Drug delivery to target tissues:
principles and mechanisms
Session 5: Targeted Drug Delivery
Prof. Dr. Paul Debbage
Medical University Innsbruck
Drug delivery to target tissues:
principles and mechanisms
Session 5: Index
Slides 3 - 5:
Topical application
Single targeting
Slides 6 – 13 Systemic application
Double targeting
Topical application
Urogenital system: bladder
Only one targeting group is needed, eg: anti-EGF-R, or anti-cadherin
Topical application
Gastro-intestinal system
Only one targeting group is
needed, eg: anti-EGF-R,
or anti-cadherin
Passage of even large
nanoparticles through the
mucus layer is rapid
(Sun et al., 1998;
Lai et al., 2007)
Topical application
General principle
Topical application requires only one targeting group,
which anchors the nanoparticle to the target cells
and allows accumulation of the active drug molecule
at those cells.
Systemic application
From injection site to target
From: Debbage & Thurner, 2010
There are 4 steps from the blood to the target cell
Systemic application
From injection site to target
Within 15 seconds after intravenous injection, the nanoparticles have
traversed the vasculature and arrived in the organ containing the lesion.
They have travelled as far as one meter ( = one million µm).
The capillary vessel located in the organ contains nanoparticles that are
only 100 µm distant from the lesion cells. This last 100 µm offers the
grand challenges that presently hinder success in Nanomedicine: there
are several barriers to be surmounted during this 100 µm.
Systemic application
From injection site to target
Systemic application
From injection site to target
General principle
Systemic application requires at least one extra targeting
group, which anchors the nanoparticles to the
endothelial lining of the capillaries close to the target
cells in the lesion. A second targeting group is also
required which anchors the nanoparticle to the target cells
and allows accumulation of the active drug molecule
at those cells.
Systemic application
From injection site to target
Targeting the caveolar
components of lung
endothelium allows
nanoparticles rapid
and specific passage
though the endothelium
into the lung parenchyma.
From: McIntosh et al., 2002
Systemic application
From injection site to target
Many directed therapeutic agents fail to reach their target cells (Tomlinson
(1987); Schnitzer, (1993); Schnitzer (1998); Denekamp (1984); Burrows &
Thorpe (1994)). Only a small proportion of intravenously applied
monoclonal antibodies - which are targeted nanoparticles in the 10 nm size
range - reach their targets on parenchymal cells (Dykes et al. (1987); Jain,
(1990); Sands & Jones, (1990). Uptake efficiency can be as low as 0.01%
(Ferrari, 2005) or less (Dvorak et al., 1991).
Targeting the endothelial caveolae of the lung resulted in nanoparticle
targeting efficiency of 89% (McIntosh et al., 2002).
Session 5: Targeted Drug Delivery
Summary:
Topical application of drug-bearing nanoparticles requires only a single targeting
group, directed at a lesion-specific molecule on the target cell.
Systemic application of drug-bearing nanoparticles requires at least one second
targeting group, directed at endothelial caveolar proteins specific for endothelial
cells in the lesion tissue.
Small-molecule drug targeting efficiency is ~0.01%.
Enhanced permeability and retention targeting efficiency reaches ~3%.
Doubly targeted nanoparticle targeting efficiency can reach ~90%.
Targeted Drug Delivery
Sources
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