Detection and Description of Tissue Disease: Advances in the Use of Nanomedicine for Medical Imaging - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 246

extending the circulation time and improving uptake at the site of
interest.
The materials used in the preparation of liposomes must provide
structural strength and stability while at the same time reducing
interactions with proteins in order to extend the circulation time.
The stability and mechanical strength of liposomes is based on
a rigid bilayer that requires lipids with a high phase-transition
temperature. The bilayer is typically comprised of a common lipid
such as phosphatidyl choline and a mixture of the fatty acids stearate
and oleate. Addition of a small amount of cholesterol increases the
fluidity of the bilayer by modifying its crystalline nature. Keeping
the formulation simple is also beneficial, as mixtures of lipids with
diff erent phase transition temperatures can lead to instability in
vivo .
The rapid loss of liposomes from the blood in early studies
was attributed to both their size and interaction with clearing
mechanisms. Since larger liposomes (> 100 nm) are cleared more
quickly than smaller ones, maintaining diameters below this
threshold during the manufacturing process is critical. On the other
hand, larger liposomes can carry more payload, increasing their
potential efficacy as contrast agents. Reducing their interaction with
clearing mechanisms has required several iterations. The primary
clearance mechanism is the mononuclear phagocyte system (MPS),
also known as the reticuloendothelial system (RES). One early attempt
to evade this system was to replicate the outer coatings of red blood
cells by incorporating molecules such as the monosialoganglioside
GM1 into the liposome [6]. GM1 carries a negative charge, and it
was found that inclusion of other negatively charged molecules,
such as phosphatidylserine (PS) or phosphatidyl glycerol (PG), on
the outer shell of the liposome also reduced RES clearance, though
at high levels this advantage was off set by increased liver uptake,
possibly through interaction with Kupff er cells [7]. An additional
consideration is that directly accessible negative charges, such as
those provided by PS and PG, can increase interaction with proteins
whereas shielded negative charges, such as those on GM1, increase
the zeta potential of the nanoparticle but are not accessible to direct
interaction with proteins [8]. This proves to be a double advantage
as increasing the zeta potential also reduces aggregation, improving
the stability of the liposomes during manufacture, storage, and after
injection. More recently, GM1 has been replaced by polyethylene