__________________________________________________________L’Institut de recherche du Centre universitaire de santé McGillThe Research Institute of the McGill University Health Centre Laurent Lecanu PharmD, PhD Associate Professor “Challenges in targeting the brain” CRS International Meeting, July 15-18 2012, Quebec, CA
The blood- • Lack of knowledge of the brain barrier gate defense • Lack of knowledge of what is beyond the gate A bridge too • Wrong equipment far?Lack of capacity to accurately plan/developand to achieve goal.
What is the blood-brain barrier?• First described by Ehrlich in 1885 and then by Goldman in 1913• The blood-brain barrier exists within 600 km of capillaries• 1 km per cm3 of brain tissue• 20 m2 surface
What is the blood-brain barrier?• Physical, chemical and metabolic barrier• The blood-brain barrier is restrictive for some compounds owing to efflux mechanisms, absence of permeation and limited pinocytosis.• Its role is to protect the brain against overexposure and toxins• The blood-brain barrier (BBB) segregates the circulating blood from interstitial fluid in the brain, and restricts drug permeability into the brain.
Brain barriers/blood exchangesThe various barriers that one can find inthe brain (broken lines), representing theblood-brain barrier (BBB), the blood-cerebrospinal fluid (CSF)-barrier, the brain-CSF-barrier, and the blood-spinal barrier.The BBB has the largest surface area, andis, therefore, considered to be the mostimportant influx barrier for solutes toenter the brain. Also shown are the pathsof fluid movement (solid arrows) betweencerebral intracellular fluid (ICF), interstitialfluid (ISF), CSF, blood, and lymphatics.Thick arrows represent major paths offluid movement under normal conditions.Thin arrows represent minor paths of fluidmovement under normal conditions.
Proportion of drug effectively release on the market From Kola and Landis, Nature Reviews, 2004
Unique structure Non permissive barrier Like the liver, the BBB should be considered as an organ on its own MetabolismRepelling transporters
• In human, the brain is the only organ that is completely sealed and isolated from the rest of the body. – Steroid – Cholesterol – Neuronal, endocrine, immunological functionsThe brain is a body within the body
Brain capillaries structure Brain capillary endothelial cells Pericytes Astrocytes• Restrictive physicochemical characteristics that limit passive diffusion• Lack of capillary wall fenestration• High efflux capacity• Metabolism within the endothelial cell• Uptake transport
Transporters• ABC family: P-glycoprotein (oncology, virology)• Influx: LAT-1 (PD, epilepsy), GLUT1, Oatp1A2 (thyroxin, prostaglandin, steroids), SVCT2 (VitC) – Phenylalanine derivatives of valproic acid (Peura et al., 2011); Tyrosine conjugated drug (Gynther et al., 2008) – Glut1 and glycosylated peptides, LMWH and D-Glu derivatives (Guo et al., 2005) – Targeting glioma cells with SVCT2-nanocarrier (Salamaso et al., 2009); Ascorbic and 2-bromoascorbic acid conjugates with neuroactive molecules (Manfredini et al. 2004)• Efflux: ASCT2, EEAT, Oatp2• And many more… Many polymorphisms, ethnic-specific Heterogeneous repartition, regio-specificity Sex, aging
Blood-brain barrier and neuropathologies• Neurodegenerative diseases• Stroke• Traumatic brain injury• Gliomas• Viral and parasitic infections Still to be fully characterized
Nanoparticles• Dendrimers (Beg et al., 2011)• Lipidic nanostructures (Bondi et al., 2012)• Sialic acid and glycopeptides conjugated NPs (Tosi et al., 2010 J Controlled Release)• Smart nanovehicle (SNV) (Agyare et al., 2008 Pharm Res)• Poly(n-butylcyano-acrylate) NPs coated with Tween®80 (Wilson et al., 2008 Brain Res)• Biotinylated-pegylated NPs (Pulkkinen et al., 2008 Eur J Pharm Biopharm)• Other polymers: albumin, dextran, chitosan, polylactic acid Not necessarily devoid of toxicity Yet clinical benefit over other platforms to be validated
BBB-targeting delivery systems• Immunoglobulin tethered to the NPs• Apo A-I, E3, B100, MMP-200 fragment covalently attached to the NPs
Miscellanous• Nanoemulsion for intranasal delivery (Kumar et al., 2009 PDA J Pharm Sci Technol) Mechanism of diffusion still to unveil• Focused ultra-sound (Alonso et al., 2010 J Cereb Blood Flow Metab)
Facts• >98% of small molecules do not cross the BBB• ~100% of larger molecules (growth factors, peptides, biotech…) do not cross the BBB
Conceptual Problem Lack of Basic Knowledge• None existing entity until it • No college/university in is too late North-America has a• Either the BBB dimension is program that emphasizes not integrated or integrated the importance of the BBB. too late • No pharmaceutical• R&D CNS budget, 99% for company has a program drug design and 1% for BBB aiming at BBB (drug or crossing delivery system)
We know it crosses, we do not know how and we do know why!Caprospinol Brain tissue CSF LogP=7.5Lecanu, Yao, Teper, Yao, Greeson and Papadopoulos, 2004Tillement, Lecanu, Yao, Greeson and Papadopoulos, 2006Lecanu, Tillement, Rammouz, Tillement, Greeson and Papadopoulos, 2009Lecanu, Rammouz, McCourty, Sidahmed, Greeson and Papaddopoulos, 2010Tillement, Lecanu and Papadopoulos, 2011Papadopoulos and Lecanu, 2012
The FDAs Nanotechnology Task Force released a report thatrecommends the agency consider developing guidance andtaking other steps to address the benefits and risks of drugsand medical devices using nanotechnology. The Task Forcewas initiated by Commissioner von Eschenbach in 2006. TheTask Force reports that nanoscale materials potentially couldbe used in most product types regulated by FDA and thatthose materials present challenges similar to those posed byproducts using other emerging technologies. The challenges,however, may be complicated by the fact that propertiesrelevant to product safety and effectiveness may change assize varies within the nanoscale.
Crossing the BBB, then what?• Crossing where?• To go where?• Brain parenchyma structure• Bound versus unbound fraction• Plasma versus brain tissue macromolecules
Not mentioning…• Tissue diffusion• In vivo – Invasive (catheterism, microdialysis…) – Non-invasive (Combining various technology, NMR/PET/MRI/CT)• in vitro model – In particular, assays and HTS that includes pericyte cell type• Imaging• PK modelization, translational pharmacokinetic