Session 5: Targeted Drug Delivery

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

2. Drug deliverytotargettissues: principlesandmechanisms Session 5:Index Slides 3 - 5: Topical application Single targeting Slides 6– 13Systemic application Double targeting

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

4. 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)

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 From: Debbage & Thurner, 2010 There are 4 steps from the blood to the target cell

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. 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%.

13. Targeted Drug Delivery 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