Acute toxicity of all-trans-retinoic acid loaded poly(L-lactide)/poly(ethylene glycol)-poly (L-lactide) microspheres in mice

Abstract

Previously, poly(L-lactide) microspheres containing retinoic acid (RA) had been prepared for parenteral administration in order to overcome "acute retinoic acid resistance." In this study, acute toxicities of RA-loaded microspheres were investigated in mice after the microspheres were injected intramuscularly. The maximum dose of RA in the microspheres was determined by considering both the injection volume and dispersion of microspheres in the vehicle media, and the close levels were determined to be 0, 90, 180, and 360 mg RA/kg. Mice were carefully observed for any clinical signs for 14 days, and gross observation of the organs was performed at 14 days. When a dose of 90 mg RA/kg was administered, no severe toxicities were observed; however, with the administration of 180 and 360 mg RA/kg, abnormal appearances of organs, such as discolor, atrophy, hemorrhage, etc., were observed. There were no mortalities or bone fractures observed at any of the doses, In our previous study of cancer treatment using the RA-loaded microspheres, the growth of herd and neck carcinoma in athymic nude mice was successfully inhibited at the dose of 100 mg RA/kg. It was concluded that a dose of approximately 90 mg RA/kg of the RA-loaded microspheres would be most desirable for cancer therapy. (C) 2002 Wiley-Liss, Inc.