Biomedical Engineering Reference
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and electrophoretic mobility failed to induce significant C activation
[78]. These observations suggest that C activation is specific to the
structure of acidic groups, and negative surface or zeta potential
per
se
, may not necessarily imply C activating potency.
Table 11.4
Observations on C activation by liposomes
in vitro
•
All types of liposomes can activate C, with neutral small unilamellar
vesicles (SUV) being the least reactogenic.
1
•
The sensitivity of human serum for C activation by diff erent liposomes
shows substantial individual (human to human) variation.
•
A serum sensitive to a certain liposome is not necessarily sensitive to
other liposomes: the individual (human to human) sensitivity variation
is large and formulation specific.
•
C activation may proceed on both the classical and the alternative
pathways.
•
Activation triggers include the binding to the vesicles of IgG, IgM, CRP
2
,
C1q, C3, and potentially, MBL
3
and ficolin.
•
C activation is enhanced by
positive or negative surface charge
increasing liposome size in the 70-300 nm range
inhomogeneity
endotoxin contamination
presence of aggregates
presence of doxorubicin or similar drugs in the extraliposome
medium that can bind to liposomes and induce aggregation and/
or surface modification
presence of high amounts of cholesterol in the bilayer membrane
(e.g., 71 mole %)
PEGylation of liposomes by insertion of the negatively charged
PEG-PE, but not with insertion of the neutral PEG-DS
4
•
C activation can be inhibited by known C inhibitors.
5
1
Egg PC SUV were injected in 10 humans (6 weekly injections) each at a dose
up to 300 mg/kg without indication of C activation (Shmeeda, Barenholz,
and Chaiejceck, unpublished).
2
CRP, C reactive protein.
3
MBL, mannose binding lectin.
4
DS, 3-polyethyleneglycol-methoxy polyethylene glycol-oxycarbonyl-3-
amino-1,2- propandiol distearoyl ester.
5
For example, by soluble C receptor type I (sCR1) [89, 90].
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