Biomedical Engineering Reference
In-Depth Information
In keeping with the above conclusions, liposomes in which the
negatively charged PEG-DSPE was replaced with near-neutral PEG-
DS showed lack of (or minimal) cardiopulmonary reactivity in pigs
[87].
Regarding the impact of doxorubicin or similar drugs that can
bind to and aggregate liposomes or lipids, it seems important to
consider that the number of liposomes introduced in the circulation
upon each treatment (in the order of 10
13
Doxil liposomes)
represents substantial phospholipid bilayer surface (in the order of
~10-30 cm
2
). Thus, small changes in liposome surface can translate
to large changes in overall surface, which may have a major biological
impact. In the case of Doxil, the presence of low curvature oval,
elongated (coff ee-bean-like), or irregular liposomes and aggregates
in commercial vials [87], may have a significant impact on the
surface area of vesicles exposed to blood. This suggestion, taken
together with a recent report on the significant influence of minor
diff erences in liposome surface curvature on C activation via the
classical pathway (via IgM binding) [73] raises the possibility that
doxorubicin could indirectly contribute to C activation via modifying
the surface of liposomes.
11.4.2
Mechanism of Liposome Reactions and Its
Individual Variation
Among the symptoms of HSRs (Table 11.3), there is no single,
or unique, symptom that would be liposome-specific. Like many
micellar and particulate drugs, radiocontrast agents, monoclonal
antibodies, and enzyme therapeutics, liposomes are “only” triggers
of a complex chain of events that involves (1) C activation, (2)
binding of anaphylatoxins to their specific receptors on mast
cells, basophils, and other anaphylatoxin-receptor-positive cells
(macrophages), (3) activation of the latter cells to release a host of
vasoactive mediators, including histamine, tryptase, PAF, LTB
2
, LTB
4
,
LTC
4
, LTD
4
,
LTE
4
,
TXA
2
, PGD
2
and TXD
4
[57] (Figure 11.4). Some
of these mediators (e.g., PAF, histamine, tryptase and TXA
2
) are
preformed and liberated from the cells immediately upon activation,
while others are
de novo
synthesized and, hence, are liberated
slower [57]. This diff erential, multistep release of allergomedins
from anaphylatoxin-responsive cells may explain the individual
variation in the start of clinical symptoms. Specifically, the activation
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