Complement activation by polyethoxylated pharmaceutical surfactants: Cremophor-EL, Tween-80 and Tween-20

Immunosafety analysis of pharmaceutical surfactants is an important step in understanding the complex mechanisms by which they induce side effects in susceptible patients. This paper provides experimental evidences that polyethoxylated surfactants, Cremophor-EL and Tween-80, also known as Polysorbate-80, activate the complement system in vitro, in normal human serum and plasma. They appeared to be more efficient reactogens than their structural homolog, Tween-20. Cremophor-EL and Tween-80 promoted the generation of biologically active complement products, C3a, C5a and C5b-9. Consistently, Paclitaxel and Taxotere (Docetaxel), pharmaceuticals formulated in Cremophor-EL and Tween-80, activated the complement system in similar extent. Moreover, comparison of serum reactivity against the drug-loaded and drug-free formulations exhibited a significant linear correlation. Taken together, these results are consistent with the hypothesis that therapeutic side effects, such as acute hypersensitivity and systemic immunostimulation, caused by intravenous nanomedicines containing polyethoxylated detergents such as Cremophor-EL and Tween-80, can be attributed to complement activation-derived inflammatory mediators

Wissenschaftliche Grundlagen und gesetzliche Moeglichkeiten der forstlichen Beteiligung bei der Raumplanung, insbesondere bei der Regionalplanung, unter besonderer Beruecksichtigung der Ergebnisse von forstlichen Meinungsumfragen

TIB: AC 8753 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Flow cytometric analysis of supravesicular structures in doxorubicin-containing pegylated liposomes

In an attempt to develop a quantitative assay for supravesicular structures (SVS) - such as aggregates, fused liposomes or solid lipid particles - in liposome preparations, forward vs. side scattering of liposomal doxorubicin (Doxil/Caelyx) was analyzed by flow cytometry. Based on calibration with fluorescent latex beads, the size resolution was between about 500 and 1000nm. Caelyx, just as structurally matched empty liposomes (Doxebo) produced dot plots clearly distinguishable from background, suggesting the presence of SVS in the above size region. A comparison of gated areas on the scattergrams obtained for different Caelyx preparations showed differences between current and expired samples, implying that SVS formation may be storage-time-dependent. Incubation of doxorubicin with Doxebo in a free drug and lipid concentration range that corresponds to that in Caelyx also led to varying SVS patterns, raising the possibility that free doxorubicin in Caelyx might contribute to SVS formation. Dynamic light scattering and transmission electron microscopic analysis of liposomes following gaiting and sorting of >500nm particles from Caelyx confirmed the presence of SVS, providing independent evidence for their stable existence. Based on a rough estimation, the amount of SVS in Caelyx is some 60 billionth part of all liposomes. These observations raise the possibility that the presence of an exceedingly small fraction of >500nm particles may be an intrinsic property of PEGylated small unilamellar liposomes, and that the described FACS analysis may be developed further as a quality assay for liposomal homogeneity