Effects of fluidity and vesicle size on antitumor activity and myelosuppressive activity of liposomes loaded with daunorubicin.
The effects of fluidity and vesicle size on the antitumor activity and myelosuppressive activity of liposomes loaded with daunorubicin, an anthracycline antitumor drug, were investigated in Yoshida sarcoma-bearing rats. Liposomes composed of egg phosphatidylcholine (EPC) or hydrogenated egg phosphatidylcholine (HEPC), cholesterol and dicetyl phosphate in a molar ratio of 5:4:1 were injected intravenously into rats 5 d after subcutaneous inoculation of Yoshida sarcoma. At non-effect dosage in free drug, HEPC-liposomes with a diameter of 58 or 142 nm showed the greatest inhibitory effect against Yoshida sarcoma among liposomes tested, whereas larger ones (272 nm) had weaker effect. Small EPC-liposomes (57 nm) had no effect. Larger HEPC-liposomes (especially 142 nm) greatly decreased the number of peripheral white blood cell compared with free drug at the same dose, indicating relatively strong myelosuppressive toxicity. However, small EPC- and HEPC-liposomes with a diameter of 57 and 58 nm, respectively, showed toxic effects comparable to that of free drug. Examination of the dose-dependency of therapeutic effects and toxicity indicated encapsulation of daunorubicin in the small HEPC-liposomes to enhance the therapeutic index about 3 times that of free drug. These findings indicate the possibility of using small HEPC-liposome as a drug carrier for targeting solid tumors.
Nagayasu
A
A
Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Shimooka
T
T
Kinouchi
Y
Y
Uchiyama
K
K
Takeichi
Y
Y
Kiwada
H
H
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D003630:Daunorubicin / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D008081:Liposomes; D008297:Male; D008560:Membrane Fluidity; D051381:Rats; D012517:Sarcoma, Yoshida / Q000188:drug therapy
D004337:Drug Carriers; D008081:Liposomes; D003630:Daunorubicin