PROTECTIVE EFFECT OF LIPOSOME ENCAPSULATION ON PACLITAXEL DEVELOPMENTAL TOXICITY IN THE RAT

Paclitaxel is an anticancer drug that has demonstrated severe embryoto xicity in chicks. This embryotoxicity is reduced by liposome encapsula tion of the drug. The current study was designed to evaluate the poten tial of liposome encapsulation for reducing paclitaxel embryotoxicity in rats. Wistar rats were treated with paclitaxel on day 8 of pregnanc y (plug = day 0) at doses of 0.67, 2.0, or 10.0 mg/kg intravenously. T he same doses of paclitaxel encapsulated in liposomes were administere d intravenously to other groups of animals. Control animals were given blank liposomes. Free paclitaxel produced maternal and embryotoxicity at 10.0 mg/kg with three of seven darns dying and resorption of all e mbryos in surviving dams. Liposome encapsulation at 10.0 mg/kg was not associated with maternal death and there were live fetuses on evaluat ion at term, although litter size was reduced and malformations occurr ed in surviving fetuses. At 2.0 mg/kg free paclitaxel, fetal weight wa s decreased and resorptions increased. Liposome encapsulation at 2.0 m g/kg produced litter results similar to those obtained in control anim als given empty liposomes. Malformations were prominent at 2.0 mg/kg f ree paclitaxel and at 10.0 mg/kg paclitaxel in liposomes and included exencephaly/anencephaly, ventral wall defects, facial clefts, anophtha lmia, diaphragmatic hernia, and defects of the kidney, cardiovascular system, and tail. Liposome encapsulation appeared to shift the develop mental response to paclitaxel such that 10 mg/kg encapsulated drug pro duced effects similar to 2.0 mg/kg free drug. These results may have i mplications for drug delivery of therapeutic agents used during human pregnancy. (C) 1997 Wiley-Liss, Inc.