Mass Transport via Cellular Barriers and Endocytosis - Intracellular Delivery: Fundamentals and Applications - page 18

The above examples demonstrate the importance of endocytic pathways involved
in a nanoparticle's uptake. Determining which pathway is taken in target and non-
target cells will allow a greater understanding of the efficacy and specificity of the
nanoparticle, and hence, permit greater knowledge of the systemic clinical effects
of a drug from the cellular level. Future work in this direction will help to elucidate
which pathways are favored by emerging nanoparticle carrier technologies, and
what determines this selection.

3.3 Impact of Size and Shape on Uptake

The geometry of nanocarriers has been recently recognized as an important design
parameter for sculpturing the interactions of the system with biological substances
in addition to elemental composition (Roh et al. 2005 ; Akagi et al. 2010 ; Kennedy
et al. 2009 ; Godin and Touitou 2004 ), surface chemistry (Shi et al. 2002 ; Park et al.
2010a ; Satija et al. 2007 ), attachment of targeting ligands (Rawat et al. 2007 ;
Torchilin 2006 ) and mechanical properties (Yum et al. 2009 ; Cho et al. 2009 ).
Various studies point towards the importance of particle geometry in cellular func-
tions such as endocytosis, vesiculation, phagocytic internalization, transport in the
vasculature and adhesion to the target receptors (Mitragotri 2009 ; Lee et al. 2010a ;
Decuzzi and Ferrari 2007, 2008b ; Serda et al. 2009a, b ; Doshi et al. 2010 ; Champion
and Mitragotri 2009 ; Ferrati et al. 2010 ).
In vitro studies using phagocytic cells have shown that macrophages internalize
IgG-coated polystyrene spherical particles (200 nm-2 mm) through different intrac-
ellular delivery pathways. Nanospheres are internalized by clathrin-mediated endo-
cytosis, while polystyrene microspheres undergo classical phagocytosis, trafficking
more rapidly to the lysosomes (Koval et al. 1998 ; Rejman et al. 2004 ). In a study (Jin
et al. 2009 ) on the intracellular uptake rates of length-fractionated single-walled
carbon nanotubes (SWNT) 130-660 nm in diameter, the authors assessed single
particle tracking using their intrinsic photoluminescence. It was suggested that nano-
particles aggregate on the cell membrane to form a cluster size-sufficient to generate
a large enough enthalpic contribution for overcoming the elastic and entropic energy
barriers associated with membrane vesicle formation. The endocytosis rate for nano-
tubes was 1,000 times higher than for spherical gold nanoparticles (Jin et al. 2009 ).
Data from a study on Inter-Cellular Adhesion Molecule 1 (I-CAM-1) targeted
spherical and elliptical shaped polymeric nanoparticles, 100 nm-10 mm in size,
have shown the effect of carrier geometry on the rate of endocytosis and lysosomal
transport in endothelial cells. Discoidal particles had higher targeting specificity;
and larger micron-size particles had an extended residency in prelysosomal com-
partments. Submicron carriers trafficked to lysosomes more readily (Muro et al.
2008 ). In another work, spheres, elongated and flat particles with an effective diam-
eter of 500 nm-1 mm and different zeta potentials were found to differently affect
endothelial cells. Needle shaped particles significantly impaired spreading and
motility of the cells through induced disruption of the cell membrane (lasting for