Chemistry Reference
In-Depth Information
Figure 8.3 Schematic representation of the effects of liposome and nanoparticle PEGylation.
capacity of a dye, outperforming optimized formulations composed of naturally
occurring phospholipids. In addition, the composition of the PEGylated chains can
be tuned to control the effect of the polymer modification (Allen et al. 1991;
Maruyama et al. 1991). The improvements in circulation and biodistribution due
to PEGylation have been attributed to the hydrated polymer layer surrounding
the modified liposomes (Fig. 8.3). The hydrated coating prevents the nonspecific
phagocytosis of liposomes (Klibanov et al. 1990), prevents plasma proteins from
marking the liposomes for elimination (Senior et al. 1991), and suppresses uptake
of the particles by the liver and spleen (Illum and Davis 1984), both major pathways
of particle elimination by the reticuloendothelial system.
The benefits of improved circulation time and altered biodistribution have import-
ant consequences for targeted drug delivery of nanocapsules. The enhanced
permeability and retention (EPR) effect, for instance, causes nanoparticles and
macromolecules to accumulate in malignant tumors at much higher concentrations
than in normal cells (Saltzman 2001). The EPR effect occurs because the vasculature
of tumors is generally very porous or “leaky,” especially to nanoparticles and macro-
molecules, which then leak into the tumors rather than continuing to circulate in
the bloodstream (Dvorak et al. 1988). PEGylated liposomes take advantage of this
effect, as shown by Papahadjopoulos and coworkers (1991) in landmark work
with liposomes encapsulating the anticancer drugs doxorubicin and epirubicin.
The liposome-encapsulated drugs showed significant improvement in antitumor
activity because the carrier liposomes preferentially accumulated in the tumors,
whereas free drug or nonPEGylated liposomes were eliminated from the body
before significant amounts could reach the cancerous cells.
In addition to the passive targeting of tumors due to the EPR effect, active target-
ing of PEGylated liposomes has also been successful. A study by Huwyler and
coworkers (1996), for example, showed that coupling a monoclonal antibody to
the surface of PEGylated liposomes resulted in significant transfer of the liposomes
across the blood-brain barrier, which is difficult to achieve otherwise. The attached
