debbage_session_5.ppt pharmacology of genetics

Pharmacology

1. Session 5: Targeted Drug Delivery
Drug delivery to target tissues:
principles and mechanisms
Prof. Dr. Paul Debbage
Medical University Innsbruck

2. 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

3. Topical application
Urogenital system: bladder
Only one targeting group is needed, eg: anti-EGF-R, or anti-cadherin

4. 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
Gastro-intestinal system

5. 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.

6. Systemic application
From injection site to target
There are 4 steps from the blood to the target cell
From: Debbage & Thurner, 2010

7. 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.

8. Systemic application
From injection site to target

9. 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.

10. 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

11. 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).

12. 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

13. Sources
Sun Z, Wang X, Andersson R (1998) Role of intestinal permeability in monitoring mucosal barrier function. History, methodology, and significance of
pathophysiology. Dig Surg 15: 386-397
 
Lai SK, O'Hanlon DE, Harrold S, Man ST, Wang Y-Y, Cone R, Hanes J (2007) Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus.
Proc Natl Acad Sci 104: 1482-1487
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 drug
and 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. Cancer
Treat 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