Laurent LecanuPharmD, PhD
Associate Professor
“Challenges in targeting the brain”
__________________________________________________________ L’Institut de recherche du Centre universitaire de santé McGill The Research Institute of the McGill University Health Centre
CRS International Meeting, July 15-18 2012, Quebec, CA
THE NEXT FRONTIER
The Brain
The blood-brain barrier
• Lack of knowledge of the gate defense
• Lack of knowledge of what is beyond the gate
• Wrong equipmentA bridge too far?
Lack of capacity to accurately plan/develop and to achieve goal.
• 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?
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 exchanges
The various barriers that one can find in the brain (broken lines), representing the blood-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, and is, therefore, considered to be the most important influx barrier for solutes to enter the brain. Also shown are the paths of fluid movement (solid arrows) between cerebral intracellular fluid (ICF), interstitial fluid (ISF), CSF, blood, and lymphatics. Thick arrows represent major paths of fluid movement under normal conditions. Thin arrows represent minor paths of fluid movement under normal conditions.
From Kola and Landis, Nature Reviews, 2004
Proportion of drug effectively release on the market
High failure rate
WHY?
The blood-brain barrier
Repelling transportersMetabolism
Non permissive barrierUnique structure
Like the liver, the BBB should be considered as an organ on its own
• 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 functions
The brain is a body within the body
Brain capillaries structureBrain capillary endothelial cellsPericytesAstrocytes
• 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
Sex, aging
Heterogeneous repartition, regio-specificity
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)
• Focused ultra-sound (Alonso et al., 2010 J Cereb Blood Flow Metab)
Mechanism of diffusion still to unveil
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• None existing entity until it
is too late• Either the BBB dimension is
not integrated or integrated too late
• R&D CNS budget, 99% for drug design and 1% for BBB crossing
Lack of Basic Knowledge• No college/university in
North-America has a program that emphasizes the importance of the BBB.
• No pharmaceutical company has a program aiming at BBB (drug or delivery system)
We know it crosses, we do not know how and we do know why!
Caprospinol Brain tissue
CSF
Lecanu, 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
LogP=7.5
The FDA's Nanotechnology Task Force released a report that recommends the agency consider developing guidance and taking other steps to address the benefits and risks of drugs and medical devices using nanotechnology. The Task Force was initiated by Commissioner von Eschenbach in 2006. The Task Force reports that nanoscale materials potentially could be used in most product types regulated by FDA and that those materials present challenges similar to those posed by products using other emerging technologies. The challenges, however, may be complicated by the fact that properties relevant to product safety and effectiveness may change as size 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
What’s left to be done? Complete characterization of the various transporters and drug interacting BBB
components
Mapping
Drug design
Initiate, develop and implement drug design based on transporter specificity
Initiate, develop and implement drug-targeting technology programs based on
transporter specificity
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