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© Fraunhofer IBMT New routes in treating brain disorders Dr. Sylvia Wagner Preclinical Nanobiotechnology Group Department of Bioprocessing and Bioanalytics.

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Presentation on theme: "© Fraunhofer IBMT New routes in treating brain disorders Dr. Sylvia Wagner Preclinical Nanobiotechnology Group Department of Bioprocessing and Bioanalytics."— Presentation transcript:

1 © Fraunhofer IBMT New routes in treating brain disorders Dr. Sylvia Wagner Preclinical Nanobiotechnology Group Department of Bioprocessing and Bioanalytics Fraunhofer IBMT Sulzbach / Germany

2 © Fraunhofer Causal interventions still lacking Current therapies only aim at easing symptoms Substances may often show promising in vitro results, but fail in vivo. Reason: > 98 % of all small molecule drugs cannot enter the brain* ~ 100 % of all large molecule drugs cannot enter the brain* The shortage of drugs for the central nervous system Why? *PARDRIDGE, 2003

3 © Fraunhofer The blood-brain barrier guards our central nervous system The blood-brain barrier restricts body distribution of substances. A Intravenous injection of radiolabelled histamine in mouse (figure copied from Pardridge 2005). B Scheme of first experiment that hinted at the existence of a blood-brain barrier. C Correct verification experiment.

4 © Fraunhofer One barrier with manifold faces: Physical, Transport and Metabolic barrier Modified after Abbott, Rönnbäck and Hansson 2006

5 © Fraunhofer Today’s strategies for blood-brain barrier circumvention Adapted and modified after WOHLFAHRT et al., 2011 InvasiveNon-invasive Possibilities Osmotic disruption of BBB integrity Intraventricular / intracerebral injection Intracerebral implantation of depots Drug modification Intranasal application (olfactory route) Inhibition of efflux transporters Carrier-mediated transport Concerns High risk for complication Intracranial infections Brain endema Expensive Long reconvalescence phase Possible loss of drug activity Adverse side effects (P-gp inhibition) Low bioavailability (olfactory route)

6 © Fraunhofer Trick the body: Nanoparticles as drug carriers < 1000 nm Minimal expectations for clinical application : non-toxic, biodegradable, non-immunogenic, non- inflammatory, functionally targeted, prolonged circulation in the bloodstream (A) modified after RE et al., 2012 Possible ligands for BBB transport: -ApoE -ApoAI -Transferrin -Insulin -Anti-Insulin receptor antibodies -…

7 © Fraunhofer Trick the body: Nanoparticles as drug carriers DrugType of actionBasis materialSurface modification CampthotecinAnticancer drugSLNPoloxamer 188 DalarginAnalgesic drugPBCATween ® 80 DexamethasoneSteroidal drugPLGAAlginate hydrogel DoxorubicinAnticancer drugPBCATween ® 80 EtoposideAnticancer drugTripalmitinWithout coating GemcitabineAnticancer drugPBCATween ® 80 KyotorphinAnalgesic drugPBCATween ® 80 LoperamideOpiate receptor agonistPBCA, HSA, PLGA Tween ® 80, ApoE3, ApoA1, ApoB100, (R)-g7 peptide MethotrexateAnticancer drugPBCATween ® 80 ObidoximeAcetylcholinesterase reactivatorHSAApo E RivastigmineAnti-Alzheimer's drugPBCATween ® 80 SulpirideAtypical antipsychotic drugPLAMaleimide PEG TacrineAnti-Alzheimer's drugPBCATween ® 80 TemozolomideAnticancer drugPBCATween ® 80 TubocurarineMuscle relaxantsPBCATween ® 80 Table: Selected examples of drugs bound to nanoparticles for brain delivery in vitro/ in vivo. Adapted and modified after WOHLFAHRT et al. 2012

8 © Fraunhofer A plethora of nanoparticle applications - Painkillers for Alzheimer’s disease Problem Alzheimer's disease prevalence rises dramatically A drug may impact positively, but cannot enter the brain Approach Pack the drug in nanoparticles and fasciliate transport via brain specific transporters! Nanoparticles against Neurodegeneration: Revisit flurbiprofen as an anti-Alzheimer’s disease drug

9 © Fraunhofer Alzheimer’s disease pathology HealthyDiseased

10 © Fraunhofer Who gets Alzheimer’s? Who doesn’t? FBP= flurbiprofen NSAID=non-steroidal antiinflammatory drug Long-term high-dose NSAID intake decreases risk for Alzheimer‘s disease FBP

11 © Fraunhofer Phase III clinical trials failed (tarenflurbil TM )  Flurbiprofen cannot reach the brain in sufficient doses Embed flurbiprofen into nanoparticles for targeted transport across the BBB Poly(lactic acid) nanoparticle Long-term high-dose NSAID intake decreases risk for Alzheimer‘s disease FBP

12 © Fraunhofer A primary porcine in vitro blood-brain barrier model Brain weights: http://mste.illinois.edu/malcz/DATA/ BIOLOGY/Animals.html Human >1000 g Pig ~180 g Mouse ~0.4 g

13 © Fraunhofer A primary porcine in vitro blood-brain barrier model – Quality checks Scale bar = 50 µm.

14 © Fraunhofer Transendothelial electrical resistance (TER)Permeability assays cellZscope® device, nanoAnalytics, Germany A primary porcine in vitro blood-brain barrier model – Quality checks DZP= Diazepam (Valium ® ) Transcellular route Paracellular route

15 © Fraunhofer Do pBCEC tolerate flurbiprofen-loaded nanoparticles (PLA-FBP NP)? Cellular viability Permeability of paracellular marker + 14 C inulin Transendothelial electrical resistance

16 © Fraunhofer Do PLA-FBP NP interact with in vitro BBB cells? Flow cytometry and confocal laser scanning microscopy

17 © Fraunhofer Can PLA-FBP NP cross the BBB and lower Aβ42 burden? HPLC analysis, Aβ42-detecting ELISA Aβ42 reductionDrug transport & retrieval PLA-FBP NP lower Aβ42 FBP destroys TER and impairs barrier  No suitable control Less total drug retrievable:  NP still endocytosed?  Actual drug content lower?  Optimization Potential! Alzheimer‘s disease model

18 © Fraunhofer Trick the body: Nanoparticles as drug carriers < 1000 nm Minimal expectations for clinical application : non-toxic, biodegradable, non-immunogenic, non-inflammatory, functionally targeted, prolonged circulation in the bloodstream (A) modified after RE et al., 2012

19 © Fraunhofer ApoE3 -modified nanoparticles bind to and enter brain endothelial cells Pilot experiments n=1

20 © Fraunhofer Résumé pBCEC Are suited as an in vitro BBB model Tolerate PLA-FBP NP Bind to and take up PLA-FBP NP PLA-FBP NP Do not impair barrier integrity Transport the incorporated drug across the BBB model Reduce Aβ42 in the „brain“-compartment ApoE Is a suitable ligand for PLA-FBP NP Increases binding and uptake capacity of PLA NP

21 © Fraunhofer IBMT  Fraunhofer IBMT: - H. von Briesen - J. Bungert and S. Wien - J. Stab  Westfälische Wilhelms-University: - K. Langer - I. Zlatev - B. Raudszus  Goethe-University: - J. Kreuter - A. Zensi - J. Kufleitner - M. Dadparvar  NIH: - T. Vogel - Bundesministerium für Bildung und Forschung (BMBF) (Project 01EW1009 and 01EW1010) - Bundesamt für Wehrtechnik und Beschaffung (Project U2.3 E/UR3G/5G031/5A802)  Bundeswehr Institute of Pharmacology and Toxicology: - F. Worek  Johannes Gutenberg-University: - C. Pietrzik - S. Meister - W. Maier Funding Acknowledgement

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