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332 L. Dymock and C. Hoskins
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13.8 Conclusion and Future Outlook
Nanotechnology for hydrophobic drug solubilisation is definitely the formulation
strategy which will revolutionise modern medicine development. The benefits and
diversity of the nano-carriers which can be developed all have their unique selling
points. There is no ‘one size fits all’ solution to drug solubilisation, and often it is a
balance between drug, clinical outcome and complexity. Despite the research force
which has been behind the nanotechnology field, the number of products using these
technologies is still relatively low, but rapidly growing. This initial inertia is widely
regarded as being due to problems with a lack of understanding of the regulatory
aspects. The regulation of nanotechnologies still falls between the gaps within
regulatory bodies, and they are assessed either as medical devices or as therapeutics
depending on the country. When assessed as therapeutics, assays used for small
molecule drugs are used which often are not appropriate. Over time, this is changing
with many regulatory bodies focussing efforts on stratifying definitions and boundaries for nanomedicines and it is expected that over the coming decade, more and
more nanoencapsulated therapeutics will hit the market.
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Chapter 14
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Active Targeting of Nanomedicines
Dolores Remedios Serrano Lopez, Aytug Kara, Bianca I. Ramirez,
Irving O. Ramirez, Baris Őngoren, and Aikaterini Lalatsa
14.1 Principles of Active Targeting of Nanomedicines
Actively targeted nanomedicines are drug delivery systems designed using
nanocarriers loaded with therapeutic and/or imaging agents and a surface-targeting
moiety. This targeting moiety may be an antibody or another protein, a carbohydrate,
or a nucleic acid sequence. Active targeting allows nanoparticles to interact precisely
with cells containing the corresponding receptor. Antibodies and ligands are frequently chosen for active targeting because of the following reasons: (i) their high
specificity, (ii) their affinity for over-expressed antigens at the target area, and (iii)
their capacity to induce receptor-mediated endocytosis after binding (Table 14.1).
However, biodistribution is still dependent on the passi ve targeting of tissues which
have a leaky vasculature (Chen et al.
It is crucial to distinguish between “targeted drug delivery” and “targeted therapy,” the latter of which is widely used in the field of drug discovery to refer to
molecular-level interactions between a medication and its receptor (Gerber
An actively targeted nanomedicine must typically meet the following four criteria
to be effective: (i) evasion from opsonization and clearance by liver and kidneys,
allowing sufficient circulation in the organism; (ii) retention within intended sites;
(iii) specific interaction between the targeting moiety of the nanomedicine and its
respective receptor; and (iv) therapeutic and/or imaging agent release/ac tivation at
2012).
2008).
D. R. Serrano Lopez · A. Kara · B. I. Ramirez · I. O. Ramirez · B. Őngoren
Department of Pharmaceutics and Food Technology, School of Pharmacy, Complutense
University of Madrid, Madrid, Spain
A. Lalatsa (
CRUK Formulation Unit, Institute of Pharmacy and Biomedical Sciences, University of
Strathclyde, Glasgow, UK
e-mail:
© The Editor(s) (if applicable) and The Author(s), under exclusive license to
Springer Nature Switzerland AG 2024
I. F. Uchegbu et al. (eds.), Fundamentals of Pharmaceutical Nanoscience,
https://doi.org/10.1007/978-3-031-59478-6_14
✉)
aikaterini.lalatsa@strath.ac.uk
337
338 D. R. Serrano Lopez et al.
https://t.me/med1917
Table 14.1 Examples of targeting moieties that are frequently used in research and clinical
formulations (Attia et al.
Class Ligand Targets Advantages Limitations
Antibodies Herceptin
Peptides RGD
Proteins Transferrin
Aptamers Pegaptanib VEGF receptor Possible to develop
Small
molecules
Key: APOE Apoliprotein E, CD20 B-lymphocyte antigen CD20, CD19 B-lymphocyte antigen
CD19, HER2 human epidermal growth factor receptor 2, LHRH luteinizing hormone-releasing
hormone or gonadotrophin releasing hormone, NGR asparagine-glycine-arginine moiety, RGD
Arginylglycylaspartic acid moiety, VEGF vascular endothelial growth factor
Rituxan
CD19
NGR
LHRH
APOE
Folate
Galactose
2019a)
HER2
CD20
CD19
α
integrins
vβ3
Aminopeptidase N
LHRH receptor
Transferrin receptor
LDL receptor
Folate receptor
Asialoglycoprotein
receptor
High affinity and
strong binding;
already in clinical
trials; therapeutic
potential
High affinity Reduced circulation
Already in clinical
trials
for any target
Low production
cost, low molecular
weight; simple
chemistry
High production cost;
pharmacokinetics;
“binding site barrier
effect” potential
immunogenicity
half-life
High production cost
High production cost
Reduction in circulation time
the targeted site (Bae and Park 2011a). Passively targeted nanomedicines use
biological mechanisms such as phagocytosis by the reticuloendothelial system
(RES) cells or the increased permeation and retention (EPR) effect, which is
observed, for example, in tumours with a leaky vasculature, to reach specific organs
or disease locations. This is the crucial contrast between passively and actively
targeted nanomedicines. These latter group of biological transport mechanisms are
ich a
not the main means by wh
tissue
passiv
(Du
ely
ncan
targe
ting
Figure 14.1 illust
2006).
nanom
ctively targeted nanomedicines reach the destination
the
rates
dist
inctions
between
acti
edicines.
vely
and
Nanomedicines can selectively reach tumours using biological mechanisms such
as the EPR effect, which results from the disorganized pathology of the angiogenic
tumour vasculature with its discontinuous endothelium, leading to
hyperpermeability to circulating nanoparticles and the lack of effective tumour
lymphatic drainage, leading to nanoparticle accumulation. On the other hand,
actively targeted nanomedicines accumulate in cells, such as cancer cells due to
the interaction between targeting moieties grafted on to the nanoparticle’s surface
that can bind precisely to receptors over-expressed by the target pathology cells.
14 Active Targeting of Nanomedicines 339
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Fig. 14.1 Active and passive targeting of nanomedicines
14.2 Targeted Drug Delivery Processes
In addition to paracellular and transcellular transport across epithelial cell membranes, endothelial cells rely on carrier-mediated transport, receptor-mediated
transcytosis (RMT), and adsorptive-mediated transcytosis (AMT) to facilitate the
entry of essential polar nutrients (such as glucose and amino acids) and other
molecules selectively into the cell (Xu et al.
The expression of transport (carrier) proteins in the luminal and abluminal
membranes of cells are polarized, with some transporters expressed exclusively in
one of these interfacial membranes and other transporters on the opposite side. Some
transport proteins are located on both luminal and abluminal membranes (Di et al.
2012). Specific transporters are unidirectional, and others are bidirectional in their
transport of solutes across the cell membrane; this polarization allows for the energyintensive prefer ential transport of some solutes into the cell and others out of the cell
(Pardridge 2012). Whether the concentration gradient favours entry into or exit from
the cell, particular solute transport can be facilitated in either direction. These transporters (mainly glucose and other amino acid or nucleoside transporters) can theoretically be used to trans port nanoparticles within the cells of interest (Fig. 14.2).
Endocytosis is the primary entrance route for intact biopharmaceuticals with a
significant molecular weight involving specific and non-specific processes. The
binding of the ligand, attached to nanoparticles, to its specific membrane receptor
on the cell surface induces the modification of the receptor protein (Fig.
induces endocytosis at the luminal membrane, most likely involving the creation of a
caveolus (clathrin-coated pits) that induces the formation of endocytotic vesicles
(Brasnjevic et al.
). These endocytotic vesicles merge with an endosome
2009
2013).
14.3). It
340 D. R. Serrano Lopez et al.
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Systemic Circulation
Release of
Drug–carrier
Conjugate
METABOLISM/CLEARANCE
(e.g. via liver)
DRUG RELEASE
Fig. 14.2 After systemic injection of a drug-carrier conjugate into the central (blood-lymph)
compartment of the body, the access, retention, release, and clearance of the conjugate and its
constituents to the relevant organ, tissue, and, ultimately, the drug target are determined. (Modified
from Karel
free drug at
the non-
target site
and
2005)
Delivery of
drug–carrier
conjugate to
the target
site
(e.g. tumor)
DRUG RELEASE
TARGET
and
Removal of
free drug
from the
target site
Elimination
of the drug–
carrier
conjugate
ELIMINATION
(e.g. via the kidneys)
Elimination
of free drug
(a pre-lysosomal compartment with an acidic pH) and detach the ligand from the
receptor, permitting the free receptor to be recycled to the cell surface (Xu et al.
2013).
Transferrin receptors are diffusely dispersed across the plasma membrane and
only move to coated pits upon ligand interaction. Most low-density lipoprotein
(LDL) receptors are situated near the membrane surface, where coated pits are
present even when no ligand is present (Xu et al.
2013). The ligand-containing
vesicles may be exocytosed, resulting in transmembrane trafficking, or merged with
a lysosome, resulting in intracellular destruction. Endosomes with intact receptorligand may be transported to the inner saccule of the Golgi complex, where enzymes
can cause the dissociation of ligands from the receptor. The separated ligand may be
ejected into vesicles for lysosomal destruction (Xu et al.
2013). A few peptides and
proteins, including insulin, transferrin, some cytokines, and leptin, have been proven
to undergo receptor-mediated endocytosis.
14 Active Targeting of Nanomedicines 341
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Fig. 14.3 The entrance pathways of conjugated drugs or liposomes into cells (Karel 2005)
In contrast to RMT, which requires particular plasma membrane receptors,
cationic large molecular weight biomacromolecules, particles can be taken up by
the brain via adsorptive induced transcytosis (AMT) (Lalatsa et al.
2012a). AMT
requires an excess positive charge on the molecule, rendering it cationic in order to
electrostatically interact with the anionic sites of acidic glycoproteins on the cell
surface (composed of type IV collagen, laminin, fibronectin, and heparin sulphate),
thereby initiating endocytosis and subsequent transcytosis (Lalatsa et al. 2012a;
Csaba et al. 2006). The processes that follow endocytosis resemble RMT. However,
AMT has a greater transport capacity than RMT, because transport saturation occurs
at higher doses with RMT. This channel is known to be utilized by ionized (cationic)
albumin to enter the brain. Other molecules include avidin, histone, cationic polyclonal bovine immunoglobulin, E-2078 (small dynorphin-like basic peptide), and
the cell-penetrating peptides HIV transactivator of transcription (TAT) protein
(Frankel and Pabo 1988) or other arginine-rich peptides such as SynB5 and pAnt(43-58) (Lalatsa et al. 2012a; Drin et al. 2003). The arginine content of these
oligomers is a crucial factor (Schmidt et al. 2010) and the essential structural
characteristics of guanidinium-rich cell-penetrating vectors are now thoroughly
characterized (Wender et al. 2008). However, the concentration of cationic peptides
in tissues may be constrained because cationic drugs are more rapidly absorbed by
the liver and kidney so that the actual mass taken into the tissue is a small fraction of
the intravenously administered dose (Wender et al.
2008). Some technologies mask
the cell-penetrating vector with another oligopeptide, intended to be broken off at the
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