Formation of complement-activating particles in aqueous solutions of Taxol: possible role in hypersensitivity reactions

We reported earlier that the anticancer drug paclitaxel (Taxol) activated t he complement (C) system in human serum in vitro, raising the possibility t hat C activation might play a role in the ill-understood hypersensitivity r eactions (HSRs) to this drug [J, Natl. Cancer Inst. 90 (1998) 300], In purs uing the mechanism of C activation by Taxol, the present study provided evi dence that dilution of the injection concentrate in aqueous solvents led to the formation of micelles and needle-like structures, both of which caused C activation in vitro. Micelles were formed mainly from Cremophor EL (CrEL ), the nonionic emulsifier vehicle of paclitaxel, whose level in Taxol infu sion exceeded its critical micelle concentration by at Least 400-fold. CrEL micelles were shown by quasi-elastic light scattering and cryo-transmissio n electron microscopy (cryo-TEM) to be spherical with diameters in the 8-22 nm range; however, de novo formation of 50-300 nm microdroplets following incubation with human plasma suggested further fundamental structural trans formation in blood. The needle-like structures extended to the multimicron range and were shown by electron diffraction to be crystalline paclitaxel, Taxol-induced C activation was manifested in varying rises of serum C3a-des arg, iC3b and SC5b-9. The causal role of CrEL micelles in C activation was demonstrated by the fact that filtration of aqueous solutions of Taxol or p ure CrEL via 30-kDa cutoff filters eliminated, while the filter retentate r estored C activation. C activation by Taxol was also inhibited by 10 mg/ml human immunoglobulin (IVIG). If proven clinically, HSRs to Taxol may repres ent a hitherto vaguely classified adverse drug reaction recently called C a ctivation-related pseudoallergy (CARPA) [Circulation 99 (1999) 2302]. (C) 2 001 Published by Elsevier Science B.V.