Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity

Abstract

Summary 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 Sp2/0DNR 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 (TIC> 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.

Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer

“…Of particular note is the evidence of antitumour activity of SP1049C in doxorubicin-resistant tumours (Batrakova et al, 1996) and in multiple drug resistance (MDR) cells (Venne et al, 1996;Alakhov et al, 1999). There appear to be several potential mechanisms, including inhibition of drug efflux transporters, abolishment of drug sequestration in acidic compartments, inhibition of the glutathione (GSH)/glutathione (GST) detoxification system and reduction of ATP selectively in MDR cells (Venne et al, 1996;Batrakova et al, 2001;Kabanov et al, 2002).…”

“…This improved efficacy of SP1049C in vitro appears to be due to increase in cellular drug influx, inhibition of energy-dependent drug efflux and changes in intracellular drug trafficking (Venne et al, 1996). Compared to doxorubicin, SP1049C demonstrated superior antitumour activity in vivo in multiple animal tumour models and activity in doxorubicin-resistant settings (Batrakova et al, 1996;Alakhov et al, 1999). The plasma pharmacokinetics and tissue distribution of doxorubicin when administered as SP1049C have been studied in normal and tumour-bearing mice.…”

Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1- and MRP2-mediated transport

“…It is not known whether it is a substrate for MDR1 Pgp (and therefore acts as a competitive inhibitor) or blocks MDR1 Pgp by another mechanism. Amphiphilic block copolymers have a low critical micelle concentration (cmc); the cmc for Pluronic L61 is 0.02% (w/v) (Batrakova et al, 1996). As we see a major inhibition of MDR1 Pgp below 0.02% (w/v) (Figure 1), we conclude that the monomeric form of Pluronic L61 is the effective species in inhibiting transport, in agreement with earlier suggestions by Miller et al (1997) and Batrakova et al (1998) for Pluronic analogues, and Nerurkar et al (1997) for other neutral surfactants.…”

A combination of poloxamers increases gene expression of plasmid DNA in skeletal muscle

“…We have previously demonstrated that lipophilic poloxamers dramatically increase membrane permeability and drug release from endosomes in multidrug-resistant (MDR) tissue phenotypes, such as drugresistant tumors, brain microvessel endothelium and small intestine epithelium. [28][29][30][31][32] All these tissues are known to express high levels of ATP-dependent transporters, such as P-glycoprotein, MRP and H + ATPase. 33 The increased ATPase activity in the above cells results in abnormally high pH gradients and is related to an enhanced tendency to phase transitions in the lipid membrane.…”