Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity.
The chemosensitising effects of poly(ethylene oxide)-poly(propylene oxide)-poly-(ethylene oxide) (PEO-PPO-PEO) block copolymers (Pluronic) in multidrug-resistant cancer cells has been described recently (Alakhov VY, Moskaleva EY, Batrakova EV, Kabanov AV 1996, Biocon. Chem., 7, 209). This paper presents initial studies on in vivo evaluation of Pluronic copolymers in the treatment of cancer. The anti-tumour activity of epirubicin (EPI) and doxorubicin (DOX), solubilised in micelles of Pluronic L61, P85 and F108, was investigated using murine leukaemia P388 and daunorubicin-sensitive Sp2/0 and -resistant Sp2/0(DNR) myeloma cells grown subcutaneously (s.c.). The study revealed that the lifespan of the animals and inhibition of tumour growth were considerably increased in mice treated with drug/copolymer compositions compared with animals treated with the free drugs. The anti-tumour activity of the drug/copolymer compositions depends on the concentration of the copolymer and its hydrophobicity, as determined by the ratio of the lengths of hydrophilic PEO and hydrophobic PPO segments. The data suggest that higher activity is associated with more hydrophobic copolymers. In particular, a significant increase in lifespan (T/C> 150%) and tumour growth inhibition (> 90%) was observed in animals with Sp2/0 tumours with EPI/P85 and DOX/L61 compositions. The effective doses of these compositions caused inhibition of Sp2/0 tumour growth and complete disappearance of tumour in 33-50% of animals. Future studies will focus on the evaluation of the activity of Pluronic-based compositions against human drug-resistant tumours.
Batrakova
E V
EV
Moscow Institute of Biotechnology, Inc., and Russian Research Center of Molecular Diagnostics and Therapy.
Dorodnych
T Y
TY
Klinskii
E Y
EY
Kliushnenkova
E N
EN
Shemchukova
O B
OB
Goncharova
O N
ON
Arjakov
S A
SA
Alakhov
V Y
VY
Kabanov
A V
AV
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015251:Epirubicin / Q000008:administration & dosage*; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008823:Micelles; D009101:Multiple Myeloma / Q000188:drug therapy; D009368:Neoplasm Transplantation; D011060:Poloxalene / Q000031:analogs & derivatives*
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D015251:Epirubicin; D004317:Doxorubicin; D011060:Poloxalene