165
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
B. Kateb et al. (eds.),
The Textbook of Nanoneuroscience and Nanoneurosurgery
,
https://doi.org/10.1007/978-3-030-80662-0_11
11
Directed Drug Convection Using
Magnetic Nanoparticles as Therapeutic
Carriers Meeting the Challenge
of Specific Brain Pharmacotherapeutics,
Non-ligand-Based Central Nervous
System Targeting, Including Magnetic
Focusing
Drora Samra-Shevy, Babak Kateb, David F. Moore,
Vinith Yathindranath, Torsten Hegmann, Donald Miller,
Marc Pelletier, and Raphael Schiffman
Abstract
This chapter, titled “Directed Drug Convection Using
Magnetic Nanoparticles,” explores the use of magnetic
nanoparticles for precise drug delivery in the central ner
-
vous system (CNS). Magnetic nanoparticles can be guided
by external magnetic fields, enabling targeted drug delivery
within the brain. The chapter covers applications in treating
neurological diseases and controlled drug release. While
highlighting the potential of magnetic nanoparticles, it
addresses considerations like biocompatibility and safety.
In summary, this chapter underscores how magnetic
nanoparticles enhance CNS pharmacotherapeutics, offer
-
ing more effective treatments for neurological disorders.
Keywords
Directed drug convection · Magnetic nanoparticles ·
Therapeutic carriers · Non-ligand-based targeting ·
Magnetic focusing
Introduction
The incidence of neurological disease in the United States is
estimated to be many millions (Hirtz et al.,
2007
; NINDS,
2009
). Though a reduction in the incidence as well as the
prevalence of several of the most common ailments, such as
stroke, has occurred thanks to the use of recombinant tissue
D. Samra-Shevy
California Institute of Technology (Caltech), Pasadena, CA, USA
B. Kateb (
*
)
Chairman, CEO and Scientific Director, Society for Brain Mapping
& Therapeutics (SBMT),
Pacific Palisades, CA, USA
President and Scientific Director, World Brain Mapping
Foundation (WBMF), Pacific Palisades, USA
Director of National Center for Nano-Bio-Electronics (NCNBE),
Los Angeles, USA
Director of Brain Technology and Innovation Park (BTIP),
Los Angeles, USA
Chairman, Neuroscience20 (Brain, Spine, Mental Health)
Initiative, Los Angeles, USA
CEO and Co-founder, Aramis Therapeutics,
Los Angeles, CA, USA
e-mail:
Babak.Kateb@worldbrainmapping.org
D. F. Moore
Department of Neurology, Tulane University,
New Orleans, LA, USA
V. Yathindranath
Department of Pharmacology and Therapeutics, University of
Manitoba, Winnipeg, MB, Canada
T. Hegmann
Advanced Materials and Liquid Crystal Institute, Kent State
University, Kent, OH, USA
D. Miller
Max Rady College of Medicine, Pharmacology and Therapeutics,
KIAM – Health Sciences Centre, Winnipeg, MB, Canada
M. Pelletier
Department of Physiology and Biophysics, Case Western Reserve
University, Cleveland, OH, USA
Aeromics, LLC, Cleveland, OH, USA
R. Schiffman
Texas Neurology, Dallas, TX, USA
Baylor Scott & White Health, Dallas, TX, USA
166
plasminogen activator (rt-PA), the standard of care for treat
-
ment of acute ischemic stroke and other major disabling dis
-
eases, such as Alzheimer and Parkinson, is still not solved.
Drug delivery to a prespecified brain area could be one of the
solutions to such diseases. However, the requirements and
challenges of such technique are very high. This is partly due
to the intricate and complicated structural organization of the
central nervous system (CNS), composed of the brain and
spinal cord, comparable to a multiorgan system, and the
unique safety gate, the blood–brain barrier (BBB) that blocks
most of the drugs and other components to be delivered to
the brain. Still due to the increased life span and a higher
number of aged people, the burden of neurological disorders
demands a new way to treat those chronic disabling diseases,
a new innovative way in brain therapeutics and drug delivery
that will bypass the BBB obstacles, with the unique partition
coefficient and mass transport problems, and the architecture
of the brain that allows drugs to disseminate and affect unde
-
sired targets. Eventually, only an interdisciplinary effort in
nanoscience can potentially solve CNS drug delivery
challenges.
The BBB is composed of physical and metabolic barriers
at the brain microvascular endothelial cells (BMECs) and of
the “glia limitans” that prohibits any foreign substances
(xenobiotics) delivery so to minimize toxicity effect on the
so delicate brain parenchyma. This sophisticated mechanism
to protect the brain is the main barrier to deliver therapeutics
to the CNS. Drugs must cross the BBB at a significant con
-
centration to be effective. Almost 98% of small-molecule
drugs and 100% of large-molecule drugs available today or
in development have significant mass transport barriers at the
BBB and restricted CNS entry (Pardridge,
2006
). As a rule of
thumb, only lipophilic molecules, under molecular weights
of around 500 Da, are capable of penetrating into the CNS by
crossing the BBB (Miller,
2002
). Most drugs have a molecu
-
lar weight in the range of tens of kilodaltons. Penetrating the
BBB is not enough though. A drug must target only the nec
-
essary anatomical section and not to be disseminated
throughout the brain in order to enhancing the CNS thera
-
peutic window and reducing toxicological consequences.
This would potentially allow significant reductions in dos
-
ing, particularly in the case of directed delivery of high-
molecular-
weight drugs to specific brain areas. Current
methods of intratumor, intrathecal, and intravenous injection
do not adequately address the above issues.
Cell and gene therapies have achieved impressive results
in the treatment of rare genetic diseases. The overlapping
fields of cell and gene therapy (CGT) offer the potential for
curative treatments for a wide range of diseases. Gene ther
-
apy is the delivery of genetic material into patient cells
in vivo with the use of vectors that are typically viral based.
Gene therapy can enable the permanent correction of genetic-
based disorders, for example by the delivery of a fully func
-
tioning gene to correct for the effects of a disease-causing
mutation. Cell therapy is defined as the administration of live
cells, derived from the patient receiving the therapy (autolo
-
gous cell therapy) or from a different source (allogeneic cell
therapy). A type of cell therapy that overlaps with gene ther
-
apy is the treatment of patients with gene engineered cells.
Examples of gene engineered cell therapies include stem
cells corrected for genetic mutations and immune cells engi
-
neered with synthetic receptors to enable their recognition of
antigens expressed on tumor cells.
For a gene therapy, the most commonly used translational
therapy (clinical practice application of basic science
research) is the use of adeno-associated virus (AAV) to
deliver proteins or genes across the BBB, in particular, the
AAV9 serotype, for example, an efficient vector delivery to
glial cells throughout the brain, dorsal root ganglia, and spi
-
nal motor neurons in nonhuman primates (Fu et al.,
2011
).
Intrathecal injections of AAV compared to intravenous pro
-
vide greater CNS distribution, less exposure to peripheral
organs and tissues, and reduced impact of immune responses
than systemic dosing (Bey et al.,
2020
). Still, the main limi
-
tation of this method is the need for repeated administration
with the likely immune response and the diminishing effi
-
cacy. Other gene therapies, such as bone marrow transplanta
-
tion cell gene therapy, are either inefficient or require the
presence of a particular type of mutation in the case of
single-
gene disorders (Khanna et al.,
2010
; Schiffmann,
2010
).
The potential of CGTs is offset by the significant chal
-
lenges facing their safety, efficacy, and manufacturing. Gene
insertions into the genome carry the risk of insertional muta
-
genesis. Cell therapies used in the treatment of cancer often
result in acute toxicities such as cytokine release syndrome
(CRS) or neurotoxicity.
The use of small molecules is a key approach to overcome
these barriers and can benefit cell and gene therapies at mul
-
tiple stages, for example, in conditioning chemotherapy or
for the manufacturing of an autologous CAR-T cell therapy.
Still all those techniques are lacking robustness, causing
immune response and are very complicated to achieve.
Magnetic Nanoparticle’s Introduction
Magnetic nanoparticles have shown great potential as thera
-
peutic carriers in various biomedical applications. Their
unique properties, such as small size, high surface area-to-
volume ratio, and magnetic behavior, make them suitable for
targeted drug delivery and imaging in the field of medicine.
Here are some key aspects of using magnetic nanoparticles
as therapeutic carriers:
D. Samra-Shevy et al.
167
Drug Delivery
Magnetic nanoparticles can be loaded with therapeutic
agents, such as drugs, proteins, or nucleic acids, and used to
deliver these payloads to specific target sites in the body. The
nanoparticles can be guided and concentrated at the desired
location using an external magnetic field, increasing the
local drug concentration, and reducing off-target effects
(Abu-Hamdeh et al.,
2020
).
Targeted Therapy
By functionalizing the surface of magnetic nanoparticles
with specific ligands, antibodies, or peptides, they can be
directed to cells or tissues. This active targeting approach
enhances the specificity and efficiency of drug delivery,
reducing side effects and improving treatment outcomes
(Ulbrich et al.,
2016
).
Hyperthermia
Magnetic nanoparticles can be utilized for hyperthermia
treatment, which involves heating targeted tissues to thera
-
peutic temperatures using an alternating magnetic field. This
approach is particularly relevant in cancer therapy, where the
elevated temperature can induce tumor cell death while spar
-
ing healthy surrounding tissues (Salunkhe et al.,
2014
).
Imaging and Diagnostics
Magnetic nanoparticles can serve as contrast agents in various
imaging modalities, such as magnetic resonance imaging
(MRI) (Avasthi et al.,
2020
), magnetic particle imaging (MPI),
and magnetic particle spectroscopy (MPS) (Yari et al.,
2023
).
They provide high-resolution images and valuable informa
-
tion about disease progression and treatment response.
Controlled Drug Release
One of the significant advantages of using magnetic nanopar
-
ticles as carriers is the ability to control drug release kinetics,
by adjusting the size, composition, and surface properties of
the nanoparticle (Abu-Hamdeh et al.,
2020
).
Crossing Biological Barriers
Magnetic nanoparticles can overcome biological barriers,
such as the blood–brain barrier, which limit the delivery of
therapeutic agents to certain organs or tissues. With appro
-
priate surface modifications, these nanoparticles can traverse
these barriers, opening up new possibilities for treating neu
-
rological disorders and other hard-to-reach diseases (Jia
et al.,
2020
).
Combination Therapy
Magnetic nanoparticles enable combination therapy, where
multiple therapeutic agents can be loaded onto the same
nanoparticle. This allows for the simultaneous delivery of
different drugs or treatment modalities, potentially synergiz
-
ing their effects and improving therapeutic outcomes (Gadag
et al.,
2020
).
Monitoring Treatment Response
In addition to their role as drug carriers, magnetic nanopar
-
ticles used as contrast agents in imaging modalities allow
real-time monitoring of treatment response. This capability
enables clinicians to assess the effectiveness of therapy and
make adjustments as needed (Lin et al.,
2020
).
Regenerative Medicine
Magnetic nanoparticles can also be employed in regenerative
medicine applications. They can serve as carriers for growth
factors or biomolecules that promote tissue regeneration and
healing. The nanoparticles can be delivered to the site of
injury or damaged tissue, providing localized and controlled
release of regenerative factors (Liu et al.,
2019
).
Nanotheranostics
The integration of therapeutic and diagnostic functionalities
in a single system, known as “nanotheranostics,” is an emerg
-
ing area in medicine. Magnetic nanoparticles can play a cru
-
cial role in nanotheranostics, as they can be designed to both
deliver therapeutic agents and act as imaging contrast agents
simultaneously (Panigrahi et al.,
2022
).
Noninvasive Treatment
The use of magnetic nanoparticles allows for noninvasive
treatment approaches. External magnetic fields are applied
externally, which means that the nanoparticles can be guided
and manipulated remotely without the need for invasive pro
-
cedures (Panigrahi et al.,
2022
).
11
Directed Drug Convection Using Magnetic Nanoparticles as Therapeutic Carriers Meeting the Challenge of Specific Brain...
168
Multimodal Imaging
In some cases, magnetic nanoparticles can be designed to
exhibit multiple imaging modalities. For example, they can
combine magnetic resonance imaging (MRI) and
fluorescence imaging capabilities, providing complementary
information for a more comprehensive understanding of the
disease state and treatment response (Burke et al.,
2017
).
Photothermal Therapy
In addition to hyperthermia, magnetic nanoparticles can be
combined with light-absorbing materials to enable photo
-
thermal therapy. This approach involves using near-infrared
light to heat the nanoparticles, leading to localized hyper
-
thermia and targeted destruction of cancer cells or other dis
-
eased tissues (Zhang et al.,
2023a
).
Magnetic-Assisted Tissue Engineering
Magnetic nanoparticles can aid in tissue engineering appli
-
cations by facilitating cell alignment and tissue regeneration
through magnetic guidance. Researchers are exploring ways
to use magnetic fields to control the orientation and migra
-
tion of cells in engineered tissues, leading to better tissue
functionality and organization (Ito & Kamihira,
2011
).
Veterinary Medicine
Magnetic nanoparticles’ applications are not limited to
human medicine; they also have potential applications in vet
-
erinary medicine. They can be used for targeted drug deliv
-
ery, imaging, and diagnostics in animals, aiding in the
treatment of various diseases (Ito & Kamihira,
2011
).
Biocompatibility and Safety
For any therapeutic application, the biocompatibility and
safety of the nanoparticles are critical. Extensive research is
being conducted to ensure that magnetic nanoparticles used
in medicine are non-toxic, stable, and well-tolerated by the
human body (Naahidi et al.,
2013
).
Brain Drug Delivery Using Magnetic
Nanoparticles
Magnetic nanoparticles can be designed to cross the blood–
brain barrier (BBB) and deliver drugs to the brain, enabling
better treatment options for neurological disorders and brain
tumors (Nance et al.,
2022
).
Challenges
Despite their potential, there are challenges to overcome,
such as maintaining nanoparticle stability, controlling the
release rate of loaded drugs, and addressing potential toxic
-
ity concerns. Additionally, more research is needed to fully
understand the long-term effects of using magnetic nanopar
-
ticles in therapeutic applications (Desai,
2012
).
Nanoparticles for the CNS
Nanocarriers include agents such as nanoparticles, den
-
drimers, and polymeric or lipid-based carriers like lipo
-
somes. Nanocarriers function by serving as a transport
carrier that determines the pharmacokinetics of transport and
distribution instead of the active drug. Nanocarriers should
facilitate the transport and delivery of drug molecules across
the BBB, in a confined site, and should not cause any adverse
immune response. In particular, nanoparticle (NP) proper
-
ties, such as size, shape, and composition, enable selective
CNS targeting, cell accumulation, and in vivo functional
imaging. NP size may range from 10 nm to a few hundred
nanometers and allows medicinal chemistry therapeutics to
be absorbed, adsorbed, encapsulated, or chemically attached
to the nanocarrier.
Even more, nanocarriers are easily convected through
brain capillaries of ~3
μ
m in diameter. By modifying its
surfaces with a cell-specific ligand, specificity can be
achieved.
BBB Penetration: The BBB presents a significant chal
-
lenge in delivering therapeutic agents to the brain. However,
magnetic nanoparticles can be engineered to cross the BBB
either through passive diffusion or active transport mecha
-
nisms. Their small size and surface modifications enable
them to bypass the BBB’s restrictive properties, allowing for
targeted drug delivery to the brain as shown in Fig.
11.1
(Teleanu et al.,
2019
).
Targeted Drug Delivery
Magnetic nanoparticles can be functionalized with specific
ligands or antibodies that can selectively recognize and
bind to receptors on brain cells or tissues. This active tar
-
geting approach ensures precise delivery of therapeutic
agents to the desired brain regions, minimizing off-target
effects and enhancing treatment efficacy (Yang et al.,
2021
).
D. Samra-Shevy et al.
169
Fig. 11.1
Different modes of transport across the blood–brain barrier (BBB) (Teleanu et al.,
2019
). (Creative Commons Attribution (CC BY)
license)
Theranostics
The integration of both therapeutic and diagnostic functions,
known as theranostics, can be achieved using magnetic
nanoparticles. By incorporating imaging agents into the
nanoparticles, treatment response can be monitored in real-
time, guiding adjustments to the therapeutic regimen as
needed (Marin et al.,
2020
).
Convection-Enhanced Delivery
Recently, it was shown that fluid convection, established by
maintaining a pressure gradient during interstitial infusion,
can supplement simple diffusion to enhance the distribution
of small and large molecules in brain and tumor tissue. This
technique called Convection-Enhanced Delivery (CED) is to
deliver drugs that would not cross the BBB and that would be
too large to diffuse effectively over required distances
(Lonser et al.
2007
). In this case, in situ drug concentrations
can be significantly greater than those achieved by systemic
administration. This technique allows the local delivery of a
wide range of substances like conventional chemotherapeu
-
tic agents monoclonal antibodies targeted toxins other pro
-
teins viruses and nanocarriers.
Superparamagnetic Nanoparticles
Another way to address drug delivery in a non-ligand-based
targeting mechanism is with versatile magnetic configura
-
tion for the control and manipulation of superparamagnetic
nanoparticles and nanocarriers. Magnetic focusing (MF) of
NPs has a huge potential for site-specific drug delivery. One
of the earliest reports on magnetic targeting (MT) of tumors
with cytotoxic agents was published three decades ago
(Widder et al.,
1981
). In these studies, external magnets were
used to localize magnetic carriers at the targeted site. Liu
et al. (
2010
) used focused ultrasound and MT using external
magnets (0.2, 0.4, and 0.55 T) tied to a rat’s head in synergy
to increase the local concentration of epirubicin linked to
Fe3O4 NPs in the rat brain (Mathieu & Martel,
2010
). Using
external magnets for focusing might work in small animals
but will be more challenging in patients as their efficiency
depends on the close proximity between the magnet and the
target tissue.
Yet, most of the applications rely on relatively large
nanoparticles, 50 nm or higher, mainly due to the fact that the
magnetic control of smaller MNPs is often hampered by the
thermally induced Brownian motion. However, microfluidic
environment SP-MNPs smaller than 10 nm can be magneti
-
cally manipulated (Surpi et al.,
2023
).
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Directed Drug Convection Using Magnetic Nanoparticles as Therapeutic Carriers Meeting the Challenge of Specific Brain...
170
Magnetic Resonance Navigation (MRN)
Magnetic resonance navigation (MRN) was recently intro
-
duced to overcome the problematic external magnets in deep
tissue MT (Felfoul et al.,
2016
). MRN is achieved by a con
-
ventional magnetic resonance imaging (MRI) scanner with
modified gradient coils and software to facilitate 3D mag
-
netic focusing. A magnetic field of 1.5 T or higher in the
MRI scanner overcomes the challenge of deep tissue mag
-
netic focusing and hence can be used for MT anywhere in the
human body. Currently, clinical MRI produces a gradient of
80 mT m
−
1
(Vachha & Huang,
2021
), which can be useful to
focus on millimeter-sized untethered ferromagnetic objects.
MF of micron-sized particles or nanoaggregates will need
gradients up to 400 mT m
−
1
(Pouponneau et al.,
2011
). There
are technical constraints in designing coils with higher field
gradient amplitude, with a current milestone of doubling
from 40 to 80 mT which is still not enough (Gudino & Littin,
2023
).
The MRN technique generally involves five steps (Li
et al.,
2019
). One of these steps includes the design of druge
-
luting beads (DEBs), which are composed of Fe3O4 super
-
paramagnetic nanoparticles. These specialized biodegradable
microbeads, typically sized between 100 and 300
μ
m, can
encapsulate drugs. Within this size range, the particles can
effectively penetrate both the tumor and its margin.
The drug is encapsulated in a biocompatible biodegrad
-
able polymer (PGLA). Those magnetic particles (5–20 nm)
are nanosized so that they can be phagocytosed without any
negative or toxic effects after the MDEBs (magnetic drug
eluting beads) have biodegraded into the body.
Moreover, the superparamagnetic property of the nanopar
-
ticles makes it so that the MDEBs have no remnant magneti
-
zation once the patient is removed from the MRI field.
Control of blood flow: blood flow will drive and drag the
particles forward. Since the MRN steering force on MDEB
aggregates is limited, we need to control the flow to have
enough time to deviate the particles into the target branches.
A combination of vibrating and constant flow, also known
as peristaltic flow or oscillating flow, can generate a stop and
go motion of the MDEB aggregates. The vibrating flow
could maintain a vibrating status over the particles; thus, the
attractive forces, such as dipolar interactions, could be over
-
come. Therefore, with a small displacement vector and MRN
steering force, a satisfactory MRN success rate can be
achieved.
Formation of MDEB aggregates should be with control
-
lable sizes (Tous et al.,
2021
).
Mathieu and Martel (
2010
) used propulsion gradient coils
in an MRI scanner with a 1.5-T field to steer a suspension of
Fe3O4 aggregates of around 11
μ
m in a y-shaped channel.
The flow rates were carefully controlled in this in vitro
experiment, and steering ratios of NPs were measured for
gradients of 50, 100, 200, and 400 mT m
−
1
. It was observed
that the steering ratio increases with the amplitude of the
magnetic gradient and that the largest magnetic aggregates
require lower magnetic gradient amplitude. Pouponneau
et al. (
2011
) used MRN to guide and image magnetic FeCo-
PLGA [iron–cobalt NPs encapsulated in poly(d,l-lactic-
co
-
glycolic acid)] microparticles 58
μ
m in diameter through a
phantom mimicking hepatic arteries. For steering studies, a
1.5-T MRI was used, with a gradient magnetic field of 400
mT m
−
1
. The microparticles formed aggregates in the MRI,
which facilitated steering with the applied field gradient.
Steering efficiency was measured by estimating the amount
of iron and cobalt from two channels using atomic absorp
-
tion spectroscopy (AAS), and this showed successful mag
-
netic steering.
Preparation
A considerable amount of work has been carried out in
designing magnetic nanocarriers that can be focused mag
-
netically. The bulk of nanotherapeutics research on drug
delivery and in vivo imaging is formulated upon well-
characterized systems in terms of synthesis, chemical modi
-
fications, biocompatibility, and, in some cases, that are
already approved by the Food and Drug Administration
(FDA). Iron oxide nanoparticles (IONPs) composed of mag
-
netite (Fe3O4) and maghemite (
γ
-Fe2O3), with diameters
ranging from 1 to 100 nm, are superparamagnetic at room
and body temperature and are magnetized only in the pres
-
ence of an external magnetic field. These particles are bio
-
compatible and are already used in clinical medicine as a T2
contrast agent for MRI (Bulte et al.
2001
). IONPs have the
potential to enable a range of drug carrier and diagnostic
options for CNS disorders. IONPs with core sizes in the tens
of nanometers and suitable surface modification have the
potential to permeate the BBB and tissue for drug delivery
(Bulte et al.
2001
; Chertok et al.
2008
; Mykhaylyk et al.
2001
; Rousseau et al.
1997
). Drug-loaded IONPs combined
with convection-enhanced diffusion (CED) techniques could
be a useful strategy for drug delivery into the CNS, allowing
novel treatment of brain tumors and fulminant neuronopathic
disorders, such as Gaucher disease (Lonser et al.
2007
). In
addition to in situ MRI (Corot et al.
2006
; Miyawaki et al.
2006
; Tiefenauer et al.
1996
), the intrinsic magnetic proper
-
ties of IONPs can be exploited to provide thermal mediation
for tumor thermotherapy (Gordon et al.
1979
).
IONPs can be prepared with relative ease and are eco
-
nomically viable compared to many other nanocarriers.
Among aqueous methods, coprecipitation of Fe(II) and
Fe(III) in the presence of a base, usually aqueous ammonia,
D. Samra-Shevy et al.
171
yields magnetite and maghemite (Massart,
1981
). In another
method, hydrolysis of an organometallic iron precursor using
sodium borohydride in aqueous media yielded pure magne
-
tite using nontoxic reagents and milder conditions
(Yathindranath et al.,
2011
). These aqueous methods yield
IONPs that are more suitable for biomedical applications as
they do not have remnant toxic surfactants on their surfaces.
In nonaqueous methods, high-temperature thermal decom
-
position of an organometallic precursor is widely used for
the narrow size distribution of resulting NPs (Sun and Zeng,
2002
). The final products, in most cases, have hydrophobic
surfactants, which have to be removed before further modifi
-
cations for biomedical applications. Other synthesis methods
include sol–gel, microemulsion, and sonochemical (Bilecka
et al.,
2008
; Kim et al.,
2005
; Sun et al.,
2004
).
To serve as prodrugs, IONPs need to have adequate blood
circulation, sustain proper half-life and targetability, and
avoid immediate phagocytosis and an unwanted immune
response (Bertram,
2006
). Hydrophobic colloids are rapidly
cleared from circulation by the reticuloendothelial system,
particularly in the spleen and liver. Attachment of hydro
-
philic biocompatible coatings on the surface of IONPs may
be used to increase their colloidal stability and circulation
half-life in the bloodstream (Gref et al.,
1994
; Sun et al.,
2008
; Wadghiri et al.,
2003
). In addition, IONP coating is
one of the available means to prevent IONP irreversible
aggregation in a selective way.
These particles are biocompatible and are already used in
clinical medicine as a T2 contrast agent for MRI (Bulte et al.
2001
). IONPs have the potential to enable a range of drug
carriers and diagnostic options for CNS disorders. IONPs
with core sizes in the tens of nanometers and suitable surface
modification have the potential to permeate the BBB and tis
-
sue for drug delivery (Bulte et al.,
2001
; Chertok et al.,
2008
;
Mykhaylyk et al.,
2001
; Rousseau et al.,
1997
). Drug-loaded
IONPs combined with convection-enhanced diffusion (CED)
techniques could be a useful strategy for drug delivery into
the CNS, allowing novel treatment of brain tumors and ful
-
minant neuronopathic disorders, such as Gaucher disease
(Lonser et al.,
2007
). In addition to in situ MRI (Corot et al.,
2006
; Miyawaki et al.,
2006
; Tiefenauer et al.,
1996
), the
intrinsic magnetic properties of IONPs can be exploited to
provide thermal mediation for tumor thermotherapy (Gordon
et al.,
1979
).
Nanotechnology Toward CNS Drug Delivery
Nanotechnology has shown great promise in advancing drug
delivery systems, particularly for targeting the central ner
-
vous system (CNS). The CNS, which includes the brain and
spinal cord, presents unique challenges for drug delivery due
to the blood–brain barrier (BBB), by improved BBB pene
-
tration, enhanced drug stability, targeted delivery, sustained
release, combination therapy, imaging and diagnosis.
Nanotechnology is an inventive, promising, and state-of-
the-art approach for conveying neurotherapeutics across
BBB. Over the most recent couple of years, nanomedicines
have shown extraordinary potential toward CNS drug convey
-
ance as an outcome of their nanosized range, their special
physic-compound properties, and capacity to take advantage
of surface-designed biocompatible and biodegradable nano
-
materials (Kaur et al.,
2008
). Nanotechnology-based appro-
aches for the site-explicit conveyance of therapeutics and
different mixtures across the BBB may possibly be designed
to complete specific capacities depending on the situation. The
medication, the pharmacologically dynamic part to be con
-
veyed, itself is one piece of the nanoengineered complex,
while staying complex is expected to achieve other key capaci
-
ties, for example, epitomizing the dynamic medication insures
against enzymatic harm, drug discharge at explicit pH, capac
-
ity to cross the BBB, and focusing on unambiguous synapses.
A broad scope of drug nanocarriers, including liposomes,
PNPs, SLNs, micelles, dendrimers, and some others, have
been created (Wong et al.,
2012
; Ozkizilcik et al.,
2017
).
Surface Modifications
To improve BBB penetration and enhance brain targeting,
micelles can be surface-modified with various molecules,
such as ligands, antibodies, or peptides, which specifically
recognize receptors or transporters expressed on the BBB
endothelial cells. This active targeting approach aims to
increase the accumulation of micelles within the brain.
Indeed, recently, they have become a subject of interest as
a unique medication transporter framework for the CNS.
When contrasted with non-polymeric micelles, polymeric
micelles are viewed as steadier, having a long span of activ
-
ity and high biodistribution (Ozkizilcik et al.,
2017
).
Micelles are approximately spherical in shape. Other
phases, including shapes such as ellipsoids, cylinders, and
bilayers, are also possible. The shape and size of a micelle
are a function of the molecular geometry of its surfactant
molecules and solution conditions such as surfactant concen
-
tration, temperature, pH, and ionic strength.
They have a center shell underlying model with size range
of 10–100 nm comprising external hydrophilic envelope
mostly composed of polyethylene glycol (PEG) and inward
hydrophobic center such as polycaprolactone, polypropylene
glycols, phospholipids, and unsaturated fats. In this manner,
they permit stacking of hydrophobic medications. The outer
hydrophilic shell gives strength to micelles in a watery cli
-
mate and drags out their dissemination time in the circulation
11
Directed Drug Convection Using Magnetic Nanoparticles as Therapeutic Carriers Meeting the Challenge of Specific Brain...
17 2
system, shielding them from the reticuloendothelial frame
-
work (RES). The class of Pluronic (Poloxamers) block copo
-
lymers is exceptionally compelling as they have a capacity to
impede drug efflux carriers, for example, restraint of P-gp
efflux carriers broadly communicated on BBB and upgrade
drug shipment to the CNS. Besides, it was shown that they
work with the cerebrum conveyance of low sub-atomic mass
medications integrated into them by raising the medication
solvency in plasma.
Many attempts have been made to change the micelles so
that upgraded centralization of stacked medication can cross
on one more side of BBB without any problem. One such
effort is appending either polyclonal antibodies against brain
explicit antigen,
α
2-glycoprotein (Miyajima et al.,
2013
)
such as Leucine-rich
α
2-glycoprotein (LRG), a protein
induced by inflammation, or insulin to focus on the receptor
at the luminal side of BBB. In mice, the intravenous organi
-
zation of these changed micelles in the wake of stacking with
a fluorescent color or the neuroleptic drug haloperidol
showed a better transport of the fluorescent color and excep
-
tional therapeutic impact of haloperidol.
Another example of manipulating the micelle framework is
an immediate formation of the medication molecules and
focusing on moiety to the amphiphilic portion. For example,
Zhang et al. (
2012
) concentrated on transferrin-changed cyclo-
(Arg-Gly-Asp-d-Phe-Lys) Paclitaxel form stacked micelle
(Zhang et al.,
2012
) which showed an expanded take-up by
the brain microvascular endothelial cells in vitro notwith
-
standing the extended maintenance in glioma growth in vivo
without any significant noxiousness effect. Poly lactic-
glycolic
corrosive (PLGA) nanoparticles (NPs) covered with Chitosan
oleate (CS-OA) (Naskar et al.,
2021
), which grants a posi
-
tive surface charge, and Chitosan Oleate Self-Assembled
Polymeric or other examples such as Caco-2 and Hela cells.
Micelles and PLGA NPs, stacked with lipophilic model medi
-
cation, i.e., resveratrol, in light of delivery profiles, TGA
examination, and the cell line association results, PLGA-
CS-OA viewed as steadier contrasted and polymeric micelles.
Liposomes
Liposomes are considered the original smart colloidal nano
-
carriers, proven to be a medication transporter framework in
the 1970s. These are small circular vesicles made out of the
hydrophilic compartment in the middle encased by solitary
or numerous phospholipid bilayers which are utilized as an
essential methodology for drug conveyance, proteins, and
peptides (Wong et al.,
2012
; Ozkizilcik et al.,
2017
; Nsairat
et al.,
2022
).
The size of liposomes can vary widely depending on the
method of preparation and the intended application as differ
-
ent sizes may affect factors such as stability, drug encapsula
-
tion capacity, biodistribution, and cellular uptake. Here are
the typical size ranges for liposomes which have potential for
drug delivery.
Small Unilamellar Liposomes (SUVs)
These are the smallest liposomes, with diameters generally
ranging from about 20 nanometers (nm) to 100 nm. SUVs
usually consist of a single lipid bilayer and have a relatively
low drug encapsulation capacity (“SUVs—Small Unilamellar
Vesicles – Big Chemical Encyclopedia,”
2019
).
LUVs are larger liposomes with diameters ranging from
100 nm to 1
μ
m (1000 nm). They can accommodate a higher
amount of drug payload compared to SUVs due to their
larger size (Akbarzadeh et al.,
2013
).
Multilamellar Liposomes (MLVs)
MLVs are liposomes with multiple concentric lipid bilayers,
resembling onion-like structures. Their size can range from 1
μ
m to several micrometers (Oscar Cruciani et al.,
2004
).
Giant Unilamellar Vesicles (GUVs)
These are liposomes with very large diameters, typically
ranging from 10
μ
m to hundreds of micrometers. GUVs are
often used in biophysical and cell biology research.
These are reversible designs because of non-covalent
communications, for example, van der dividers powers and
hydrogen holding between atoms (Cruciani et al.,
2004
).
Unmodified ordinary liposomes have a short flow time in
the body as they are immediately destroyed by the RES (Liu
et al.,
2022
), several efforts have been made to foster long-
circling and designated liposomes. Among such attempts are
polyethylene glycol (PEG) covering on liposomes (Wong
et al.,
2012
).
Designated conveyance of PEG-changed liposomes can
be worked with by additional adjustments with different
ligands like monoclonal antibodies (mAbs) against glial
fibrillary acidic proteins and transferrin receptors (TRs) or
human insulin receptors.
Transferrin-formed liposomes have been exhibited to
convey the payload like 5-fluorouracil to the cerebrum,
which is worked with by receptor-interceded endocytosis.
D. Samra-Shevy et al.
17 3
The formation of prednisolone-stacked liposomes with
mAbs that will be perceived by cell surface receptors in the
designated tissue called immunoliposomes exhibited further
improvement in the dissemination of liposomes inside the
brain and high viability against exploratory immune system
encephalomyelitis (Hofkens et al.,
2013
; Naqvi et al.,
2020
).
Immunoliposomes as nanocarrier frameworks for neuro
-
logical drug conveyance, as shown by TRsMAbs-designated
liposome, formed with a plasmid for tyrosine hydroxylase in
treating PD in a rodent model (Pardridge,
2005
). This
approach has additionally been utilized for the conveyance
of little meddling RNA (siRNA) against epithelial develop
-
ment factor receptor (EGFR) and showed the wreck of EGFR
articulation and expanded endurance of mice embedded
intracranially with brain cancers (Gomes et al.,
2015
).
One more way to deal with work on the productivity of
liposomes in crossing the boundaries and increment reme
-
dial achievement is their adjustments with cell entering pep
-
tides (CPP). For example, explicit ligand transferrin (T7) and
vague cell entering peptide (TAT) formed doxorubicin epito
-
mized liposomes exhibited high accessibility across BBB
and explicit cell focusing to the brain glioma (Kang et al.,
2022
). As of late, nimodipine proliposomes, which structure
liposomal structure upon contact with water, increase the
oral bioavailability of the medication. In another review,
intensifies like
α
-tocopherol (Toc) and omega3 unsaturated
fat were stacked into liposomes with hostile to Alzheimer’s
drug tacrine for the therapy of AD with an intranasal course.
Some examples of liposomal formulations that have been
developed for CNS drug delivery:
Doxil (Doxorubicin Liposomal)
Doxil is a liposomal formulation of the chemotherapeutic
drug doxorubicin. It has been investigated for the treatment
of brain tumors, such as glioblastoma multiforme. The lipo
-
somal encapsulation of doxorubicin allows for better drug
delivery to the brain tumor, reducing systemic toxicity and
improving drug efficacy (Raju et al.,
2023
).
AmBisome (Amphotericin B Liposomal)
AmBisome is a liposomal formulation of the antifungal drug
amphotericin B. It is used for the treatment of fungal infec
-
tions, including those affecting the CNS. The liposomal
encapsulation enhances drug delivery to the brain and
reduces the toxic side effects commonly associated with con
-
ventional amphotericin B (Maertens et al.,
2022
).
Liposomal Nanoparticles for Gene Delivery
Liposomes have been used as carriers for gene therapy appli
-
cations in the CNS. By encapsulating therapeutic genes
within liposomes, they can be delivered to specific brain
regions to treat genetic disorders or neurodegenerative dis
-
eases (dos Santos Rodrigues et al.,
2019
).
Liposomal Gadolinium-Based Contrast Agents
In diagnostic imaging, liposomes can be loaded with
gadolinium-
based contrast agents to improve the visualiza
-
tion of brain tissues in MRI scans. The liposomal formula
-
tion enhances the stability and circulation time of the contrast
agent, leading to better imaging results (dos Santos Rodrigues
et al.,
2019
).
ONPATTRO (Patisiran Liposomal)
ONPATTRO is a liposomal formulation used for the treat
-
ment of hereditary transthyretin-mediated amyloidosis, a
rare neurological disorder. The liposomal delivery system
allows for targeted delivery of the therapeutic RNA interfer
-
ence agent, patisiran, to liver cells, reducing the production
of the faulty protein that causes the disease (Urits et al.,
2020
).
DepoDur (Extended-Release Morphine
Liposomal)
DepoDur is a liposomal formulation of morphine used for
the management of postoperative pain, including after neu
-
rosurgery. The liposomes release morphine gradually over an
extended period, providing sustained pain relief and reduc
-
ing the need for frequent dosing (Pooja et al.,
2018
).
Liposomal Encapsulated Cytarabine
and Methotrexate
Liposomal formulations of the chemotherapeutic drugs cyta
-
rabine and methotrexate have been developed for the treat
-
ment of leptomeningeal metastases and lymphomatous
meningitis. These formulations allow for targeted drug deliv
-
ery to the CNS, improving the efficacy of treatment while
reducing systemic side effects (Scott et al.,
2014
).
Liposomes for Parkinson’s Disease
Liposomes have been explored as carriers for neuroprotec
-
tive agents and gene therapy to treat Parkinson’s disease. The
liposomes can deliver therapeutic molecules, such as anti
-
oxidants or neurotrophic factors, to protect neurons and
potentially slow the progression of the disease (Kumar et al.,
2020
).
Liposomal Curcumin
Curcumin, a natural compound found in turmeric, has shown
potential in neuroprotection and the treatment of neurode
-
generative disorders. Liposomal formulations of curcumin
can improve its bioavailability and brain uptake, enhancing
its therapeutic effects in the CNS (Diomede et al.,
2021
).
11
Directed Drug Convection Using Magnetic Nanoparticles as Therapeutic Carriers Meeting the Challenge of Specific Brain...
174
Liposomes for Alzheimer’s Disease
Liposomal delivery systems have been investigated for the
delivery of drugs targeting beta-amyloid plaques and tau pro
-
tein tangles in Alzheimer’s disease. These liposomal formu
-
lations aim to improve the selectivity and efficacy of drugs
that can potentially modify the course of the disease (Ross
et al.,
2018
).
Liposomal Nanocarriers for RNA Therapeutics
Liposomes have been used to deliver RNA-based therapeu
-
tics, such as small-interfering RNA (siRNA) or messenger
RNA (mRNA), to target specific genes or pathways impli
-
cated in neurological disorders. This approach holds promise
for precision medicine and personalized therapies (Zhang
et al.,
2023b
).
Nanoparticles-in-Liposomes (NILs) for CNS Drug
Delivery
As mentioned before, NILs are a hybrid liposomal system
where nanoparticles (e.g., gold nanoparticles, quantum dots)
are encapsulated within liposomes. This combination allows
for synergistic benefits, such as improved drug loading
capacity and targeting capabilities, making them promising
for CNS drug delivery (Malam et al.,
2009
).
Anti-inflammatory Liposomes
Liposomes loaded with anti-inflammatory agents have been
investigated for their potential in reducing neuroinflamma
-
tion in CNS disorders, such as multiple sclerosis and trau
-
matic brain injury (van Alem et al.,
2021
).
Polymeric Nanoparticles
Polymeric nanoparticles are small-sized particles made of
polymers, which are long chains of repeating molecular
units. These nanoparticles are usually in the range of
1–1000 nm in size. They have gained significant attention in
various fields, including medicine, drug delivery, and materi
-
als science, due to their unique properties and potential
applications (Begines et al.,
2020
; Zieli
ń
ska et al.,
2020
).
Polymeric nanoparticles can be synthesized through dif
-
ferent methods, such as emulsion polymerization, nanopre
-
cipitation, and emulsification-solvent evaporation. The
choice of method depends on the desired size, shape, and
properties of the nanoparticles.
Polymeric nanoparticles can be made from a wide range
of natural and synthetic polymers, each offering distinct
properties (Crucho & Barros,
2017
). Examples of commonly
used polymers include poly(lactic-co-glycolic acid) (PLGA)
(Huang & Zhang,
2018
), polyethylene glycol (PEG)
(Vaughan,
2023
), chitosan, polyvinyl alcohol (PVA), and
polylactic acid (PLA) (Ilyas et al.,
2021
).
They are strong colloidal scattering of biodegradable
and biocompatible polymers, for example, poly (alkylcya
-
noacrylate) (PACA) (Øverbye et al.,
2021
), polyesters, for
example, poly (lactide) (PLA), poly (D,L-lactide-co-
glycolic corrosive) (PLGA), and a few others, for example,
normal proteins and polysaccharides with size range of
10–100 nm. They comprise a center of thick polymer lattice
to exemplify the lipophilic drugs and a hydrophilic crown
to give steric security to NPs. The medication to be con
-
veyed might be embodied, adsorbed, or artificially con
-
nected to the outer layer of the NPs. The home season of
these NPs in foundational dissemination can be expanded
by the surface change either with actual adsorption or cova
-
lent restricting of hydrophilic polymers like PEGs and
polysaccharides, while the consideration of tissue-explicit
ligands works with designated conveyance to the brain. It
has been laid out that covering of poly (n-butylcyanoac
-
rilate) (PBCA) NPs with 1% polysorbate 80 (PS80) intensi
-
fied the centralization of rivastigmine or tacrine drug inside
the cerebrum as contrasted and free medication and specifi
-
cally focused on to the CNS for AD lessening the hepatic or
gastrointestinal secondary effects combined with tradi
-
tional therapy approach.
Another review demonstrated that dalargin containing
PS80-covered PACA nanoparticles was able to cross the
BBB and produce its antinociceptive result, after oral
organization. A potential system of such conveyance is
adsorption of PS80-covered PACA nanoparticles on ApoE
and B from the circulation system upon intravenous infu
-
sion followed by transcytosis across BBB utilizing the
low-thickness lipoprotein receptors. PLGA nanoparticles
show great transporter for conveying drugs across BBB. In
vivo conveyance of venlafaxine-stacked PLGA nanoparti
-
cles as treatment for depression tried in C57/bl6 mice and
in vitro BBB model utilizing hCMEC/D3 cell (Weksler
et al.,
2013
). Figure
11.2
describes polymerics nanoparti
-
cles drug targeting, oncological applications, and future
perspectives.
Magnetically Directed Drug Convection
Yathindranath et al. demonstrated a proof of principle for
magnetically directed drug convection (MDDC) of a model
drug-protein using an IONP nanocarrier in vitro in agarose
gel mimicking healthy brain tissue in a 7-T MRI
(Yathindranath et al.
2009
,
2011
). For the studies, IONPs
were synthesized using Massart’s method of coprecipitation.
The nanocarrier design used is schematically illustrated in
Fig.
11.5a
and has an iron oxide core, biocompatible poly
-
mer coating, and bovine serum albumin (BSA, MW ~ 65 kD)
on the particle surface. L-Arginine was used as a stabilizer to
prevent irreversible aggregation and preserve protein
D. Samra-Shevy et al.
175
Fig. 11.2
Overview of the main features of polymeric nanoparticles (Gagliardi et.al.,
2021
)
conformation during drying and resuspension in a physio
-
logical buffer. Biocompatible surfactants, polyethylene gly
-
col (PEG), glutamic acid, poly(ethyl methacrylate) (PEMA),
and poly(2-hydroxyethyl methacrylate) (PHEMA) were
used to coat IONPs. Figure
11.3
shows the high-resolution
transmission electron microscopy (HRTEM) and transmis
-
sion electron microscopy (TEM) images of synthesized
PEG-coated IONPs, a precursor for protein-immobilized
particles. Protein-immobilized particles demonstrated excel
-
lent colloidal stability in water and stayed well suspended
without any sign of agglomeration or settling (Fig.
11.4
).
This is illustrated in Fig.
11.5b
, where three differently con
-
stituted nanocarriers demonstrate their colloidal stability and
their accumulation under a magnetic field.
For directing NPs magnetically in vitro, different IONPs
with immobilized BSA were suspended in agarose gel
(0.4–1.0%) and egg white while positioned in a 7-T mag
-
netic field. A gradient of the 7-T horizontal-bore MRI mag
-
net was applied, followed by direct magnetic resonance
(MR) visualization. Agarose gel 0.6% closely resembles the
mass transport properties of healthy brain tissue, and egg
white is a suitable model for a complex biological fluid.
Figure
11.6
illustrates the effect of increasing the agarose gel
concentration across the 0.4–1.0% range.
As would be expected, there is decreasing mass transport
convection under the MRI gradient field. The co-migration
of BSA and a nanocarrier from concurrent protein staining
was observed. Figure
11.7
illustrates the mass transport of
PEMA-coated IONPs in egg white (Yathindranath et al.,
2009
). Such nanocarriers for large molecules might be able
to carry and deliver large peptide molecules, such as growth
factors to injured brain regions or genes for gene therapy of
inherited metabolic disorders such as Gaucher disease type II
and type III. It is likely that future development of therapeu
-
tic agents across the BBB will also include not only the com
-
bination of vascular endothelium-specific epitopes but also
11
Directed Drug Convection Using Magnetic Nanoparticles as Therapeutic Carriers Meeting the Challenge of Specific Brain...
176
other means to manipulate gene expression, such as RNA
interference (RNAi) in cases of dominant disorders (Chen
et al.
2009
; McBride et al.
2011
).
As a potential treatment paradigm, MT might be helpful
in achieving CNS targeting specificity of drug delivery,
thereby allowing an increased therapeutic window and
reducing the risk of drug toxicity while increasing drug tis
-
sue selectivity. At present, the magnetic focusing of NPs is
still in the development phase, and a thorough understanding
of potential carrier systems coupled with advancements in
technology to steer IONPs magnetically inside the body is
important before MT can find its full potential, particularly
for the CNS.
In Conclusion
The field of magnetic nanoparticle-based therapies is
dynamic and continually evolving, with ongoing research
pushing the boundaries of what is possible. As more innova
-
tive strategies and technologies are developed, magnetic
nanoparticles have the potential to revolutionize various
aspects of medicine, ranging from diagnostics and imaging
to targeted therapy and regenerative medicine. However, it is
essential to address challenges related to manufacturing scal
-
ability, biocompatibility, and long-term safety to ensure suc
-
cessful translation from this to clinical practice.
In recent years, several magnetic nanoparticle-based ther
-
apeutics and imaging agents have entered preclinical and
clinical trials, showcasing the progress made in this field.
Fig. 11.3
Schematic of the iron oxide core-shell nanoparticles (IO
cs-NPs)
Fig. 11.4
(
a
) HRTEM and
(
b
) TEM micrographs of
PEG-coated IONPs
Fig. 11.5
(
a
) Dispersion of BSA-immobilized on (A) PEG-, (B) dextran-, and (C) PEMA-coated IONPs in deionized (DI) water. (
b
) Illustration
of IO cs-NP attraction to small, rare-earth magnet
D. Samra-Shevy et al.
17 7
Fig. 11.6
T2-weighted MR
images of C: BSA
immobilized PEMA-coated
IONPs in gels prepared in DI
water with different agarose
concentrations (w/v): (
a
)
0.4%, (
b
) 0.5%, (
c
) 0.6%, (
d
)
0.7%, (
e
) 0.8%, and (
f
) 1.0%.
(
g
) Plot of movement after
3 days (mm) versus %
agarose gel
However, it is important to note that the regulatory approval
and widespread adoption of these therapies may take time as
their safety and efficacy are thoroughly evaluated.
Overall, magnetic nanoparticles hold promise as versatile
and effective therapeutic carriers with potential applications
in cancer treatment, drug delivery, and medical imaging.
Continued research and development will undoubtedly lead
to further advancements and the realization of their full
potential in clinical settings.
11
Directed Drug Convection Using Magnetic Nanoparticles as Therapeutic Carriers Meeting the Challenge of Specific Brain...
178
Fig. 11.7
Representative
T2-weighted MR images of
an egg injected with
BSA-immobilized PEMA
coated IONPs acquired (
a
) at
time zero and (
b
–
d
) at three
slice positions within the egg
after 60 h of exposure to a
magnetic field gradient. The
magnetic field was lowest at
the injection site, indicated
with a white arrow, and
highest at the bottom of the
images shown. The scale bar
represents 1 cm
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