Session 5: Targeted Drug Delivery

Drug delivery to target tissues: principles and mechanisms

Prof. Dr. Paul DebbageMedical University Innsbruck

Drug delivery to target tissues: principles and mechanisms

Session 5: Index

Slides 3 - 5: Topical applicationSingle targeting

Slides 6 – 13 Systemic applicationDouble targeting

Topical application

Urogenital system: bladder

Only one targeting group is needed, eg: anti-EGF-R, or anti-cadherin

Only one targeting group isneeded, eg: anti-EGF-R,

or anti-cadherin

Passage of even largenanoparticles through the

mucus layer is rapid(Sun et al., 1998;Lai et al., 2007)

Topical application

Gastro-intestinal system

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

There are 4 steps from the blood to the target cell

From: Debbage & Thurner, 2010

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 targetTargeting the caveolar

components of lungendothelium allowsnanoparticles rapid

and specific passagethough 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).

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%.

Session 5: Targeted Drug Delivery

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Debbage P, Thurner GC (2010) Nanomedicine Faces Barriers. Pharmaceuticals 3: 3371 - 3416; doi:10.3390/ph3113371

McIntosh DP et al. (2002) Targeting endothelium and its dynamic caveolae for tissue-specific transcytosis in vivo: A pathway to overcome cell barriers to drugand gene delivery. PNAS 99: 1996-2001

Tomlinson, E. (1987) Theory and practice of site-specific drug delivery. Adv Drug Deliver Rev 1: 87-198

Schnitzer, J.E. (1993) Update on the cellular and molecular basis of capillary permeability. Trends Cardiovasc Med 3: 124–130

Schnitzer, J.E. (1998) Vascular targeting as a strategy for cancer therapy. N Engl J Med 339: 472-474

Denekamp, J. (1984) Vasculature as a target for tumour therapy. Prog Appl Microcirc 4: 28-38

Burrows, F.J.; Thorpe, P.E. (1994) Vascular targeting--a new approach to the therapy of solid tumors. Pharmacol Ther 64: 155–174

Dykes, P.W.; Bradwell, A.R.; Chapman, C.E.; Vaughan, A.T.M. (1987) Radioimmunotherapy of cancer: clinical studies and limiting factors. CancerTreat Rev 14: 87-106

Jain, R.K. (1990) Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res 50: 814s-819s

Sands, H.; Jones, P.L. (1990) Physiology of monoclonal antibody accretion by tumors. Cancer Treat Res. 51: 97-122

Ferrari, M. (2005) Cancer nanotechnology: opportunities and challenges. Nature Rev Cancer 5: 161-171

Dvorak, H.F.; Nagy, J.A.; Dvorak, A.M. (1991) Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells 3: 77-85

Targeted Drug Delivery