Sp1049c

SP1049C is a doxorubicin-loaded Pluronic® copolymer micelle formulation developed by Kaba-nov's group and Supratek Inc. (Montreal, Canada). In this formulation, doxorubicin is physically encapsulated in micelles assembled from two different types of Pluronic® copolymers, L61 and F127 in a 1:8 w/w ratio.26 In October 2005, SP1049C was granted orphan drug status by the FDA for the treatment of oesophageal carcinoma based on results from the phase I study; meanwhile, its phase II clinical trial results are currently under final review. In contrast to NK911, the phase I clinical trial of SP1049C deliberately recruited patients with cancers that were refractory following conventional treatment and patients with previous anthracycline treatment.81 This is due to the established chemosensitizing effect of SP1049C against multi-drug resistant (MDR) cancers, an effect that is attributed to its Pluronic® copolymer composition.

The Pluronic® copolymers are the class of copolymers that have been most widely evaluated and employed in pharmaceutical applications. Studies have indicated that Pluronic® copolymers having an hydrophile-lipophile balance (HLB) of less than 19 and a moderate molecular weight are most effective in overcoming MDR.34 In a separate study, Pluronic® L61 that has an HLB value of 7 was found to be the most effective chemosensitizer among other Pluronic® copolymers.26,34 Doxorubicin loaded in Pluronic® L61 micelles was found to be 2-3 orders of magnitude more toxic than conventional doxorubicin when evaluated in a range of drug-resistant cancer cells (e.g., MCF-7/ADR breast carcinoma, SKVLB ovarian carcinoma, KBV oral epithelial carcinoma, LoVo/ Dox colon adenocarcinoma, P388-Dox murine leukemia cells, SP2/0Dox myeloma as well as others).26 Furthermore, mechanistic studies have shown that it is the unimers rather than the micelles that are responsible for the reversal of MDR.26,34 More details on the mechanisms and effects of Pluronic® as chemosensitizers are given in Section 17.4.

Despite the effectiveness of micelles formed from only Pluronic® L61, the hydrophobicity of the copolymer results in unfavorable stability issues. Phase separation and micelle aggregation leading to microembolic effects have been observed in preliminary in vivo toxicity studies of the L61 formulation. Kabanov and co-workers solved this problem by introducing a higher molecular weight and more hydrophilic Pluronic® copolymer (F127) into the L61 micelle formulation. By varying the ratio of the L61 to the F127 copolymer, it was found that at 0.25 w/w% L61 (i.e., effective dosing concentration of L61) and 2.0 w/w% F127, the Pluronic® micelles maintained their effective diameter of 22.4 nm with no aggregation.26 In addition, the IC50 of doxorubicin loaded in the L61/F127 micelles was similar to that of the L61 formulation. Therefore, the optimized SP1049C formulation utilized for the clinical studies contains 2.0 mg/mL doxorubicin, 2.5 mg/ mL L61, and 20 mg/mL F127 in 0.9% sodium chloride.81

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