Chemistry Reference
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neurotrophins but themselves are active on neuronal cells via the incorporated
omega-3 potentiating function. Monoolein is a monoglyceride lipid that allows
the production of various types of biocompatible carriers for nondestructive
peptide and protein administration (Caboi et al., 2001; Larsson, 1989). The use
of a PEGylated lipid in the design of the nanovector compositions is expected
to increase the steric stability and slow down the elimination of the carriers
by the reticuloendothelial endoplasmic system. To model the neurodegenera-
tion phenomenon with human neurons, the neuroblastoma cell line SH-SY5Y
is differentiated by sequential treatment with retinoic acid and BDNF. It is
established that the remedy of the human neuroblastoma cells with EPA-
containg lipid nanoparticles induces a neuronal phenotype with neurite growth
following intense TrkB receptor expression.
11.2
PEPTIDE TARGETING AND DELIVERY
11.2.1
Choice of Therapeutic Peptide with Neurotrophic Properties
Neurotrophins are peptide molecules that ensure the development and sur-
vival of neurons (Bemelmans et al., 1999; Burdick et al., 2006; Jaboin et al.,
2002 ). They exert signifi cant control over the life and death of the neuronal
cells (Zuccato and Cattaneo, 2009). Among these modulators, the BDNF is a
major regulator of the neuronal plasticity, survival, and differentiation (Fuma-
galli et al., 2006; Matsumoto et al., 1995; Vogelin et al., 2006). Studies have
shown its involvement in the pathogenesis of neurodegenerative diseases such
as the Huntington's disease, Alzheimer's disease, Parkinson's disease, as well
as depression (Table 11.1). The peptide BDNF thus appears as a promising
therapeutic candidate against neurodegenerative disorders. So far, the short
plasma half-life and the low bioavailability of the molecule have limited its
therapeutic development. However, the encapsulation in lipid nanocarriers
should overcome the problems of its degradation after administration. The
vectorization should permit to achieve a longer plasma half-life and better
controlled biodistribution and release.
Crystallographic structural data (Fig. 11.1) have shown that neurotrophins
are biomolecules that exist exclusively as dimers of about 27 kDa (Robinson
et al., 1995). The neurotrophic peptides have a common structural motif of
three disulfi de bonds. The homologous sequence encompasses around 50% of
all amino acid residues. Each monomer, consisting of about 120 amino acids,
involves three pairs of antiparallel
sheets connected to four loops. The neu-
rotrophins are active in the form of homodimers and operate by binding to
two types of brain receptors (Pattarawarapan and Burges, 2003; Schramm
et al., 2005). The common (lower affi nity) receptor, the p75
NTR
protein, is a
member of the family of tumor necrosis factor receptors.
The second type of receptor is the greater affi nity receptor, tropomyosin-
related kinase (Trk), belonging to the family of tyrosine kinase receptors. The
β
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