Abstract
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.
Highlights
This paper investigates anti-tumour effects of doxorubicin (DOX) and epirubicin (EPI) formulated with Pluronic L61, P85 and F108 copolymers with varying hydrophobicity, using s.c. drug-sensitive and -resistant murine myelomas Sp2/0 and Sp2/oDNR, and leukaemia P388
The critical micelle concentrations (CMCs) of L61, P85 and F108 were determined using a pyrene solublisation technique previously described by Kabanov et al (1995)
One major result of this work is that Pluronic copolymers significantly increase the anti-tumour effects of anthracycline antibiotics in vivo observed in conditions of high tumour inoculum
Summary
Pluronic L61, P85 and F108 (abbreviated below as 'L61', 'P85' and 'F108' respectively) were purchased from Serva (Germany) and used without further purification They were dissolved at various concentrations (0.1 to 1%) in phosphatebuffered saline (PBS) at 4°C and sterilised by filtration through a 0.2 gm filter. Drug/copolymer compositions were obtained by dissolving EPI (Farmitalia Carlo Erba, Milan, Italy) or DOX (Farreign, Moscow, Russia) in the copolymer solutions. These compositions were incubated for 30 min at 37°C before administration to mice. The partitioning coefficients, P, were determined from the dependencies of drug fluorescence at Aem = 547 nm on the copolymer concentration using the linear plots: Ima -I (1)
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