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362 D. R. Serrano Lopez et al.
https://t.me/med1917
14.5.1.3 Angiogenesis-Related Targeting
Solid tumours rely on an adequate blood supply to grow. Tumour and host cells
secret different pro-angiogenic factors to develop new blood vessels including
epidermal growth factor (EGF), vascular endothelial growth factor (VEGF),
interleukin-8, platelet-derived growth factor, platelet-derived endothelial cell growth
factor, tumour necrosis factor-α, basic fibroblast growth factor, angiogenin,
angiotropin, and transforming growth factor-α (Baker and Fidler
2007). Inhibiting
the angiogenesis process may regulate the size and the metastatic capabilities of
tumours (Folkman 1996). Moreover, actively targeting the tumour vasculature is
advantageous as it has broad applicability since the tumour vasculature is not
specific for the type of cancer. There is a lower risk of drug resistance with tumour
vascular targeting due to the fact that the endothelial cells are more stable genetically
than cancer cells, and due to the fact that nanomedicines could bind directly to their
receptors without being required to extravasat e and penetrate the solid tumour
(Kumar and Li 2001). Table 14.3 summarizes the active targeting nanomedicines
developed against the major angiogenic targets including:
• VEGF and their receptors, VEGFR-1, and VEGFR-2. VEGF levels are
upregulated by tumour hypoxia and oncogenes which leads to the upregulation
of VEGFR on tumour endothelial cells, with VEGFR-2 being highly expressed in
tumour neovasculature (Veikkola et al.
2000). Thus, the two main approaches are
to target: (i) VEGF to inhi bit binding toVEGFR-2 receptor or (ii) the VEGFR-2
receptor to decrease the VEGF binding (Carmeliet
• α
integrin. This is an endothelial cell receptor (which contains Arg-Gly-Aps or
vβ3
2005).
a RGD sequence) for extracellular matrix (ECM) proteins such as fibrinogen,
fibronectin, vitronectin, von Willebrand factor, osteopontin, and thrombospondin
(Desgrosellier and Cheresh
2010). Α
integrins are highly expressed in tumour
vβ3
and angiogenic endothelial cells having a key role in the calcium-dependent
signalling pathways responsible for endothelial cell migration (Desgrosellier
and Cheresh
2010; Nisato et al. 2003). Thus, RGD peptides or non-peptide
mimetics are potentially useful targeting ligands in cancer therapy.
• Vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 is an immunoglobulin-
like transmembrane glycoprotein expressed on the surface of endothelial cancer
cells that promotes cell-to-cell adhesion (Osborn et al. 1989). During angiogenesis and metastasis, integrins bind to ECM proteins or cell surface immunoglobulins like VCAM-1 (Chen and Massague 2012). On normal vasculature, VCAM1 is present and is inducible by angiogenesis and it is over-expressed in lymphomas, leukaemias, melanoma, lung, breast, and gastric cancer, and renal cell
carcinoma (Byrne et al. 2008).
• Matrix metalloproteinases (MMPs). MMPs belong to the zinc-dependent endo-
peptidase family which can degrade all ECM proteins (Vihinen et al. 2005).
MMPs have been implicated in many pathological processes such as carcinogenesis. Their role in angiogenesis and metastasis is crucial as they are involved in
forming the capillary tubes and recruiting accessory cells (Danhier et al. 2010 ). In
14 Active Targeting of Nanomedicines 363
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particular, the membrane type 1 matrix metalloproteinase (MT1-MMP) activates
MMP-2 (Gelatinase-A, 72 kDa gelatinase) which hydrolyses one of the major
components of the basement membrane, the Type IV collagen, but also
MT1-MMP cleaves the α
et al. 2005). Thus, additive anticancer effects can be obtained by targeting the
MT1-MMP. MT1-MMP is expressed on endothelial tumour cells and in a variety
of cancer cells such as gliomas, melanomas, malignancies of lung, gastric, breast,
cervical, and colon carcinomas (Genis et al.
the aminopeptidase N/CD13 which is an endothelial cell-surface receptor
involved in tumour-cell invasion, tumour metastasis, and extracellular matrix
degradation by tumour cells. NGR (Asn–Gly–Arg ) peptides are used as targeting
ligands because of their ability to bind this aminopeptidase (Danhier et al.
Pasqualini et al. 2000).
integrin which enhances its binding activity (Sato
vβ3
2006). Another metalloproteinase is
2010;
14.5.2 Actively Targeted Nanomedicines for Transport
Across the Blood-Brain Barrier
Currently, more than 1.5 billion individuals are affected by CNS diseases such as
cancer, psychiatric disorders, neurodegenerative, inflammatory, and infective diseases (McGonigle 2012). There is an unmet clinical need and the development of
actively targeted nanomedicines can be a potentially useful non-invasive approach in
treating brain diseases. The major obstacle to delivering any therapeutic and/or
imaging agent to the brain is the blood-brain barrier (BBB) which is a unique
membranous barrier composed of tightly bound endothelial cells and perivascular
astrocytes whose function is to segregate the brain from the systemic blood circulation to ensure CNS homeostasis for neuronal functions to optimally take place
(Serrano-Lopez and Lalatsa 2013; Lalatsa et al. 2012c). The transport systems
expressed within the cerebral endothelial cells have been exploited to design BBB
active targeting nanomedicines. These transport systems are carrier-mediated transporters (CMT), receptor-mediated endocytosis (RME) transporters, and adsorptivemediated endocytosis (AME) transporters and they all play a key role in the delivery
of essential substances to the CNS (Beduneau et al. 2007). One of the major
approaches is based on the use of targeting moieties able to mimic endogenous
substances, which exhibit specificaffinities with CMT, RME, or AME systems.
Table 14.4 summarizes several examples of CNS active targeted nanomedicines.
Carrier-Mediated Transport
The passage of nutrients of low molecular weight is mediated by carrier-mediated
transport (CMT), which are highly expressed in the cerebral vessels of the BBB,
including carriers for glucose (GLUT), monocarboxylic acids (MCT1), large neutral
amino acids (LAT1), cationic amino acids, excitatory amino acids (EAAT), organic
cations, choline, adenine, nucleoside, etc. (Beduneau et al.
2004). Among all the transporters, GLUT and choline transporters have exhibited
2007; Tsuji 2005; Begley
364 D. R. Serrano Lopez et al.
https://t.me/med1917
Therapeutic
agent Outcome Status References
(2012)
In vitro Gromnicova
Preclinical Xie et al.
6 h after intravenous administration
Coumarin Higher accumulation in the brain
– More efficiently transport across
et al. (2012)
(2011)
Preclinical Li et al.
primary human brain endothelium
and higher gene expression in vivo
than non-brain endothelium
Plasmid DNA Higher uptake efficiency in vitro
(2011)
Preclinical Ulbrich et al.
antinociceptive effect prolonged
Loperamide Significant increase of
(2009)
Preclinical Ulbrich et al.
over 2 h after intravenous
antinociceptive effect prolonged
administration
over 2 h after intravenous adminis-
tration in rats
2010)
Feng (
Preclinical Gan and
24 h post-
®
IC50 than Taxotere
Docetaxel Higher efficient (229%) in terms of
2002)
t al. (
e
Preclinical Huwyler
Preclinical Aktas et al.
2005)
(
increased
efflux and
treatment; higher accumulation in
brain
Enhanced brain translocation after
intravenous administration
Peptide
Z-DEVDFMK
uptake across the BBB
Nanocarrier- Name
(particle size)
Target Targeting ligand
Carrier-mediated transport
Table 14.4 Examples of CNS actively targeted nanomedicines
GLUT1 Glucose PEGylated liposomes
Gold nanoparticles
(~4 nm)
(<100 nm)
Glucose
poly-L-lysines
a
PEGylated nanoparticles
Choline Dendrigraft
Choline
transporter
Receptor-mediated endocytosis
Albumin nanoparticles
(~150 nm)
Insulin or anti-
insulin receptor
MAb (29B4)
Insulin
receptor
Albumin nanoparticles (150 nm) Loperamide Significant increase of
5 kDa –MAL
OX26 MAb or
R17217—PEG
Transferrin
receptor
Nanoparticles of PLA-TPGS
Transferrin
linker
diblock copolymer
(~137 nm)
PEGylated chitosan nanoparticles
conjugated to biotin (~590 nm)
Liposomes (~100 nm) Digoxin Inhibited p-gp
a
MAb—
OX26 MAb con-
jugated to
streptavidin
OX26
PEG 2 kDa –MAL
linker
14 Active Targeting of Nanomedicines 365
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Pardridge
Preclinical Zhang and
Three weeks treatment of intrave-
nous therapy with these
GDNF plas-
mid DNA
(2009)
immunoliposomes loaded with a
glial-derived neurotrophic factor
led to near-complete recovery of
2007)
(
Preclinical Pardridge
Parkinson’s disease
rats with neurotoxin-induced
Weekly, intravenous RNAi with
pegylated liposomes enables a 90%
knockdown of the human epider-
mal growth factor receptor, which
shRNA,
siRNA
results in a 90% increase in survival
time in mice with intra-cranial brain
Preclinical Venishetty
cancer
A 20-fold increase in the uptake in
Docetaxel
et al. (2013)
®
brain endothelial cells and 44-fold
enhancement in brain permeation
coefficient value both compared to
Taxotere
Ketoconazole
In vitro Wagner et al.
– Enhance brain uptake of the
2012)
(
nanoparticles through the LDL
receptor-related protein without
opening tight junctions
Preclinical Ke et al.
2009)
(
gene expression in vivo
Preclinical Huang et al.
Neuroprotective effects in a
2010)
(
rotenone-induced rat model of
Parkinson’s disease
gene
factor
Preclinical Barrett et al.
2009)
(
(1:5:2 w/w/w) resulted in higher
(continued)
OX26 MAb PEGylated liposomes (~100 nm)
PEGylated liposomes (~ 100 nm,
Anti-transferrin—
PEG 2 kDa)
Mab
Solid lipid nanoparticles
(~80 nm)
Folate
Folate
receptor
PEGylated albumin nanoparticles
(~186 nm)
ApoE
LDL
receptor
Angiopep-2 PEGylated PAMAM dendrimers DNA Higher brain uptake and enhanced
Lactoferrin PEGylated PAMAM dendrimers Neurotrophic
PEGylated Poly-lysine dendrimers DNA Polylysine dendrimer: PEG: DNA
61-90
Leptin Leptin
366 D. R. Serrano Lopez et al.
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uptake in the brain and enhanced
Therapeutic
agent Outcome Status References
Preclinical Lu et al.
gene expression
Plasmid DNA Accumulation in the brain upon
(2006)
intravenous administration; signifi-
Preclinical Liu et al.
growth
cant delay in brain tumour
TAT peptide Suppression of bacterial growth in
(2009)
Staphylococcus aureus-infected
meningitis rabbits
Nanocarrier- Name
(particle size)
Target Targeting ligand
Table 14.4 (continued)
(~109 nm)
Cationic albumin PEGylated nanoparticles
Adsorptive-mediated endocytosis
Anionic
sites in the
BBB
TAT peptide Nanoparticles formed by self-
assembly of an amphiphilic peptide
with a hydrophobic cholesterol core
(<150 nm)
Key: GLUT D-glucose transporter, dendrigraft polymer that has the form of a dendrimer, GDNF glial-derived neurotrophic factor, IC50 drug concentration
required to induce the death of 50% cell incubated in a designated period, MAb monoclonal antibody, MAL maleimide, OX26 MAb monoclonal antibody with
high affinity for transferrin receptor and was conjugated to the surface of the PEGylated chitosan nanoparticles through the specific interaction streptavidin—
Ketoconazole was used to inhibit the P-gp efflux of docetaxel at the BBB
a
ability to the neuronal cell death being potentially useful after cerebral ischemia, PLA-TPGS poly(lactide)-D-a-Tocopheryl polyethylene glycol succinate, TAT
peptide sequence Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg
biotin, PAMAM Polyamidoamine dendrimers, PEG polyethylene glycol, peptide Z-DEVDFMK specific caspase inhibitor which significantly reduces vulner-
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greater potential as targets to cross the BBB. The GLUT1 transporter facilitates the
transport from the blood to the brain not only of the D-glucose but also of other
molecules with a similar structure such as galactose, mannose, 2-deoxy glucose, and
glucose analogues (Pardridge
transport glucose (1420 nmol/min/g tissue) compared to other transporters like
MCT1 (91 nmol/min/g tissue) and LAT1 (28 nmol/min/g tissue) (Tsuji
choline transport
molecules such as choline (precursor for the neurot ransmitter acetylcholine) but
also with other molecules like carnitine and thiamine and with positively charged
quaternary ammonium groups (Lockman and Allen
major advantage of this transporter is the fact that there is no saturation under
physiological concentrations, thus other components may be transported without
altering choline transport to the CNS (Allen and Smith
Receptor-Mediated Endocytosis
On the contrary, large molecules required for normal brain function are transported
by specific receptors (which are highly expressed) localized on the endothelial cells
of the BBB (Gabathuler 2010). The binding of the ligand to specific receptors results
in the internalization of the complex (receptor-ligand) within an endocytotic vesicle
(Beduneau et al.
to deliver compounds across the BBB are the insulin receptor, folate receptor,
transferrin receptor, and low-density lipoprotein (LDL) receptor (Gabathuler
The LDL receptor binds lipoprotein particles carrying ApoE and ApoB100 and
targeting this receptor is a very promising strategy for the endocytosis of
nanoparticles across the BBB (Lalatsa et al.
lipoprotein receptor that interacts with a large variety of ligands such as ApoE,
tissue plasminogen activator, amyloid precursor protein (APP), lactoferrin, and is
expressed in many tissues as well as the CNS (Rebeck et al. 1993). LRP is expressed
in the cerebellum, in neuronal cells, and in astrocytes. LRP is over-expressed in
malignant astrocytomas, especially glioblastomas (Yamamoto et al.
meric nanoparticles overcoated with polysorbate 80 have been shown to adsorb
ApoE and ApoB from the blood and it is postulated that they are taken up via the
LDL receptor. Rather than coating particles with surfactants and relying on spontaneous adsorption of ApoE from the plasma, covalent attachment of ApoE to the
particles has been carried out and the result was particles that were able to be taken
up into the brain parenchyma without any effect on the tight junctions (Zensi et al.
2009). Lactoferrin is normally present in very low physiological levels and so it is
unlikely to compete with a vector-conjugate making it a good target as it is
transcytosed across the brain capillary endothelial cells and is not intracellularly
degraded. Lactoferrin conjugated via a PEG spacer to polyamidoamine dendrimers
was used to deliver a neurotrophic factor gene to a rotenone-induced rat model of
Parkinson’s disease with some neuropr otective effects observed (Huang et al.
BBB permeable peptides based on the structure of aprotinin called Angiopeps are a
family of 19 amino acid peptides derived from the kunitz domain that have a high
transcytosis rate using the LRP-1 receptor and LRP-2 receptor (Demeule et al.
er exhibits an anionic-binding area that interacts with cationic
2007). The main receptors used in actively targeted nanomedicines
1995). One advantage of GLUT1 is its high capacity to
2005). The
2002; Kang et al. 1990). The
2001).
2010).
2012c). LRP is a multifunctional
1997). Poly-
2010).
2008).
368 D. R. Serrano Lopez et al.
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Angiopep-2 has been studied for gene delivery when covalently linked to a PEG
spacer linked to a PAMAM dendrimer (Ke et al. 2009). An increased loading of
Angiopep-2 was required to
the majority of the dose detected in the kidneys at 2 hours post-administration. The
advantages of the lipoprotein receptor system over other receptor systems, such as
the hexose receptor systems, include more efficient cellular delivery and the potential for transcytosis of ligands across tight endothelia, including the blood-brain
barrier. Several examples o
Table 14.4.
Adsorptive-Mediated Endocytosis
With the AME system, the transport across the BBB takes place through a less
specific mechanism based on elect rostatic interactions between the negatively
charged mem brane of the BBB and a positively charged ligand (Beduneau et al.
2007). Thus, cationic proteins because of their basic isoelectric point are positively
charged at physiological blood pH which makes them able to bind to the luminal
plasma membrane triggering adsorptive endocytosis (Gabathuler 2010). It has been
reported that the transport of cationic albumins or immunoglobulins into the CNS is
significantly enhanced compared to native proteins (Vorbrodt et al. 1996; Triguero
et al. 1989). Positively charged ligands can be conjugated to nanomedicines to
enhance their passage across the BBB. As such, cell-penetrating peptides have
become a very effective class of transporters composed of short cationic sequences
with a remarkable capacity for membrane trans location with minimal toxicity
(Fonseca et al. 2009). To date, TAT (RKKRRQRRR), poly-arginine
(RRRRRRRRR), penetratin (RQIKIWFQNRR MKWKK), and transportan
(GWTLNSAGYLLGKINLKALAALAKKIL) are some of the most used cellpenetrating peptides that have successfully delivered small molecule therapeutics,
proteins, nucleic acids, contrast agents, etc. (Fonseca et al.
summarizes several examples of CNS active targeting nanomedicines through
AME systems.
achieve a 0.25% of the injected dose to the brain with
f n
anomedicines targeting RME are included in
2009). Table 14.4
14.5.3 Actively Targeted Nanomedicines for Rheumatoid
Arthritis
Rheumatoid arthritis (RA) is an autoimmune disease, characterized by inflammation
and synovial hyperplasia that mainly affects the joints (Smolen et al. 2018). RA
attacks around 5 out of 1,000 people and early diagnosis and treatment can prevent
or delay joint damage by up to 90% (Sarzi-Puttini et al. 2019).
The conventional treatment of this disease is based on antirheumatic drugs in the
first instance, which need a high and constant dosage due to their low bioavailability
and short half-life (Wang et al.
selectively for RA can reduce the risk of affecting adjacent tissues, reducing side
effects.
2021). Developing treatments that can be targeted
14 Active Targeting of Nanomedicines 369
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Folate Receptor on M1 Macrophages
Rheumatoid arthritis produces synovial inflammation, which is caused by the
inflammatory cytokines secreted by M1-type macrophages (Smolen et al. 2018).
The switching of M1 to the anti-inflammatory M2 type is crucial. Silver
nanoparticles with folic acid were developed to target the folate receptor localized
on M1 macrophages, whose function is to produce apoptosis of M1 macrophages
and help towards the polarization of M2-type macrophages eliminating reactive
oxygen species (ROS) (Yang et al.
MMP2 Receptor
Abnormal high cell-free DNA (cfDNA) activates toll-like receptors 9 (TLR9), which
produce inflammatory cytokines that aggravate rheumatoid arthritis. Methotrexate
was encapsulated within poly(lactic-co-glycolic acid)-b-poly(2-(diethylamino)ethyl
methacrylate) cationic nanoparticles using a peptide linkage (PVGLIG) and PEG to
target MMP2 receptors on macrophages. The nanoparticles exhibited a prolonged
bloodstream circulation and an enhanced accumulation in the joint triggering cfDNA
scavenging and delivery of the drug into the activated macrophages (Liu et al. 2022).
pH-Dependent
Similar to tumours, a low pH (around 6) is one of the main characteristics of
rheumatic joints due to an imbalance in metabolic activity, resulting in anaerobic
glycolysis that produces lactate, in inflamed tissues (Smolen et al. 2018). The
development of pH-dependent formulations with sensitivity to acid pH helps in
the selectivity of drug transport. Modified micelles (mPEG-PDEA-PCL, methoxypoly(ethylene glycol) 2000-poly(2-(N,N-diethylamino)ethyl methacrylate)polycaprolactone) were developed to be pH-responsive. PDEA transforms to its
protonated form (PDEAH
release selectively (Li et al. 2017). Dexamethasone- N-(2-hydroxypropyl)
methacrylamide (HPMA) copolymers were cleavable under an acidic pH due to
the hydrazone bond linking dexamethasone to HPMA. This allowed a superior and
prolonged anti-inflammatory effect with selective accumulation compared with the
free drug (Wang et al.
+
2007) (Table 14.5).
2021).
) in an acidic environment which triggers the cargo
14.6 Manufacturing Methods of Targeted Nano medicines
14.6.1 Conventional Manufacturing Methods: Bottom-up
Versus Top-Down Approaches
Various manufacturing methods can be employed. Techniques for manufacturing
nanomedicines can be grouped under two headings: the bottom-up and top-down
approaches. When nanopar ticles are created from the molecular level up to nanoparticle size, these processes are commonly referred to as “bottom-up.” When
370 D. R. Serrano Lopez et al.
https://t.me/med1917
Therapeutic
agent Outcome Status References
Preclinical Yang et al.
(2021)
. Alleviation of inflamma-
a
ELVIS Effect
(2022)
Preclinical Liu et al.
tion by synergistic M1 macrophage
reduction and M2 macrophage induction.
decreased toxicity, prolonged therapeutic
Methotrexate Greater accumulation at the joint,
effect.
(2017)
Preclinical Li et al.
Accumulation selective in acid regions,
reduction of inflammation
drug
et al.
2007)
(
Targeting
ligand Nanocarrier (Particle size)
Target
Table 14.5 Examples of RA actively targeted nanomedicines
Membrane receptor
Folic acid LA-PEG- Silver nanoparticles Ag+ Greater colloidal stability and increased
Folate
receptor
Cationic nanoparticles made of
MMP2 MMP2 sen-
copolymer (50 nm)
PLGA-b-PDMA-pp-PEG triblock
sitive pep-
tide (pp)
HPMA Dexamethasone Preclinical Wang
mPEG-PDEA-PCL micelles Hydrophobic
Hydrazine
groups
pH-dependent
Acid sites in
inflamed
regions
ELVIS effect Extravasation through Leaky Vasculature and the subsequent Inflammatory cell–mediated Sequestration effect, which is similar to the EPR effect
observed in the treatment of tumours; pp peptide linkage (PVGLIG), PLGA-b-PDMA poly(lactic-co-glycolic acid)-b-poly(2-(diethylamino)ethyl methacrylate),
LA-PEG α-lipoyl-ω-amino poly (ethylene glycol); mPEG-PDEA-PCL methoxy-poly(ethylene glycol) 2000-poly(2-(N,N-diethylamino)ethyl methacrylate)-
a
polycaprolactone; HPMA N-(2-hydroxypropyl)methacrylamide copolymer
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nanoparticles are generated from a large scale to a nanoparticle level, these processes
are typically referred to as “top-down” (Serrano et al. 2015).
Bottom-up Manufacturing of Nanomedicines
This method produces nanocrystalline, nano amorphous, or nano polymeric suspensions. Combining an organic solvent with a nonsolvent creates dissolved and
precipitated molecules to initiate the procedure. In this case, nanoparticles can be
produced using condensation techniques (formati on of particles by nucleation and
crystal growth). The drug and biocompatible and biodegradable polymers such as
polylactides, polyglycolide, and poly (lactide-co-glycolides) dissolve in a watermiscible organic solvent while surfactants such as the Tweens, Spans, or polyvinyl
alcohol are dissolved in water (Fig.
14.7). The two solutions are combined to form a
precipitate through the diffusion of an organic solvent in water. The organic solvent
is then removed by extraction or evaporation (Cornier et al.
2017). Using the bottom-
up met hod, it is frequently difficult to control the growth of particles and crystals. In
addition, scaling up the process is complicated (Shah et al.
2016).
Top-Down Manufacturing of Nanomedicines
Depending on the application, the top-down process is commonly either a bead mill
or a high-pressure homogenizer. The top-down method is the most prevalent technique for producing nanocrystalline suspensions. The particle size can be controlled
by selecting a suitable stabilizer and employing the most efficient operating settings
for the process (Peltonen and Hirvonen
2010). The top-down strategy entails drug
distribution throughout the vehicle. The third step is particle size reduction. The
Fig. 14.7 Bottom-up manufacturing of nanomedicines
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