another important challenge for nano-
technologies is the requirement for multitargeting molecules which can interact with mul-
tiple receptors and play specific cellular and physiological functions (Kemp, Shim, Heo, &
Kwon, 2016; Wang, 2016). Another major challenge for nanotechnology is the anatomically
restrictive BBB of the CNS. Nanotechnologies designed for brain disorders including brain
cancer should efficiently deliver at the target site with minimal disruption of the BBB and
minimal systemic and local side effects (Giles, 2003; Oberdo
¨rster, Oberdo
¨rster, &
Oberdo
¨rster, 2005; Wang, 2016). On the other hand, the inherent complexity of the CNS,
cellular heterogeneity, and multidimensional cellular connections in the brain are also a
challenge for nanotechnology (Shah, 2016). Nanotechnology products are designed to
interact physically with target cells at a molecular level. However, due to the complexity
of the CNS at present, there are only a few applications of this type (Shah, 2016). As nano-
technology advances and broadens its applications in medicine and diagnostics, the safety
concerns about nanotechnologies is also an emerging area of research (Braydich-Stolle,
Hussain, Schlager, & Hofmann, 2005; Dobrovolskaia & McNeil, 2007; Maynard & Aitken,
2016; Voura, Jaiswal, Mattoussi, & Simon, 2004). The morphological characteristics of
nanoparticles can modulate pharmacokinetics and biodistribution of drug molecules and
can cause systemic toxicity (Moghimi, Hunter, & Murray, 2001; Moghimi, Hunter, &
Murray, 2005). However, there is a lack of systemic studies on the safety issue, particularly
for brain-related disorders. Previous studies reported that the nanoparticles could
modulate the activity of P-glycoprotein efflux pumps (Batrakova, Li, Alakhov, Miller, &
Kabanov, 2003; Huang et al., 2011; Miller, Bauer, & Hartz, 2008).
Earlier studies also reported the carcinogenic potential of nanoparticles in various
in vitro and in vivo studies. Nanoparticles are noncarcinogenic, however photo-dependent
carcinogenesis has been observed in some fullerenes and fullerene derivatives (Magaye,
Zhao, Bowman, & Ding, 2012; Rancan et al., 2002; Remya, Syama, Sabareeswaran, &
42115.8 CHALLENGES AND SAFETY CONSIDERATIONS OF NANOTECHNOLOGIES USED
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
Mohanan, 2016; Roller, 2009). The environmental hazard of nanotechnologies is another
important safety aspect because of their size and possible nonbiodegradable nature; they
can rapidly distribute and accumulate in the environment (Brandeburova
´et al., 2017;
Oukarroum, Zaidi, Samadani, & Dewez, 2017).
15.9 FUTURE PERSPECTIVES AND CONCLUSION
In the last 20 years, tremendous efforts have been observed to fabricate novel delivery
strategies against brain cancer, ranging from invasive to noninvasive strategies. However,
as far as the prognosis is concerned, little or few improvements have been noted, which
does not enable the enhancement of the median survival of patients. However, some inno-
vative reports are encouraging and may be path breaking. For instance, temozolomide,
alone or in combination with other alkylating agents, seems to be a better platform in the
treatment of brain tumors, owing to its good BBB permeability properties and low toxicity.
BBB permeability is significant, which enables greater accumulation in the CNS for
successful antitumor therapy. In recognition of the important roles of the BBB in brain
tumor chemotherapy and a better understanding of transport mechanisms and their mod-
ulators, it is possible to overcome the limitations presented by traditional chemotherapy.
Research in this field is now focused on the development of noninvasive, more specific,
and targeted strategies that exploit the knowledge of the pathogenesis of brain cancers.
Tumor growth critically depends on the formation of new blood vessels. Thus, the inhibi-
tion of angiogenesis pathways constitutes an attractive strategy for targeted therapy,
which has been investigated by single or combined agents. Further improvements will
result from a better understanding of tumor biology and the pathways involved therein.
Another promising and noninvasive tool for the delivery of therapeutic drugs to brain
tumors employs drug-loaded nanocarrier systems that take advantage of the disrupted
BBB at tumor sites with disorganized vasculature and leakier capillaries to achieve selec-
tive tumor delivery. Modification of the nanocarrier surface properties improves uptake
by endothelial cells. Also, to selectively deliver chemo drugs in brain tumors, magnetic
NPs are of great interest, with the possibility of monitoring and quantifying the process by
Mr imaging. Furthermore, SLNs have been found to be advantageous in delivering chemo
drugs due to their good BBB permeability, low intrinsic cytotoxicity, and the biodegrad-
ability of lipids used in their preparation.
In another dimension to the delivery strategies, the invasive strategies, local delivery of
chemotherapeutic agents to brain tumors by CED improves drug distribution compared to
other strategies only driven by diffusion. However, this technique is also confounded by
notable side effects. Overall, despite several issues that need to be addressed, targeted
therapy and particulate systems are promising strategies that are worth investigating
further for efficient CNS delivery of chemo drugs.
Acknowledgments
The authors would like to acknowledge the Science and Engineering Research Board, Department of Science
and Technology, Government of India, for a grant allocated to Dr Tekade for research work on gene delivery
422 15. BEYOND THE BLOODBRAIN BARRIER
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
(ECR/2016/001964) and N-PDF funding (Dr. Maheshwari; PDF/2016/003329). RT would also like to thank
NIPER-Ahmedabad for providing research support for research into cancer and arthritis. The authors acknow-
ledge support by the Fundamental Research Grant (FRGS) scheme of the Ministry of Higher Education, Malaysia,
to support research into gene delivery. The authors are also thankful to Department of Health Research (DHR),
Ministry of Health and Family Welfare, Govt. of India, New Delhi for sanctioning the Young Scientist Grant to
Mr. Piyoosh Sharma (25011/215-HRD/2016-HR).
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437FURTHER READING
NANOTECHNOLOGY-BASED TARGETED DRUG DELIVERY SYSTEMS FOR BRAIN TUMORS
