Delivery to Intracellular Targets by Nanosized Particles - Intracellular Delivery: Fundamentals and Applications - page 76

of the complement system, in particular C3b, and other proteins known as opsonins,
adsorb onto the surface of the particles. This makes the particles susceptible to
phagocytosis by macrophages, especially those of the liver and spleen (Szebeni
1998 ). Thus intracellular delivery occurs, but only in a particular cell type. As
described below, there are some therapeutic scenarios in which intracellular deliv-
ery to macrophages is a useful strategy. However, it is often desirable to deliver
drugs to other cell types; for example cancer cells. Opsonization and interaction
with complement proteins can be reduced by decorating the surface of the drug
delivery system with end-attached hydrophilic polymer chains (Jeon et al. 1991 ).
Poly (ethylene glycol) (PEG) is the most commonly used hydrophilic polymer
(Woodle 1998 ). The resulting liposomes or nanoparticles persist in the circulation
after intravenous injection and are often referred to as “Stealth” particles. They are
then able to carry drug to other cell types. In particular, they are able to extravasate
into solid tumors by the “EPR” effect (Jain 1987 ) and also penetrate into infected
or inflamed tissue (Oyen et al. 1996 ).
Cell-specific delivery with colloidal drug carriers can be achieved by attaching
a ligand to the surface (ideally at the far end of a PEG chain). Antibodies and frag-
ments thereof have often been used for this purpose, although a smaller ligand has
some advantages. Small molecules that have been used for targeted drug delivery
systems include folic acid and RGD-containing peptides. Carrier systems that bind
to cell-surface receptors in this way will be internalized if receptor ligation nor-
mally leads to internalization and if the particle size is consistent with the size of
the endocytic vesicle formed (in non phagocytic cells generally 150-200 nm).
However, uptake by endocytosis or phagocytosis results in the carrier system being
sequestered in endosomes or phagosomes, which are then acidified and fuse with
lysosomes containing hydrolytic enzymes. Labile, hydrophilic drugs which cannot
escape from this compartment may be destroyed without reaching their target. In
response to this, pH-sensitive carrier systems which destabilize the endosome
membrane and allow the drug to reach the cytoplasm have been developed. These
are discussed in the section dealing the intracellular delivery of nucleic acids.

2 Interactions Between Colloidal Drug Carriers and Cells

As explained above, colloidal drug carriers have the potential to deliver their cargo
to the interior of cells under certain conditions. Whether intracellular delivery
occurs and to which compartment depends on the cell type and the composition of
the carrier. The interactions of nano-sized carriers with cells have recently been
reviewed by Hillaireau and Couvreur ( 2009 ). Whatever the mechanism of uptake,
it must be preceded by contact and binding between the particle and the cell sur-
face. Both hydrophobic and electrostatic interactions can occur, and increased bind-
ing is seen with charged particles, whether they are negatively or positively charged.
As explained in the section above, binding to the cell surface is enhanced by the
presence of proteins adsorbed on the cell surface. The presence of PEG or other