ABSTRACT
Acknowledgments ............................................................................................ 500
References ........................................................................................................ 500
Many drugs cannot unfold their full potential because of poor solubility, low chemical
stability, unspecific toxicity, or unfavorable pharmacokinetics. Often, their inability
to recognize their target cells and to cross cellular barriers further limits their
application. Incorporation into drug-delivery systems, including natural and synthetic
polymer nanoparticles and surfactant-based systems such as liposomes and micelles,
can largely overcome these disadvantageous properties and suppress recognition by
cellular efflux systems. Liposomal formulations1,2 have been most successful so far as
they can function as a reservoir for both hydrophilic compounds entrapped within the
aqueous lumen and hydrophobic drugs localized in the lipid bilayer. Moreover,
liposomes allow for the transport of high drug payloads, and as many lipids used are,
or at least resemble, natural compounds, their administration is expected to be low
risk. Small liposomes bearing a net neutral charge and including lipids with a high
phase transition temperature or cholesterol have been found to circulate for hours, but
breakdown mediated by various components of the blood plasma may cause
premature release of the encapsulated drug. Furthermore, recognition of the carrier by
macrophages in the liver and spleen results in its removal from circulation. The
natural homing ability to the reticuloendothelial system (RES) is advantageous when
this cell population is addressed; however, it constitutes a serious hurdle when
targeting other cells. Substantial blockage of the RES has been reached with so-called
sterically stabilized or stealth liposomes containing polyethylene glycol (PEG)-
modified lipids.3 PEG coating reduces the adsorptive binding of proteins and inhibits
the uptake by macrophages. Simultaneously, the porous structure of the endothelial
cell layer of tumors and inflamed tissues or organs enables the passive targeting of
these long-circulating liposomes. However, there is little extravasation of liposomes
from the blood into tissues fed by continuous, nonfenestrated capillaries, such as
muscle, skeleton, skin, and the central nervous system.
