The brain is protected by the blood-brain barrier (BBB), which regulates the transport of substances from the blood into the brain. The BBB prevents 98% of drug candidates from reaching the central nervous system (CNS) to treat diseases. Several major diseases require brain treatment, including neurodegenerative disorders like Parkinson's and Alzheimer's, as well as CNS diseases like schizophrenia, epilepsy, and bipolar disorder. For drugs to treat brain diseases, they must be able to cross the BBB.

1. The brain is protected by a barrier of cells that tightly
regulates the transport of substances from the blood into this
organ. The essential protective function of the blood-brain
barrier (BBB) is also a red light for 98% of drug candidates
for the treatment of the central nervous system (CNS).
The capacity of a drug to cross the BBB is crucial, as several
major diseases require brain treatment. These include
neurodegenerative disorders such as Parkinson’s and Alzheimer’s,
but also CNS diseases, such as schizophrenia, epilepsy, and
bipolar disorder. Brain cancer, HIV, and some aspects of obesity
can also be included as pharmaceutical targets inside the brain.
pwvpswmpprht THRre
Inmunogenicity
Control THRre
Intravital two-photon microscopy images of the brains of mice after
injection of naked QDs or QDs labeled with retro-enantio peptide.2
Protease Resistance
meritxell.teixido@irbbarcelona.org
Antibodies
Therapeutic
Peptides
siRNA, DNA,..
Proteins
Small Molecules
Polimeric Nanoparticles
Two approaches with different strategic
points:
• Viral vectors for gene therapy, allow the
BBB transport of genetic material, even
the whole gene.
• Polimeric nanoparticles allow the BBB
transport of cDNA, antibodies, small
molecules or proteins and could be
interesting for their protection of the
cargo during the transport.
• It is important that the cargo is not
prematurely release until it reaches the
CNS.
Viral Vector
* Malakoutikhah M.; Teixidó, M. ; Giralt, E. Angew. Chem.
Int. Ed. 2011, 50, 7998-8014.
Oller-Salvia,B. et al. Chem Soc.Rev. 2016,DOI: 10.1039/C6CS00076B
Carrier-mediated
transport
Adsorptive-mediated
transyctosis
Transcellular
passive diffusion
Receptor-mediated
transcytosis
Inside the nanoambulances we can put different types of drug candidates
that could be interesting for the treatment of CNS disorders but can not
cross the BBB unaided.
Over recent years we have worked extensively on the
use of peptides as BBB-shuttles (or Nanoambulance
drivers) to carry drugs that cannot cross the BBB
unaided and therefore cannot reach the CNS.1
Patent: E. Giralt and M. Teixidó PCT/ES2007/000499; WO/2008/025867-
WO-ES-USA.
Publication: Diketopiperazines as a tool for the study of transport across
the blood-brain barrier (BBB) an their potencial use as BBB-shuttles.
Teixidó, M.; Zurita, E.; Malakoutikhah, M.; Tarrago T.; Giralt, E. JACS,
2007, 129, 11802-11813.
X2
N
N
O
O R1
R3
R2
X1
Small
Molecules
Small Molecules
(N-metil-Phe)x-CONH2
Publications:
* Malakoutikhah, M. et al. J. Med. Chem. 2010, 53, 2354-2363.
* Malakoutikhah, M. et al. J. Med. Chem. 2008, 51, 4881-4889.
(PhPro)x-CONH2
Small molecules Patent: E. Giralt, M. Teixidó, M. Malakoutikhah
Compounds that act as a vehicle for delivery through the
blood-brain barrier and charge delivery vehicle constructions.
PCT/ES2010/00930.
Publication: Arranz-Gibert, P. et al. JACS, 2015
137, 7357-7364.
Publication: Delivery of gold nanoparticles to the brain as a
potential tool for the treatment of neurodegenerative diseases.
Prades, R.; Guerrero, S.; Araya, E.; Molina, C.; Salas, E.; Zurita,
E.; Selva, J.; Egea, G.; López-Iglesias, C.; Teixidó, M.; Kogan,
M.J.; Giralt, E. Biomaterials, 2012, 33, 7194-7205.
Drug THRPPMWSPVWP
Patent: E. Giralt, M. Teixidó, R. Prades. Protease-resistant
compouds useful as shuttles through the blood-brain barrier and
shuttle-cargo constructs. WO2013/127829 A1.
Publication: Prades, R.; Oller-Salvia, B.; Schwarzmaier, S. M.;
Selva, J.; Moros, M.; Balbi, M.; Grazu, V.; de La Fuente, J. M.;
Egea, G.; Plesnila, N.; Teixidó, M.; Giralt, E. Angew. Chem. Int.
Ed. 2015, 54, 3967-3972.
Half-life
> 24 h
> 24 h
8 min
3 h
> 24 h
MiniAp-4
• Patent: E. Giralt, M. Teixidó, B. Oller,
PCT/EP2014/064173
• Publications:
* Oller-Salvia, B.; Teixidó, M.; Giralt, E.
Biopolymers-Peptide Science, 2013, 100,
675-686.
* Oller-Salvia, B. et al. Angew. Chem.
Int. Ed. 2015, 55, 572-575.
Drug