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342 D. R. Serrano Lopez et al.
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target tissue by specialized extracellular proteases, exposing the cationic vector to
facilitate absorption mostly at the desired site (Jiang et al. 2004). Lipidation of the
cationic polypeptide has also been utilized to improve the transcytosis of a
myristoylated polyarginine vector (Pham et al.
Attaching ligands to nanoparticles that can serve as substrates for carrierfacilitated diffusion or receptor-mediated transcytosis enables the transport of
nanoparticles within the cell and can be exploited for specific transport in tissues
that over-express these carriers or receptor-mediated proteins.
2005).
14.3 Components of Active Targeting-Based
Nanomedicines
Active targeting-based nanomedicines can be classified into three main components:
(i) the targeting ligand/moiety, (ii) the nanocarrier system, and (iii) the therapeutic
(such as gene, radiopharmaceutical, or chemotherapeutics)/imaging (optical, fluorescent, radioactive and magnetic) agent (Fig.
Targeting ligands are conjugated either directly to the surface of the nanocarriers
or via a linker molecule (such as polyethylene glycol) to minimize steric hindrance
and successfully deliver the therapeutic or imaging agent to the target area (Danhier
et al. 2010; Byrne et al. 2008). In some cases, targeting liga nds may be conjugated
directly to therapeutics or imaging molecules (Allen
example, carbodiimide-mediated conjugation (based on the formation of amide
bonds between carboxylic acid groups of the nanocarrier and primary amine groups
of the ligand) is commonly used, but it is largely non-site-specific (Chapman
However, site-specific binding may be performed through maleimide-based-conjugation chemistries, which use native or engineered thiol-containing cysteine residues
localized on known positions that are away from, and still preserve, the ligand
binding sites (Chapman et al. 1999).
It is crucial to consider the characteristics of the targeting ligand per se. The
characteristics of the targeting ligands play a vital role in the binding affinity, cell
specificity, circulation time, extravasation, and cellular uptake of the nanocar rier
systems (Byrne et al. 2008). The purity and biocompatibility of the ligand, as well as
the ease of synthesis of the conjugated nanoparticle and the feasibility of industrial
production, are essential factors in the successful development of actively targeted
nanocarriers (e.g. cost, stability, and scalability) (Swami et al. 2012).
14.4) (Veiseh et al. 2010).
2002; Daniels et al. 2012). For
2002).
14.3.1 Nanocarriers
A growing number of novel therapeutics are poorly soluble drugs. Nanocarriers
capable of encapsulating these therapies are useful delivery technologies for in vivo
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Fig. 14.4 Components of actively targeted based nanomedicines: (1) Targeting ligands,
(2) nanocarrier systems, and (3) therapeutic (gene, radiopharmaceutical, or chemotherapeutic) or
imaging (optical, fluorophore, radiopharmaceutical, and magnetic) agent. Key: LHRH luteinizing
hormone-releasing hormone, IGF insulin-like growth factor, GM CSF granulocyte-macrophage
colony-stimulating factor, HER human epidermal receptor, VCAM-1 vascular cell adhesion
molecule-1, RGD domain Arginine-Glycine-Aspartic acid, NGR Asparagine-Glycine-Arginine,
WYRGRL Tryptophan-Tyrosine-Arginine-Glycine-Arginine-Leucine, TAT polycationic peptide
(Glycine-Arginine-Lysine-Lysine-Arginine-Arginine-Glutamine-Arginine-Arginine-Arginine-Proline-Glutamine)
administration via parenteral and non-invasive routes (Danhier et al. 2010). Most
active targeted nanomedicines are currently administered intravenously, and their
benefits are summarized in Fig. 14.5. These benefits are reflected in the increasing
number of patents in this area (Plaza-Oliver et al. 2021
actively targe
ted nanom edicine should be to deliver the highest level possible of
therapeutic or imaging molecule load to the targeted active site. This has to be
achieved, while avoiding drug degradation and opsonization during circulation in
the body. Opsonins are blood proteins that can quickly bind to the surface of
nanocarriers, render them easily recognizable by macr ophages of the reticuloendothelial system and lead to the nanopartic
phagocytosis
protect
before they can elicit their function (Owens and Peppas
the nanocarriers from opsonization and phagocytosis by macrophages, the
most common method employed relies on coating the nanocarriers with a hydrophilic polymer such as polyethylene glycol (PEG), which would limit the absorption
). The primary goal of any
le being removed from the circulation by
2006). To
344 D. R. Serrano Lopez et al.
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Active Targeted
Nanocarriers
TOXICITY
HIGH LOADING
EFFICIENCY &
CONTROLLED
RELEASE
Fig. 14.5 Objectives of active-targeted nanocarriers
STABILITY
-Protection from
drug degredation
-Minimise drug levels in
tissues to avoid
undesired adverse
effect
-Biocompatible and
biodegredable
SOLUBILITY
-Improve drug solubility
to allow IV
administration
-Improve oral absorption
and bioavailability
PHARMACOKINETICS
-Drug accumulation at the
desired site
-Avoid opsonization
-Improved internalization
and intracellular delivery
of opsonin proteins on the surface of the nanocarrier by steric repulsion (Owens and
Peppas 2006). The large number of molecules that PEG can be conjugated with,
increases its potential to have a promising future in this field (Rahme and Dagher
). However, it should be borne in mind that the active region of the targeting
2019
moiety (especially of small
molecules) could be blocked or made inaccessible by the
coating, in which case, a linker that allows the ligand’s exposure on the coated
particle’s surface is essential for a successful strategy. The second advantage of
actively targeted nanotechnologies is that they can minimize the amount of drug
delivered to non-targeted tissues or tissues lacking the specific rec
et al.
2010). These medicines
and biodegradable carriers
should also ideally be prepared from biocompatible
to avoid undesirable toxicities. Moreover, as with other
eptor (Danhier
nanoparticulate technologies, the nanocarrier needs to be able to encapsulate the
therapeutic or imaging agent with a high loading efficiency as well as being able to
temporally and spatially control the active agent’s release (Swami et al.
2012).
Various nanocarriers have been used for active targeting, including solid
nanoparticles, micelles, liposomes, dendrimers, and viruses (Fig. 14.4). Solid
nanoparticles are solid and spherical structures where therapeutic or imaging agents
are encapsulated within the polymeric matrix, ranging in size from 10 nm to 1 μm
(colloidal range). However, to minimize uptake by RES, sizes are preferentially
between 20 and 200 nm (Jain 2008; Bader 2012). Entrapment within solid
nanoparticles aims to reduce the drug’s toxicity to non-target organs or enhance
delivery to/or uptake by target cells (De Jong and Borm 2008).
Liposomes are closed spherical vesicles formed by one or multiple phospholipid
bilayers surrounding an aqueous core (Danhier et al.
2010) and can present as small
unilamellar vesicles (SUVs) of less than 100 nm in size or large unilamellar vesicles
(LUVs) and multilamellar vesicles (MLVs) that are larger than 100 nm (Jain
2008).
Based o n the physicochemical characteristics, the therapeutic or imaging molecule
will be either entrapped in the aqueous core if hydrophilic or intercalated into the
phospholipid bilayer if amphiphilic or hydrophobic.
Polymeric micelles are formed through the self-assembly of amphiphilic block
copolymers resulting in core-shell structures able to entrap drugs with low aqueous
14 Active Targeting of Nanomedicines 345
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solubility (Kwon 2003; Lalatsa et al. 2012b ). Micelles are characterized either by a
hydrophobic core and hydrophilic shell or by a polar core and hydrophobic shell,
which are called reverse micelles (Jones et al. 2008) and are usually smaller than
liposomes, ranging around 5–50 nm in size (Reddy and Swarnalatha
Dendrimers are synthetic, branched macromolecules with a controlled threedimensional architecture based on an initiator core of either ethylenediamine
(EDA) or ammonia and consist of multiple layers with active terminal groups
(amino groups) on the surface (Dufes et al.
from between 1 and 20 nm in size. One of the most critical characteristics of
dendrimers is particle size, which determines clearance kinetics, biodistribution,
and in vivo efficiency. In essence, nanoparticles (NPs) (>200 nm in size) induce
immune responses and are absorbed by an essential component of the mononuclear
phagocytic system, the Kupffer cells. By contrast, smaller NPs (<150 nm in size) are
rapidly cleared from the circulation, with the smallest NPs (<10 nm in size) being
quickly cleared through the kidney or lymph nodes (Mignani et al.
Dendrimers are typically less than 10 nm in size and are thus rapidly cleared.
Drugs or imaging molecules can be either covalently conjugated to the surface of
dendrimers or encapsulated in the core through chemical linkage, hydrophobic
interactions, or hydrogen bonds (Swami et al.
Virus capsid proteins may also be used in nanosystems. Ultimately, because of
their dual function as a carrier and a ligand, viral capsid proteins have the potential to
be useful in tumour-targeting gene therapy (Manosroi et al.
For example, parvovirus particles loaded with different genes (26 nm in size) were
shown to be able to bind to receptors over-expressed in a variety of tumour cells,
such as the transferrin receptor (Jain
The nanocarriers described above are currently in different phases of preclinical
and clinical development (Ojha et al. 2020).
2008).
2005; Paleos et al. 2010). They range
2012; Lee et al. 2005).
2012; Xu et al. 2008).
2010).
2020).
14.3.2 Targeting Moieties
Nanoparticulate actively targeted delivery strategies use a variety of targeting
ligands, which can be classified into five main categories: proteins, peptides, oligonucleotides, carbohydrates, and small molecules (Fig. 14.4).
Proteins
Today, antibodies are one of the most widely used classes of targeting moieties.
They are characterized by a broad range of binding affinities and a high degree of
specificity for cellular receptors due to the presence of two epitope binding sites in a
single molecule (Torchilin 2008). However, there are two major challenges associated with using antibodies as targeting liga nds. First of all, they are complex and
large molecules (~150 kDa) with expensive and time-consuming manufacturing
processes and are associated with batch-to-batch variation and stability problems
(Yu et al. 2012; Weinberg et al. 2005). Secondly, the administration of antibodies
346 D. R. Serrano Lopez et al.
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can cause immunogenicity (Yu et al. 2012). The antibodies are composed of two
domains: Fc (fragment crystallizable) and Fab (fragment antigen binding). The Fc
domain binds to Fc receptors localized particularly on macrophages, leading to liver
and spleen uptake, resulting in increased immunogenicity of the attached particle
(Allen
2002). Advances in antibody engineering partly mitigated this problem by
using humanized or fully human antibody fragments that are less immunogenic
2002)
(Allen
and Fab
activating region, while keeping their antigen-binding af finity (Swami et al.
Carter 2001). These variants are attractive due to their decreased immunogenicity,
ease of identification, and production compared to whole antibodies (Allen
Even though antibodies and antibody fragments exhibit very effective and sitespecific binding, they are far from ideal as antibodies may have lower receptor
affinity as a result of their conjugation to nanoparticles, may bind to non-specificFc
receptors, cannot respond to changes in the target antigen or avoid circulating
competing free antigen, and antibodies sometimes have low tumour penetration
due to their large size (Byrne et al.
Apart from antibodies, many other proteins have been used as active targeting
ligands, such as hormones (e.g. luteinizing hormone-releasing hormone (LHRH),
insulin, insulin-like growth factor, leptin), glycoproteins (e.g. transferrin,
lactoferrin), and lipoproteins (e.g. Apo E) (Daniels et al.
2007; Taheri et al. 2011; Tosi et al. 2012; Wagner et al. 2012; Kanwar et al. 2012;
Singh et al. 2011; Lalatsa and Leite 2019). Protein conjugation onto the surface of
the nanocarrier can result in loss of the binding affinity as more than one functional
group from the protein can react with the nanocarrier making the conjugation, not
site-specific (Veiseh et al. 2010). Additionally, non-specific physical interactions
(electrostatic, hydrophobic) between the nanoparticles and the protein can result in
aggregation and loss of bindi ng affinity (Veiseh et al.
immunogenic reactions in a similar manner to antibodies.
. Antibody fragments such as scFv (single-chain variable fragments)
are smaller in size and lack the Fc domain and the complement system-
2012;
2002).
2008).
2012; Beduneau et al.
2010). Proteins can cause
Peptides
Peptides have shown an increasing targeting potential because of their smaller size,
higher stability, lower immunogenicity, and relative ease of large-scale synthesis and
lower production cost (Swami et al.
source of active components due to their structural variations. However, due to their
metabolic instability, the development of orally administered targeted medicines is
limited (Zizzari et al. 2021). Moreover, engineered peptides may be synthesized to
have a single active functional group allowing for site-specific anchoring to the
nanocarrier surface and thus they maintain their binding affinity (Hong et al.
New peptide-targeting domains have been discovered that possess high binding
activity against different targets such as integrins (RGD domain peptide), collagen
(WYRGRL peptide), or matrix metalloproteinases (NRG peptide) (Danhier et al.
2010; Swami et al. 2012). Glutathione is a valuable tripeptide used as a targe ting
ligand to enhance drug delivery to the brain (Kannan et al. 1990). The fusion of
chlorotoxin, a potent toxin isolated from scorpion venom to IgG-Fc, results in an
2012; Yu et al. 2012). Peptides are a unique
2007).
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immunotoxin targeted to glioblastoma cells (Kasai et al. 2012). Lipopep tides,
designed based on the last eight amino acids of human and mouse phosphatase
and tensin homolog deleted on chromosome 10 (PTEN) (N-Lauryl-QHSQITKV) are
capable of crossing the blood-brain barrier (BBB) (Lalatsa et al.
2020). These
lipopeptides inhibit the recruitment of PTEN to synapses in response to Aβ and
avoid Aβ-induced synaptic depression and in turn diminish the synaptic and cogni-
2020)
tive deficits in a mouse model of Alzheimer’s disease (Lalatsa et al.
.
Oligonucleotides
Nucleic acids known as aptamers have been used as targeting ligands. Aptamers are
composed of single-stranded DNA or RNA oligonucleotides between 15 and
40 bases, which fold into unique 3D conformations exhibiting high affinity and
specificity for protein targets. They have been used as targeting ligands (Swami et al.
2012; Yu et al. 2012; Lee et al. 2006). Aptamers also have several advantages over
antibodies, such as better tissue penetration due to their smaller size (15 kDa), lower
immunogenicity, the ability to be chemically synthesized with minimal batch to
batch variation, and a faster and easier method of industrial production through the
systematic evolution of ligands by exponential enrichment process (SELEX)
(Swami et al.
2012; Fang and Tan 2010). Nevertheless, one of the significant
disadvantages of aptamers is their rapid blood clearance, mainly as a consequence
of nuclease degradation (Lee et al.
2006). To overcome their low serum stability,
aptamers can be chemically modified with PEG or have the 2′- fluoro unit incorporated in their backbone (Nimjee et al.
2005; Potti et al. 2004). However, they can also
be chemically synthesized as spiegelmers (mirror image of natural oligonucleotides)
composed of L-oligonucleotides instead of the natural D-oligonucleotides (Eulberg
and Klussmann 2003). Spiegelmers can be considered biostable aptamers (stable for
up to 60 hours in biological fluids) due to L-oligonucleotides not being suitable
substrates for nucleases (Eulberg and Klussmann
®
Pegaptanib (brand name Macugen
) is the first therapeutic aptamer approved for
2003).
human use. It is a pegylated RNA aptamer that binds with high specificity and
affinity to extracellular vascular endothelial growth factor (VEGF
), a protein
165
involved in angiogenesis, vascular permeability, and inflammation processes in
age-related macular degeneration (EMEA
2006). In particular, VEGF
165
is the
isoform preferentially responsible for pathological ocular neovascularization,
which leads to vision loss (Ng et al. 2006). Pegaptanib can be directly injected
into the vitreous cavity, where it will bind to VEFG
inhibiting its function and
165,
delaying the progression of the disease (Lee et al. 2006; Ng et al. 2006).
Numerous anticancer medications, such as epirubicin, camptothecin, Bcl-xL
short hairp in (sh)RNA, and 5-fluorouracil rhodamine-labelled dextran, have been
encapsulated using dendrimers complexing with aptamers. To target certain tumour
cells, further varieties of polymeric nanoparticle (NP)-aptamer bioconjugates have
been created and loaded with Pt(IV) derivatives (Mignani et al.
2020).
348 D. R. Serrano Lopez et al.
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Carbohydrates
Carbohydrates such as lactose, galactose, mannose, and galactosamine interact with
lectins (specific carbohydrate-binding proteins) on the surface of cells and thus, can
be exploited as targeting ligands (Berg et al.
2002). Lectins are over-expressed on
numerous cancer cells (Swami et al. 2012; Minko 2004). For example, the
asialoglycoprotein receptor is only expressed in high density (500,000 receptors/
cell) on hepatocytes and can specifically bind to ligands such as galactosamine, with
galactosamine being a suitable ligand to target nanocarrier-chemotherapy to liver
tumours (Yu et al. 2012; Shen et al. 2011). Hyaluronan (hyaluronic acid) is a
biocompatible and biodegradable polysaccharide composed of repeating disaccharides of glucuronic acid and N-acetylglucosamine (Toole
2004) and is known to bind
specifically to cell-surface receptors (such as CD44), which are over-expressed on
various cancer cells (Choi et al. 2010). Carbohydr ates as targeting ligands suffer
from low binding affinity to the target receptors, necessitating a high targeting ligand
density on the surface of the particles to achieve efficacy (Swami et al.
2012;
Managit et al. 2003). Therapeutic peptides have been used to effect some form of
targeting and as such therapeutic peptide nanofibres (involving a self-assembled
peptide prodrug) have been used to deliver peptides across the blood-brain barrier,
with a polymer coating on the peptide nanofibres further enhancing peptide delivery
to the brain via the intravenous route. Leucine
5
-enkephalin (LENK) prodrug
nanofibres entrapped in N-p almitoyl-N-monomethyl-N,N-dimethyl-N,N,Ntrimethyl-6-O-glycolchitosan (GCPQ) showed enhanced brain targeting with
GCPQ reducing protein binding and diverting the peptide nanofibres away from
the liver to elicit higher brain levels (Lalatsa et al.
2015).
Small Molecules
Small molecules have been used as targeting ligands. Using a small molecule as a
targeting ligand is advantageous due to the low synthetic cost and ease of conjugation to the nanocarriers (Swami et al.
folic acid (also called folate or vitamin B
processes for cell survival. Folate has a high specificity and binding affinity for the
folate receptor (dissociation constant, K
2012). One of the most studied molecules is
). Folic acid is vital in many metabolic
6
-10
d
= 10
M) that is over-expressed in many
types of cancer cells (Yu et al. 2012; Ross et al. 1994; Low et al. 2008). Folate has
versatile ligands and has been successfully conjugated with a variety of nanocarriers
(such as liposomes, nanoparticles, and dendrimers) to develop targeted theranostic
agents (agents with therapeutic and diagnostic capabilities in the same system) (Low
et al. 2008).
Nevertheless, one of the significant concerns regarding the use of folates as
targeting moieties is the over-expression of folate receptors not only in cancer
cells but also in normal tissues such as the placenta and kidneys (Swami et al.
2012). Methotrexate, which is a potent cytotoxic and anti-inflammatory agent
closely resem bling folate (Phillips et al. 2003), has been used as a ligand with a
binding affinity a thousand times higher than folate and is an ideal ligand for
targeting the folate receptor and active chemotherapeutic strategies (Goodsell
1999; Thomas et al. 2012). Whereas folate acid has been widely studied, other
14 Active Targeting of Nanomedicines 349
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therapeutic compounds are being developed as potential ligands against overexpressed receptors in targeted cells, such as biotin (against breast carcinoma
MCF7 and murine lung cancer M109) (Taheri et al. 2011), vitamin B
Jones et al.
2004), and riboflavin (Karande et al. 2001). Additionally, high-
(Russell-
12
throughput screening libraries and phage display libraries can yield high-affinity
ligands for targeting nanocarriers to specific receptors or sites (Weissleder et al.
2005; Kuohung et al. 2010). In addition, the identificatio
n and manufacture of all of
these ligands are easier when compared to whole antibodies.
14.4 Optimal Design of Actively Targeted Nanomedicines
The design goal of actively targeted nanomedicines is to improve efficiency and
specific binding to target cells (Chen et al. 2017). This requires consideration of the
nature of the targeted receptor, the particle characteristics (particle size, zeta potential, surface functional groups, drug loading ability), and the ligand’s specificity and
affinity (Fig.
The Target
Target cells should possess a high density of the targeted receptor on their surface
ideally, either uniquely expressed or over–expressed at the tissue of interest
14.6).
Fig. 14.6 Optimal design of actively targeted nanomedicines
350 D. R. Serrano Lopez et al.
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compared to non-targeted cells (Allen 2002; Pearce and O'Reilly 2019). The larger
the difference in receptor density between targeted and normal cells, the higher the
specificity would be. Specificity results in an improved therapeutic index with the
nanosystem and can potentially improve patients’ tolerance to treatments. However,
toxicity in other tissues may remain an issue if the nanomedicine accumulates in
them even if the particles are actively targeted. The target cells should not have a
or o
high degree of heterogeneity in the recept
geneity can
Nguyen et
because any circulating shed antigen could bind to the targeted nanomedicine
resulting in complexes that would be quickly cleared from the bloodstream (Allen
2002).
The microenvironments of the target tissues must also be considered, as it is
possible to achieve release of the drug in respon se to tissue factors. These factors are
outlined below. Changes in pH may affect release. Lac tic acid production or reduced
capacity to excrete waste products as a result of angiogenesis may increase the
acidity of the tumour environment allowing targeting of systems that are stable at
physiological pH (around 7.4), but release their cargo on contact with a more acidic
tumour environment (pH 6.5–7.0) (Attia et al.
site may affect drug release. For example, matrix metalloproteinases in metastasis
may catalyse reactions that result in the release of anticancer drugs from targeted
nanoparticles (Hejmady et al.
An important aspect about the selection of the target involves the specifics of
receptor-mediated internalization as a result of ligand binding (Allen 2002), especially if drug internalization is necessary for efficacy. Internalization of the receptor
may be detrimental for certain active strategies such as ADEPT (antibody-directed
enzyme prodrug therapy). ADEPT is a strategy designed to overcome the lack of
tumour selectivity and involves an antibody against a tumour antigen that is linked to
an enzyme and injected in the blood, resulting in selective binding of the enzyme in
the tumour. When the discrimination between tumour and normal tissue enzyme
levels is sufficient, a prodrug is administered into the blood circulation, which is
converted to an active cytotoxic drug by the enzyme, only at the tumour site.
Selectivity is achieved by the tumour specificity of the antibody and by delaying
prodrug administration, until there is a large differential between tumour an d normal
tissue enzyme levels. The antibody-enzyme complex should not be internalized so
that the enzyme is available intact at the target tumour site to activate the chemotherapeutic prodrug, and this could be problematic if the drug itself needs to be
internalized to be efficacious (Senter and Springer 2001).
The type of target cell dictates the pharmacokinetic properties of the actively
targeted nanomedicine. Targeting vascular tumour cells (haematological cancers or
metastatic cells distributed via the blood circulation) does not require nanosystems
with a long circulation half-life, as nanoparticles can quickly bind to the target cells
after intravenous administration (Allen
target, it is crucial that the nanomedicine possesses a long blood circulation time, so
result in the growth of drug-resistant cells (Allen
al. 2021). Also, the targeted antigen or receptor should not be shed
2020).
2002). However, when solid tumours are the
r antigen expression as such hetero-
2002; Wu et al. 2006;
2019b). Enzyme activity at the tumour
14 Active Targeting of Nanomedicines 351
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that the nanoparticles may be taken up by the tumour cells following extravasation
from the blood vessels (Allen 2002). This phenomenon is illustrated by reports of
large targeted particles (100–150 nm in size) taking 48 hours or longer to reach peak
levels in solid tumours (Allen et al.
Three important parameters have to be considered in designing actively targeted
nanomedicines: (i) the target, (ii) the nanocarrier, and (iii) the targeting ligand. Based
on the characteristics of the target cell (over-expres sed receptors, heterogeneity of
cells, internalization of the ligands), the carrier and the ligand will be chosen. The
surface properties, the shape, and the hydrodynamic size of the carrier should be
considered to achieve suitable pharma- and toxicokinetic profiles. The specificity of
the ligand and the ligand density per particle needs to be considered for a suitable
binding affinity to the receptor for the stability of the system.
Choice of Nanocarrier
The main reason for using nanocarriers is to transport the active substance or
imaging agent to the target tissues while sparing normal tissue. These nanocarriers
must be able to travel, in a stable manner, through the blood till they reach the
tumour microenvironment, thus crossing physiological and biological barriers (Attia
2019b). The hydrodynamic size, shape, and surface properties such as charge
et al.
and hydrophobicity and the ligand density play a critical role in cellular uptake,
clearance, and the biodistribution of the targeted nanomedicine (Chouly et al. 1996).
Nanomedicine particle size influences the distribution of the nanoparticles in the
body. Nanomedicines with a particle size smaller than 10 nm can be quickly cleared
by the kidney s (Petros and DeSimone 2010), while particles below 100 nm usually
experience reduced hepatic filtration and can circulate in the bloodstream for longer
(Swami et al.
cleared by the macrophages of the RES and to be accumulated in the liver and spleen
(Yokoyama 2005; Litzinger et al. 1994). Spherical and small particles have a higher
diffusion rate and circulate at the centre of the blood vessel resulting in reduced
interactions with the endothelial cells (Decuzzi et al. 2006). Blood vessels have a
pore cut-off size between 4 and 25 nm whereas the pore cut-off size of tumour blood
vessels allows extravasation of particles between 380 and 780 nm, which explains
the higher accumulation of the nanomedicines within tumour cells than normal
tissues (Rippe et al. 2002; Hobbs et al. 1998). Particle size and surface coating are
significant for permeation across the blood-brain barrier (BBB) with reports of
particles of between 40 and 100 nm coated with PEG being able to preferentially
permeate across the BBB (Nance et al. 2012). Smaller-sized nanoparticles can
penetrate moe easily into solid tumour tissues as long as their size is big enough to
escape kidney clearance (Allen 2002), and a size ranging between 10 and 250 nm
(Alexis et al. 2008) is deemed optimal compared to smaller (<5–10 nm) and bigger
particle sized (>400 nm) particles. These smaller and larger particles may be useful
for targeting to the kidney or liver/spleen respectively.
Surface hydrophobicity and charge are key quality attributes of nanocarriers as
both result in shorter blood circulation times due to either particle agglomeration
which then leads to opsonization or complement activation and/or non-specific
2012). Particles larger than 400 nm have a higher tendency to be
1998).
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