Blood brain barrier hurdle in drug development. Where are we, what is being done, what should be done.

1. __________________________________________________________
L’Institut de recherche du Centre universitaire de santé McGill
The 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

2. The Brain
THE NEXT FRONTIER

3. 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/develop
and to achieve goal.

4. 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

5. 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.

6. 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.

7. Proportion of drug effectively release
on the market
From Kola and Landis, Nature Reviews, 2004

8. High failure rate
WHY?
The blood-brain barrier

9. Unique structure
Non permissive barrier
Like the liver, the BBB
should be considered
as an organ on its own
Metabolism
Repelling transporters

10. • 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

11. 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

12. 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

13. Blood-brain barrier and
neuropathologies
• Neurodegenerative diseases
• Stroke
• Traumatic brain injury
• Gliomas
• Viral and parasitic infections
Still to be fully characterized

14. 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

15. BBB-targeting delivery systems
• Immunoglobulin tethered to the NPs
• Apo A-I, E3, B100, MMP-200 fragment covalently
attached to the NPs

16. 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)

17. Facts
• >98% of small molecules do not cross the BBB
• ~100% of larger molecules (growth factors,
peptides, biotech…) do not cross the BBB

18. 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)

19. We know it crosses, we do not know
how and we do know why!
Caprospinol Brain tissue
CSF
LogP=7.5
Lecanu, Yao, Teper, Yao, Greeson and Papadopoulos, 2004
Tillement, Lecanu, Yao, Greeson and Papadopoulos, 2006
Lecanu, Tillement, Rammouz, Tillement, Greeson and Papadopoulos, 2009
Lecanu, Rammouz, McCourty, Sidahmed, Greeson and Papaddopoulos, 2010
Tillement, Lecanu and Papadopoulos, 2011
Papadopoulos and Lecanu, 2012

20. 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.

21. Crossing the BBB, then what?
• Crossing where?
• To go where?
• Brain parenchyma structure
• Bound versus unbound fraction
• Plasma versus brain tissue macromolecules

22. What’s left to be done?
Mapping

23. Drug design

24. 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