Antitumor effects and pharmacokinetics of aclacinomycin A carried by injectable emulsions composed of vitamin E, cholesterol, and PEG-lipid.
The aim of this study was to prepare injectable emulsions of aclacinomycin A (E-ACM) and evaluate its acute toxicity, antitumor effects, and pharmacokinetics. In E-ACM, the surfactants were polyethylene glycol-lipid and cholesterol, and the oil phase was a vitamin E solution of ACM. The particle size distribution and the zeta potential of E-ACM were measured by the laser light dynamic scattering method. The ACM-loading efficiency was measured by using Sephadex G50 column chromatography. The acute toxicity, antitumor effects, and pharmacokinetics of E-ACM were studied in C57BL/6 mice bearing mouse murine histiocytoma M5076 tumors. The average diameter, zeta potential, and ACM-loading efficiency of E-ACM were 123.0 +/- 1.2 nm, - 12.67 +/- 1.35 mv, and 96.3 +/- 0.3% (n = 3), respectively. When stored at 7 degrees C in the dark for 1 year, the average diameter and ACM-loading efficiency of E-ACM changed into 126.3 +/- 2.3 nm and 97.4 +/- 0.8%, respectively, whereas 6.5 +/- 0.2% ACM decomposition was observed (n = 3). The plasma areas under the biodistribution curves (AUC)(0.03-48h) of E-ACM was significantly greater than that of free ACM (F-ACM). The heart, lung, and kidney AUC(0.03-48h) of E-ACM were significantly smaller than those of F-ACM whereas the liver and spleen AUC(0.03-48h) of E-ACM were not significantly different from those of F-ACM. The tumor AUC(0.03-48h) of E-ACM was significantly greater than that of F-ACM. E-ACM had lower acute toxicity and greater potential antitumor effects than F-ACM in M5076 tumor-bearing C57BL/6 mice. E-ACM is a useful tumor-targeting drug delivery system.
Wang
Junping
J
Department of Pharmaceutics, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan.
Maitani
Yoshie
Y
Takayama
Kozo
K
D015250:Aclarubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D000975:Antioxidants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002784:Cholesterol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000493:pharmacokinetics / Q000494:pharmacology; D004655:Emulsions / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D018219:Histiocytoma, Benign Fibrous / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D014810:Vitamin E / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D004337:Drug Carriers; D004655:Emulsions; D014810:Vitamin E; D011092:Polyethylene Glycols; D015250:Aclarubicin; D002784:Cholesterol