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352 D. R. Serrano Lopez et al.
https://t.me/med1917
binding to untargeted cells (for highly cationic particles) (Owens and Peppas 2006;
Chouly et al. 1996; Salvador-Morales et al. 2009). Therefore, for a long circulation
half-life actively targeting nanomedicines with minimal non-specific interactions, a
hydrophilic surface (achieved by, e.g., using a hydrophilic coating such as PEG,
chitosan, or dextran) and a zeta potential of between - 10 and +10 mV is ideal
(Swami et al.
through modification of the
induce PEG-specific IgM, which accelerates blood clearance and alters the pharmacokinetics and pharmacodynamics of liposomes and PEGylated particles. Another
aspect to consider is the possible interaction between the steric efficiency of the PEG
corona, which may prevent cell internalization of the nanomedicine. A possible
ution t
sol
a
balanc
intracellular interactions (Attia et al.
on biodistribution has not
suggested that non-spherical-shaped nanocarriers are better at avoiding
bioelimination when compared to spherical systems (L iu et al. 2007). Other studies
have shown that an increase in the length-to-width aspect ratio of nanosystems is
correlated with an increase in their blood circulation time (Veiseh et al. 2010; Geng
et al. 2007
Thus, different types of nanocarriers have been developed that can be used
depending on the therapeutic or diagnostic application. Generally speaking, these
platforms can be classified into three categories: (1) organic-based nanoparticles
such as liposomes, micelles, polymeric nanoparticles, dendrimers; (2) inorganicbased nanoparticles from iron oxide, gold, ceramics, and carbon nanotubes to name a
few examples; and (3) hybrids of these last two categories (Attia et al. 2019b).
In summary, nanocarriers must remain stable in the blood, escape clearance from
the reticuloendothelial system as well as not be phagocytosed, accumulate in the area
of interest, penetrate the target tissue, reach the active site, and interact, ideally, only
with target cells.
2012; Davis 2009
o this would be the use of short PEG chains (i.e. Mw < 2000)
e
between the prolongation of the circulation time of the nanosystem and its
).
). Thus, although PEGylation prevent s aggregation
nanocarrier surface, its administration has been found to
and
2019b). The effect of the nanomedicine shape
yet been completely elucidated. To date, it has been
thus fi
nd
Choice of Targeting Moiety
The choice of ligand is not trivial and depends on the targeted site which can vary
from intravascular tumour cells to endothelial cells in the blood vessels of a tumour
(Pearce and O'Reilly 2019).
In this sense, targeting angiogenic endothelial cells can reduce the blood flow to
cancer cells, leading to hypoxia and necrosis due to the lack of oxygen and nutrients
required by tumour masses. For example, derivatives of the peptide sequence
arginine-glycine-aspartic acid (RGD) may be used as ligands to target the overexpressed integrin (α2bβ3, ανβ3, and α5β1) receptors on tumour endothelial cells.
This type of targeting reduces drug resistance by allowing adaptation to differences
in receptor expression in different tumour types (Pearce and O'Reilly 2019; Attia
et al. 2019b ).
Targeting tumour cells requires high density of receptor expression to allow for
greater interaction with ligands. However, not all tumour cells over-express
14 Active Targeting of Nanomedicines 353
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Table 14.2 Selection of targeting ligands and advantages and disadvantages of using the whole
antibody, antibody fragment, or non-antibody ligands as targeting moieties
Whole antibody Antibody fragment
Advantages High degree of specific-
ity
Broad range of binding
affinities
Signalling synergism
Higher binding avidity
Antibody and
complement-dependent
cytotoxicity
Disadvantages High-cost manufacture
Variation batch-to batch
Time-consuming production
Immunogenicity
Binding to non-specific
Fc receptors
Low tumour penetrability
Complexity of the conjugation process
High degree of specificity
Broad range of binding
affinities
Signalling synergism
Lower immunogenicity than
whole antibodies
Easier identification and production than whole
antibodies
Lower stability than whole
antibodies
Lower binding avidity
Non-antibody
ligand
Readily available
Low-cost manufacture
Ease of scale-up
synthesis
Minimal variations
from batch-tobatch
Ease of handle
Easier conjugation
Higher stability
Better tissue penetration
Low
immunogenicity
Limited selective
expression
Weak binding
affinity
receptors at the same level. Some simulations show that an increase in targeting
ligands may cause steric hindrance or a preference for surface cells rather than the
penetration deep into the tumour tissues, while the addition of ligands may increase
opsonization of the nanomedicine (Attia et al. 2019b).
Taking the above into consideration, in the selection of the targeting ligand for an
actively targe ted nanoparticle to a specific receptor, it is important to identify
whether the high specificity of an antibody or antibody fragment is required or
whether a non-antibody ligand is preferred (Table 14.2).
The major advantages of antibodies or antibody fragments are the high degree of
specificity for the target cell, the wide range of binding affinities that can be
achieved, and the possibility of synergism between the signalling antibodies and
the therapeutic agents resultin g in a more efficient targeting and pharmacology
(Allen
2002; Maynard and Georgiou 2000; Baselga 2001). Non-antibody ligands
such as transferrin and folic acid have relatively non-selective expression, thus, they
can bind to a greater extent to non-target tissues (Allen
ligand used should have sufficient high affinity for the receptor, but be able to allow
the cargo to be released into the cell. The endogenous ligand should not compete
2002). The non-antibody
354 D. R. Serrano Lopez et al.
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with the delivery vector for receptor occupancy. Thus, careful consideration of the
relative binding affinities and the physiological levels of the endogenous ligand need
to be considered. Transferrin is thought not to be a suitable vector as its plasma
concentration is >1000-fold higher than the Kd of 5.6 nM. Ideally, the vector should
not be pharmacologically active (e.g. insulin is undesirable). The vector conjugate
should have a high receptor affinity that is not aff
used. If the binding
first target molecule encountered and dissociation and further diffusion would not be
possible. This might be useful for readily available targets, such as in the case of
vasculature tumours, but could be detrimental in the therapy of solid tumours, where
penetration deeper into the tumour is needed (Adams et al.
exhibit the
certain antibody fragments (scFv and Fab), which have only one binding domain.
Some non-antibody ligands (such as carbohydrates) show a weaker binding affinity,
which may be counteracted by several ligands being attached to the surface of the
carriers (Allen
target cells, but this may be accompanied by a higher manufacturing cost and the
enhanced possibility of clearance and particle in vivo instability (Allen
de Menezes et
Despite the use of humanized or human antibodies, immunogenicity remains a
problem to be addressed and presents in the form of anti-idiotypic respon ses,
especially with the use of whole antibodies (Dillman
Fc domain in the antibody may lead to binding to Fc receptors of normal tissues
(particularly macrophages which might increase their immunogenicity) and may also
lead to an enhancement of activity, because of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity (Allen
One of the major advantages of the non-antibody ligands is the ease of scaling-up
their synth esis resulting in low-cost and time-efficient manufacture with minimal
variation from batch to batch. This reduces the overall cost and complexity of
engineered nanomedicines. Compared to antibodies, the smaller number of active
sites for modification present in proteins and peptides allows for uncomplicated sitespecific conjugation to nanoparticles (Swami et al.
targeting moieties are their higher stability upon storage and better tissue penetration, which can be potentially useful in the treatment of solid tumours.
highes
affinity is very high, the nanomedicine will bind stro ngly to the
t affinity, because they have two binding sites per molecule unlike
2002). High ligand density on the surface can increase the binding to
1998).
al.
ected by the linker/spacer strategy
2001)
. Whole antibodies
2002; Lopes
2001). The presence of the
2002).
2012). Other advantages of these
The Therapeutic Agent
The last point to consider is the potency of the encapsulated or loaded drug. When
the ratio between the ligand and drug is too high, more potent drugs need to be used.
In this case, each ligand moiety can only deliver a few drug molecules. If the drug is
not potent enough, large amounts of ligands are required, which would increase the
cost as well as the immunogenicity of the system. However, when the drug is
encapsulated in nanocarriers, the number of drug molecules delivered per carrier is
exponentially higher, which is important for low-potency drugs (Swami et al.
Nevertheless, there are limitations related to drug loading in terms of the technology
currently used for the manufacture of nanomedicines. Among these limitations is the
2012).
14 Active Targeting of Nanomedicines 355
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small drug loading in the nanostructure (less than 5% drug versus the carrier
composition), which can lead to drug concentrations not being high enough for the
expected therapeutic effect. Additionally trying to achieve therapeutic concentrations with high levels of the carrier may cause adverse effects (Attia et al.
2019b).
14.5 Examples of Active Targeting Nanomedicines
14.5.1 Focus on Cancer-Active Targeting
14.5.1.1 EPR Effect
Although actively targeted nanomedicines can bind specifically to receptors localized on cancer cells, the enhanced permeation and retention (EPR) effect plays a
critical role too as it helps to accumulate the nanomedicines in higher concentrations
in solid tumours than in normal tissues (Allen
asation of nanomedicines from the blood vessel to the tumour interstitial space is
enhanced because of the unique properties of the tumour vasculature, such as the
lack of tight junctions between adjacent endothelial cells (Ruoslahti 2002) and the
presence of porous blood vessels with a pore cut-off size of 380–780 nm (Hobbs
1998). At the same time, the retention of nanomedicines within solid tumours is
et al.
enhanced due to poor lymphatic drainage and slow venous return from the
interstitium of the tumour (Danhier et al.
lymphatic drainage can lead to higher osmotic pressures within the tumours resulting
in an outflow of fluids, which might severely restrict the nanomedicine distribution
to some areas of the tumour (Stohrerm et al. 2000).
2002). Permeation and then extrav-
2010; Maeda et al. 2001). However, poor
14.5.1.2 Cell Proliferation Targeting
One of the advantages of active targeting nanomedicines is their potential to interact
specifically with endocytosis-prone surface receptors (over-expressed by cancer
cells) leading to cellular internalization of the nanomedicine resulting in direct cell
death (Danhier et al. 2010; Kirpotin et al. 2006). Table 14.3 summarizes several
approaches of actively targeted nanomedicines towards (i) membrane-bound internalization-prone receptors and (ii) intracellular receptors.
Membrane-Bound Internalization-Prone Receptors
1.
Folate receptor. Folic acid is crucial for the synthesis of purines and pyrim idines
and binds to folate receptors being internalized via receptor-mediated endocyto-
sis. Because of the high replication rate of cancer cells, the folate receptor is
upregulated compared to normal tissues by up to two orders of magnitude (Low
and Antony
2004). The alpha isoform of the folate receptor is over-expressed on
356 D. R. Serrano Lopez et al.
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Preclinical Kukowska-
Therapeutic agent Indication (outcome) Status References
Latallo et al.
(2005)
(10-fold higher efficacy)
Preclinical Zhu et al. (2013)
Gastric carcinoma, hepatoma,
10-Hydroxy-
tumour growth rate)
leukaemia, tumour of head and
neck (62% reduction in
camptothecin
(2012)
Preclinical Zhao et al.
(more than 3-fold reduction
tumour growth and 3-fold drug
Paclitaxel Human cervix carcinoma
In vitro Salmaso et al.
accumulation in tumour)
(2004)
KB cells
(2021)
In vitro DeCarlo et al.
Signalling to α-folate receptor
present in prostate and breast
cancer
Active
nanocarrier
Mebiopharm
Co., L (2013),
Suzuki et al.
(2008)
Phase
Ib/II
tric and gastroesophageal car-
cinoma (6-fold reduction in
tumour growth ratio)
Oxaliplatin Metastatic solid tumour, gas-
(2018)
In vivo Ke and Xiang
drug in tumour tissue
Sorafenib Increased accumulation of the
exhibiting a better tumour-
killing effect and delayed thy-
roid cancer progression
Nanocarrier
(particle size)
Targeting
ligand
Membrane-bound internalization-prone receptor targeted nanomedicines
Folate receptor Folic acid Dendrimer (< 5 nm) Methotrexate Human epithelial cancer
Target
Table 14.3 Examples of cancer-actively targeted nanomedicines
Chitosan based-polymeric
micelles (100–200 nm)
PEGylated PLGA-core
(~194 nm)
PEGylated β-cyclodextrin Rhodamine-B 19% higher accumulation in
nanoparticles
Folic acid conjugated with
poly(styrene-alt-maleic
anhydride) via biological
acid
Transferrin PEGylated liposomes—
Transferrin
MBP-426 (180 nm)
receptor
linker 2,4-diaminobutyric
Mesoporous silica
nanoparticles with transferrin
modification (160–200 nm)
14 Active Targeting of Nanomedicines 357
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SynerGene
Therapeutics, I
(2013), Camp
Phase
Ib/II
Solid tumours (increase of
transfection efficiency in
70–80% of the gene encoding)
Plasmid DNA
coding for p53
gene for tumour
Calando Phar-
et al. (2013)
Phase Ib Davis (2009),
Solid tumours (inhibition of
tumour engraftment with
siRNA against
ribonucleotide
suppression
2013)
maceuticals
(
safer profile without liver tox-
icity and complement
antitumor efficacy at the dose
of 0.6–1.2 mg siRNA/kg and
reductase subunit
2
, b)
ilane et al. GE11 peptide
2011a
(
Preclinical M
activation)
Multi-Drug Resistance cancer
(maximal tumour accumula-
Paclitaxel/
Lonidamine
tion occurs at 3 hours after
intravenous administration;
5-fold decrease in tumour
weight is achieved at 28 days
1997)
2002), Kirpotin
et al. (
(
Preclinical Park et al.
ble constructs without drug
(prolonged circulation as sta-
post-treatment)
leakage or MAb dissociation
Doxorubicin BT-474/MCF-7 breast cancer
In vitro Li et al. (2010 ),
efficacy with 50% cure rates)
resulting in superior antitumor
– A431 epidermoid carcinoma
Master and Sen
c internalization of the
(specifi
Gupta (2012)
nanoparticles conjugated to
EGFR-targeting aptamer via
(continued)
receptor-mediated
endocytosis)
Liposome- SGT 53
(<400 nm)
fragment
Transferrin Polymeric nanoparticle with
Single-chain
antibody
cyclodextrins on their surface
and adamantane-PEG
conjugate—CALAA-01
(~70 nm)
PLGA-PEG-GE11 construct
conjugated to PCL
nanoparticles
EGFR
(120–160 nm)
PEGylated liposomes
(~100 nm)
Anti HER-2
MAb fragment
(scFv)
Gold nanoparticles
(~20 nm)
Aptamer J18
Galactosamine Doxorubicin Phase I/II
358 D. R. Serrano Lopez et al.
https://t.me/med1917
al.
et
2002)
Seymour
(
admin-
arcinoma
intravenous
after
h
Hepatocellular c
(24
Therapeutic agent Indication (outcome) Status References
admin-
liver)
the
of
the
doxorubicin
to
of
16.9%
dose
targeted
was
istered
istration,
(2011)
Preclinical Choi et al.
can-
via
normal
endocytosis
internaliza-
cells
by
MDAMB-231
cancer
(specific
and
uptake
into
low
cells
cer
tion
receptor-mediated
and
Camptothecin SCC7
acid
cholanic
higher
in
resulting
accumulation in tumour tissue
compared to bare
fibroblast
Preclinical Rai et al. (2008)
nanoparticles)
higher accumulation in cancer
Doxorubicin Breast cancer (13.9-fold
cells)
In vitro He et al. (2010 )
affinity and better antitumor
Mitoxantrone MCF-7 breast cancer (higher
efficiency)
Preclinical Chen et al.
I Hepatic carcinoma cells (high
131
(2006)
non-targeted nanomedicines)
delay and safer treatment than
efficacy in tumour growth
90
Preclinical Li et al. (2004)
(significant tumour growth
Y K1735-M2 melanoma cells
olymer-drug
Nanocarrier
(particle size)
HPMA p
conjugate—PK2
Targeting
ligand
Hepatic
asialoglycoprotein
Target
Table 14.3 (continued)
receptor
with
hyaluronic
core
nanoparticles
acid
receptor Hyaluronan PEGylated
CD44
nm)
320
~
(
(~200 nm)
Intracellular receptor targeting
Oestrogen receptor Estrone Liposome
(120–150 nm)
LHRH receptor Gonadorelin PEGylated liposome
Dextran magnetic
nanoparticles
MAb
Angiogenesis targeting
VEGF Anti-VEGF
Dextran-coated polymerized
(Sc-7269)
VEGFR-2 Anti-VEGFR-
nanoparticles
2 MAb
14 Active Targeting of Nanomedicines 359
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(continued)
vessel density in tumours)
delay and marked decrease in
In vitro Das et al. (2011)
(specific intracellular uptake
Doxorubicin NIH-3T3 and BAEC cells
In vitro Cai et al. (2011)
cinoma cells (7.2-fold higher
via endocytotic mechanism)
cytotoxicity in cancer cells
Doxorubicin BEL-7402 hepatocellular car-
compared to free drug)
Preclinical Xu et al. (2012)
longer retention time and
Oridonin Hepatocarcinoma 22 (4-fold
Preclinical Meng et al.
volume)
4-fold decrease for tumour
Paclitaxel A549 lung adenocarcinoma
(2011)
tumour microvessel
density compared to Taxol-
treated group)
(lower
(2008)
Preclinical Gosk et al.
(effectively targeted to endo-
– Human Colo 677 tumour
thelial cells in vivo; 91.7% and
73.1% liposomes were
colocalized in endothelial cells
post-
and 24 h
30 min
Preclinical Gu et al. (2013)
administration, respectively)
mulation in tumour cells via
lipid raft-mediated endocyto-
Paclitaxel Glioblastoma (specific accu-
2004)
(
Preclinical Kondo et al.
(4-fold higher accumulation in
Colon 26 NL-17 carcinoma
sis and energy-dependent
macropinocytosis)
Gold nanoparticles
(~10 nm)
Anti-VEGFR-
2 MAb
grafted chitosan micelles
) RGD peptide PEGylated stearic acid-
3
β
v
Integrins (α
(~25 nm)
Poly(D,L-lactic acid)
nanoparticles
(~105 nm)
RGD peptide
liposomes
PEGylated
(<100 nm)
Cyclic RGD
peptide
PEGylated liposomes
(~83 nm)
MAb
VCAM-1 Anti-VCAM
PEGylated
PCL-nanoparticles
(~121 nm)
Activatable
low molecular
weight
protamine
MMP-2,
MMP-9
Liposomes
(~191 nm)
peptide
MT1-MMP GPLPLR
360 D. R. Serrano Lopez et al.
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(2003)
Preclinical Pastorino et al.
lipo-
tumour
times
(10
unmodified
significant
han
suppression)
growth
uptake than
non-targeted liposomes 24 h
higher
in all animals after metro-
post-administration; complete
tumour eradication is induced
nomic administration)
tumour t
and
somes
Nanocarrier
(particle size) Therapeutic agent Indication (outcome) Status References
Targeting
ligand
Target
Table 14.3 (continued)
Hydrophobized
derivative of
CNDAC
peptide Liposome Doxorubicin Neuroblastoma
NGR
Aminopeptidase
N/CD13
Key: Aptamer J18 80-residue aptamer that binds specifically to EGFR, CNDAC (1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl) cytosine), EGFR
HPMA N-(2-hydroxypropyl) methacrylamide, LHRH luteinizing hormone-releasing hormone, MAb Monoclonal Antibody, MMPs Matrix metalloproteinases,
epidermal growth factor receptor, GE11 12-residue peptide (YHWYGYTPQNVI) with affinity for EGFR, GPLPLR peptide stearoyl-Gly-Pro-Leu-Pro-Leu-Arg,
growth factor, VEGFR vascular endothelial growth factor receptor, antitumor nucleoside, Y Yttrium
NGR peptide Asn–Gly–Arg peptide, PEG polyethylene glycol, PLGA poly(d,l-lactide-co-glycolide), PCL poly(epsilon-caprolactone), RGD peptide Arg-Gly-
Asp peptide, scFv single-chain variable fragments, siRNA small interfering RNA, VCAM-1 Vascular cell adhesion molecule-1, VEGF vascular endothelial
14 Active Targeting of Nanomedicines 361
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ovarian, renal, and pancreatic carcinomas and the beta isoform on malignant
hematopoietic cells (Kelemen 2006).
2. Transferrin receptor. Transferrin is a glycoprotein that transports iron through the
blood into the cells and is expressed in many organs (liver, spleen, lung, and
brain). Transferrin is internalized via receptor-mediated endocytosis after binding
to transferrin receptors. These receptors are over-expressed (up to 100-fold
higher) in cancer cells which makes them an attractive target for cancer therapy
(Danhier et al.
transferrin-conjugate with high levels of endogenous transferrin limits its use as
a vector. The anti-transferrin monoclonal antibody (mAb) (OX26) has also been
used as a ligand for nanoparticulate drug deli very (Ulbrich et al.
Pardridge 2009).
3. Epidermal growth factor receptor (EGFR). EGFR belongs to the tyrosine kinase
receptor family. It is expressed in epithelial, mesenchymal, and neuronal tissues
playing a crucial role in proliferation, differentiation, and development. It is overexpressed in a variety of solid tumours (such as colorectal, lung, ovarian, kidney,
pancreatic, brain, and prostate cancer) and its activation is correlated with tumour
progression and poor prognosis (Yano et al. 2003).
4. Lectins and glycoproteins expressed on cell surfaces. Lectins are glycan-binding
proteins that selectively recognize and bind to carbohydrate moieties expressed
on cell surfaces and can be differently expressed in cancer cells compared to
normal tissues (Clark and Mao 2012). Thus, two strategies can be used. The first
involves direct lectin targeting with lectins attached to the surface of the
nanocarriers for targeting to cell carbohydrates or reverse lectin targeting with
carbohydrates grafted to the nanocarriers and directed to cell lectins (Minko
2004).
2010; Daniels et al. 2012). However, competition of the
2009; Zhang and
Intracellular Receptors
1. Oestrogen receptor. Oestrogen receptors belong to the nuclear hormone family of
intracellular receptors. Once receptors are activated by oestrogens, they are
translocated into the nucleus and bind to DNA to regulate diverse genes (Osborne
1998). Oestrogen receptors are over-expressed up to 60–80% in breast cancers
(oestrogen positive breast cancers) (Paliwal et al.
LHRH receptor (luteinizing hormone-releasing hormone). LHRH is a hypotha-
2.
lamic decapeptide known as gonadotropin-releasing hormone (Kakar et al.
LHRH receptor is an intracellular G-protein coupled receptor expressed on the
nuclear membrane and on the cell surface (Re et al. 2010). LHRH receptors are
barely expressed in healthy visceral organs but are over-expressed in many
tumours like breast, ovarian, endometrial, prostate, pancreatic, hepatic and colorectal cancers, melanomas, oral, laryngeal and renal cell carcinomas, and nervous
system tumours (He et al. 2010
2011).
2008).
).
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