Escape from the systemic circulation

Whilst clearance of a drug delivery system is a major concern, drug delivery

systems that circumvent recognition by the MPS do not necessarily offer the
solution to drug targeting. Prolonged circulation is ideal foe slow or controlled
release of therapeutic agents or in the treatment of vascular disorders and in
vascular imaging. However, a long circulation profile does not ensure effective
targeting. The delivery system generally needs to leave the vasculature before it
can reach its target. This requires the system to cross the endothelial lining of the
blood circulation. The structure of the blood capillary wall is complex and varies in
different organs and tissues. We can differentiate between three types of capillaries
with respect ti their endothelial lining (Figure 7.3)

1. Continuous : These are common and widely distributed in the body. They have
tight junctions between the endothelial cells and a continuous basement
membrane (e.g. capillaries in the brain, lung and muscles.

2. Fenestrated : these have gaps of between 20 and 80 nm between the

endothelial cels (e.g. capillaries in the kidney, and gastrointestinal tract)

3. Sinusoidal : here the endothelial cells have gaps of up to 150 nm between them
and the basement membrane is either discontinuous (e.g. in the spleen) or
absent (e.g. in the liver).

In most parts of the body the endothelial lining is continuous and the endothelial
cells are situated on a basal membrane with tight junction between adjacent cells.
Macromolecules can cross this endothelium by passive processes; however
transport across the endothelium decreases with increasing molecular size.
Therefore, for drug delivery systems their escape from the circulation is normally
restricted to sites where the endothelial lining is fenestrated or sinusoidal and has a
number of gaps between the cells. This resembles the structure of capillaries within
the liver, spleen and bone marrow, or where the integrity of the endothelial barrier
has been disturbed by inflammatory processes or by tumour growth. In the liver, the
size of the gaps can be as large as 150 nm. At sites of inflammation the endothelial
fenestrations can be as large as 200 nm and in tumour capillaries they are generally
no larger than 300 nm.
KEY POINTS
There are two main types of targeting: passive targeting and active targeting.
Passive targeting exploits the natural conditions of the target organ to direct the
drug to the target sites

 Active targeting uses targeting groups such as antibodies to bind to specific

receptors on cells.
TYPES OF DRUG TARGETING
The mechanism by which a drug delivery system is targeted can be devided into
two main types:
1. Passive targeting. The distribution of the carrier is dictated by the local
physiological conditions or by the MPS.
2. Active targeting. The distribution of the carrier is dictated by interactions
between a ligand and its associated receptor.
PASSIVE TARGETING
Passive targeting is the mechanism by which we take advantage of the natural
pathological conditions of our target to allow the preferential accumulation of
drug carrier at the target site.
Passive targeting by the Mononuclear Phagocyte System (MPS)
We have already seen that the network of blood and lymphatic vessels within the
body combined with the MPS provides natural routes for the distribution of
nutrients and the clearing of unwanted material. When injected intravenously,
particulates are cleared rapidly due to the action of the liver and spleen
macrophages and the site-specific, but passive, mechanisms of clearance is a
feature of the immune system. After macrophage uptake, the drug carrier will be
transported to lysosomes and the drug can be released upon breakdown of the
carrier. Consequently, this mechanism can be used to target these cells and
therapeutically can be used for :
The treatment of macrophage intracellular microbial, viral or bacterial disease
(e.g visceral leishmaniasis)
The treatment of lysosomal enzyme deficiencies (e.g. Gauchers disease,
caused by a deficiency of the enzyme glucosylceramidase).
If passively targeting specific lymph nodes, interstitial injection may be a
preferred option. The size and surface characteristics of the particles injected by
this route again control their residence time at the target site, with particles less
than 100 nm rapidly leaking into the blood capillaries.
TIP
Visceral leismaniasis (also known as black fever) is a Leishmania parasite
infection. The parasite accumulates in the liver, spleen and bone marrow of the
host. Symptoms include fever, weight loss anaemia and swelling of the liver and

spleen. Treatment includes the use of AmBisome, Abelcet and Amphocil, which
are all formulations of Amphotericin B.
Local Physiological Conditions
In addition to exploiting the action of the MPS, passive targeting can take place a
result of the local conditions in the body. The local pH or presence of specific
enzyme within a target organ can also be used to facilitate the release of the
active drug from its carrier system specifically at these sites. For example,
elevated enzyme levels at a target site can be used to release the active drug
selectively from its prodrug or carrier system. Enzymes such as alkaline
phosphates and plasmin are known to have increased levels at tumor sites.
Enhanced permeability and retention (EPR) effect
As mentioned in the section on escape from the systemic circulation, the
integrity of the endothelial barrier at sites of inflammation or tumours is often
disrupted by the presence of endothelial fenestrations as large as 200-300 nm.
The change in the tumour endothelial barrier is a result of angiogenesis
occurring during tumour growth which results in defective hypervasculature and
a deficient lymphatic drainage system. This modified permeability of the
endothelium resulting from pathological conditions can be exploited in drugtargeting strategies to allow the escape of the drug carrier from the central
circulation. This phenomenon is called the enhanced permeability and retention,
or EPR, effect.
The EPR effect can be exploited to target drug carriers passively to a site where
the vasculature is leaky and gaps in the endothelium are present, such as sites
of inflammation or certain tumour sites. However, for this to take effect, the
delivery system should be designed to avoid their recognition and clearance by
the MPS (via modification of its surface characteristic and size; as already
discussed) such that the circulation time in the blood compartment is long
enough to allow the carrier to accumulate at the tumour site and release the
drug. Targeting via the EPR effect is driven by the plasma concentration of the
delivery system (figure 7.4)
The hyperpermeability of the tumour vasculature is a key feature controlling the
targeting of liposomes (e.g. Caelyx/Doxil) and polimer-based (e.g. Oncaspar)
cancer therapies. Due to the leaky vasculature of the tumour site, after
intravenous injection these drug carriers can either selectively move into the
tumour tissue directly, or the particulate carrier system can become trapped in
the tumour vasculature and release its drug load locally, where again due to the
leaky vasculature it can reach the tumour tissue. As the tumour tissue generally
lacks effective lymphatic drainage, this further promotes the retention and
accumulation of the drug and delivery system.

ACTIVE TARGETING
With Active targeting we are relying on the interactions between a targeting
moiety and a corresponding receptor to facilitate the targeting of a carrier to a
specific cell. These targeting groups are generally covalently, rather than noncovalently, attached to the drug or the surface of the carrier. There are various
molecules/receptors that can be used to facilitate active targeting. However it is
important to remember that if active targeting is to be affective, the carrier
system should be the designed to avoid the passive targeting route, particularly
the phagocytes of the MPS.
TIP
Caelix is a formulation of Dexorubicin encapsulated within liposomes. Oncaspar
is a polymer conjugated enzyme (Asparaginase).
Key Point
Active targeting is based on ligand-receptor binding and takes advantage of
elevated levels of such receptors at a target site.