Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials

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

“…Area under the curves and maximal tissue concentrations were similar for SP1049C and free doxorubicin in liver, kidney, heart, lung and plasma. SP1049C exhibited similar toxicology to conventional doxorubicin in toxicology studies in mice and rats (Alakhov et al, 1999). This is the first clinical trial of SP1049C.…”

“…For the covalently linked polymer formulation of doxorubicin, PK1 (mw 30 000), the phase I trial MTD of 320 mg m À2 on a 3 weekly regimen is much higher than that for doxorubicin or for SP1049C (Vasey et al, 1999). This was predicted by preclinical toxicology of PK1 which demonstrated an rodent LD 10 of approximately 150 mg m À2 compared to circa 50 mg m À2 for doxorubicin and SP1049C (Alakhov et al, 1999). For the liposomal doxorubicin formulation TLC D-99, the MTD in preclinical toxicology in rodents of approximately 100 mg m À2 translated well into the clinic where a clinical MTD of 75 -90 mg m À2 was seen (Lohri et al, 1991;Cowens et al, 1993;Swenson et al, 1998).…”

“…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.…”

Porphyrins Encapsulated into Pluronic F127 Micelles: Evaluating the Effect of the Central Metal and Substituents on the Photophysicochemical Properties in Water

“…[3] Due to their biocompatibility and high drug loading ability, several Pluronics have been approved by Food and Drug Administration (FDA) for oral or intravenous administration because they are widely employed as solubilizers, emulsifiers or coating agents. [1,[4][5][6] Porphyrins have poor solubility [7] and are also known to aggregate, [8] which affects their photophysical behaviour. The driving forces behind the aggregation of porphyrins are the cooperative formation of hydrogen bonds, van-der-Waals forces and the hydrophobic effects.…”