Biomedical Engineering Reference
In-Depth Information
Influence of carrier geometry on intracellular delivery can be explained in part
by different effects that particles with variable sizes and shapes may have on mem-
brane remodeling. This process, important in endocytosis, vesiculation and vesicle
transport through endoplasmic reticulum and Golgi apparatus, protein sorting and
other vital cellular functions, is highly dependent on membrane curvature, naturally
affected by some proteins through curvature-mediated attractive interactions
(Reynwar et al.
2007
). The formation of a coordinated actin cup is crucial to initial-
izing phagocytosis and probably follows the local geometry of the particle. Because
actin remodeling is a metabolically intensive process, it may provide the basis for
the fact that particles requiring only gradual expansion of actin rings are phagocy-
tosed more effectively (Champion and Mitragotri
2006
).
Recent developments in micro and nano-fabrication of shape and size-specific
vectors, following rational design, show great promise in overcoming one of the
chief constrains in drug delivery - the specific delivery into the diseased cells.
Further incorporation of stimuli-responsive biomaterials into the rationally designed
vectors will enable the development of conceptually novel drug delivery systems.
3.4
Receptor-Mediated Uptake of Nanoparticles
One of the major problems encountered with existing therapeutics is their harmful
effects on healthy tissues. To overcome these systemic effects, nanocarriers are
intended to concentrate the drug selectively at the lesion. This is achieved through
targeted delivery of therapeutics via encapsulation in nanocarriers that are surface-
coated with lesion-specific ligands.
Targeting moieties are, predominately, focused on receptors or antigens that are
overexpressed on the plasma membrane of diseased cells or adjacent vasculature
(Fuchs and Bachran
2009
; Cho et al.
2008
). Interaction of these targeting moieties
or ligands with their respective receptors aids in the internalization of the nanocar-
riers into the cells through various processes such as receptor-mediated endocyto-
sis, phagocytosis, macropinocytosis, etc. Several targeting ligands have been
examined and tested for the delivery of nanocarriers into cells.
Molecular signatures on the cell surface can be identified and used as a target. One
such technique to reveal new and unique markers on cell surface is
in vivo
phage
display. Using this technology, various tumor blood vessel endothelial markers such
as Aminopeptidase N (Pasqualini et al.
2000
), 78 kDa Glucose-Regulated Protein
(GRP78) (Wood et al.
2008
), integrins including a
v
b
3
(Pasqualini et al.
1997
) and
a
v
b
5
(Nie et al.
2008
), and CRKL (Mintz et al.
2009
) have been exposed. Other
markers, specific for lung vasculature (targeted by CGSPGWVRC peptide) (Giordano
et al.
2008
) and white adipose tissue (prohibitin) (Kolonin et al.
2004
) have also been
described. These markers can be exploited for inducing targeted apoptosis when
conjugated with proapoptotic peptides, such as D-(KLAKLAK)
2
(Ko et al.
2009
).
Some of the main membrane targets and related delivery systems are summarized
in Table
1
and discussed below. Folate (Vitamin B9) is an essential vitamin for
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