Alf Lamprecht Laboratory of Pharmaceutical Engineering (EA3924),

1. Nanoparticulate drug delivery systems for different therapeutic applications Alf Lamprecht Laboratory of Pharmaceutical Engineering (EA3924), University of Franche-Comté, Besançon, France Contact: alf.lamprecht@univ-fcomte.fr

3. C B A drug intestinal barrier cells, receptors organs “Le Menu” • Nanoparticles for the absorption of drugs with low bioavailability (oral heparin) • Nanoparticles for the selective drug targeting (inflammatory bowel disease) • Nanocapsules for intracellular drug therapy (cancer)

4. polymeric nanoparticles and their therapeutic applications Nanoparticles for oral delivery of macromolecules Objective: enhanced absorption of the drug transport across biological barrier avoidance of repetitive injections

5. Nanoparticles for oral absorption Heparin - anionic glycosaminoglycans - treatment and prophylaxis of venous thrombosis • parenteral administration • no oral absorption •  do not pass the intestinal barrier • NANOPARTICLES: • drugentrapment (protection) • emulsion techniques • biocompatible polymers • diameter: 300-500nm

6. Nanoparticles for oral absorption Pharmacokinetic parameters after oral administration of UFH-loaded NP (2000 IU) in rabbits (n=6)

7. Nanoparticles for oral absorption Cell culture model for adsorption studies: 1. Absorption barrier (cells) 2. Mucus ??? no influence on absorption kinetics of small drugs but macromolecules ??? adhesion studies on the cells, but adhesion to the mucus ???  mucoadhesion is the starting point!!!

8. Nanoparticles for oral absorption resonant mirror system: NP adhesion differs with surface charge

9. Nanoparticles for oral absorption • mucin coated Caco-2 cells • confluent but not homogeneous mucin layer • stained with astra blue Aqueous boundary layer (ca. 40 µm) Mucus layer Epithelial cells Basolateral compartment

10. Nanoparticles for oral absorption • cationic NP adhesion • LMWH adhesion correlates!!!

11. Nanoparticles for oral absorption LMWH transport across mucin coated Caco-2 cell layers

12. Conclusion Particle adhesion to Caco-2 cells

13. Nanoparticle targeting in inflammatory bowel disease Objective: local drug delivery in IBD treatment targeting on tissue level lower adverse effects by a selective drug release

14. Inflammatory bowel disease • chronic, relapsing inflammation of the colon • unknown etiology • swelling and ulceration of mucosa and submucosa • therapeutic principles: • induce remission of outbreaks • prevent outbreaks during remission • drug treatment • oral (standard) • rectal (limited use) • intravenous (recent) • surgery ulcerative colitis Crohn’s disease

15. Nanoparticles in colitis Histology of the inflamed colonic mucosa (TNBS-model for the rat) healthy control colitis group increases mucus production colitis group with ulcerated tissue

16. Nanoparticles in colitis Localization of 100nm particles in the colon healthy control mucus layer of colitis group ulcerated tissue of colitis group TNBS intrarectal; 5 days particles orally

17. Nanoparticles in colitis • higher deposition in inflamed colon  selectivity • size dependent accumulation • no influence on the deposition in other gut regions

18. Nanoparticles in colitis • tacrolimus: • (also FK-506 or Fujimycin) • use in organ transplant • immunosuppressive • use in IBD

19. Nanoparticles in colitis NP efficient after rectal administration  significant drug loss during intestinal transit

20. Nanoparticles in colitis solution: inflamed healthy NP: inflamed healthy NP increase drug tissue penetration selectively

21. NP tissue penetration into inflamed tissue into healthy tissue Nanoparticles in colitis P-gp CYP

22. Conclusion Nanoparticles target the inflamed tissue in IBD A) accumulate the drug in the inflamed tissue: B) increase and selectivity of drug tissue penetration I) high therapeutic efficiency II) reduction of adverse effects

23. Lipid nanocapsules and their therapeutic applications Nanocapsules in the treatment of cancer Objective: local drug delivery of anticancer drugs targeting on cell level higher efficiency by a selective drug release

24. Lipid nanocapsule preparation • controlleddrug release • controlled surfactant release (P-gp inhibitor) • slower release for higher drug loading

25. Nanocapsules in cancer in-vitro testing of LNC on glioma cell cultures: • etoposide LNC up to 80-fold more potent • more effective in F98 cells

26. Nanocapsules in cancer Confocal laser scanning microscopy • LNC uptake in F98 (a) and 9L (b) cells • etoposide + blank LNC no effect •  cellular uptake required !!!

27. Nanocapsules in cancer Proposed mechanism of action:

28. Nanocapsules in cancer LNC - an promising concept in cancer treatment ? - intracellular uptake - drug release - PEG-HS release - potentially blocking the P-gp  overcoming the multidrug resistance ???

29. Acknowledgments Angers J.P. Benoît F. Lacoeuille E. Garcion Gifu Y. Kawashima H. Takeuchi Yamamoto Nancy P. Maincent N. Ubrich Y. Meissner Saarbrücken C.M. Lehr U. Schäfer D. Neumann T. Betz

30. Acknowledgements • - Japanese Society for the Promotion of Science • - Alexander-von-Humboldt Foundation • Monbugakushō • Egide • Fujisawa Pharmaceutical Co. Ltd.