Abstract A116: Stable and efficient delivery of docetaxel by micelle encapsulation using a tripodal cyclotriphosphazene amphiphile.
Authors: Sohn Youn Soo , Jun Yong Joo , Lee Hwa Jeong 
Published: June 2012

Docetaxel, a semi-synthetic analogue of paclitaxel, is currently one of the most important chemotherapeutic agents, since it is clinically very efficacious against a variety of tumors. Docetaxel is known to be more potent than paclitaxel, but its photo-instability causes more inconveniences in drug storage and patient treatment compared with paclitaxel. Docetaxel is solubilized in aqueous solution by formulation using a surfactant polysorbate 80 (Tween 80). Docetaxel in such a formulation named Taxotere is known to cause several adverse effects. Therefore, a great deal of efforts has been devoted to replace the surfactant polysorbate 80 with polymeric micelles composed of linear amphiphilic block copolymers. However, most of the linear block copolymers exposed commonly a few critical problems for practical application, and in particular, docetaxel-loaded polymeric micelles are not stable enough to hold the drug component in the micelle core and drug precipitates mostly within 24 h after drug loading.

We have recently developed a novel class of cyclotriphosphazene micelles of a general formula [N=P(X)(Y)]3 prepared by stepwise substitutions of cyclic chlorophosphazene [N=PCl2]3 with equimolar hydrophilic (X) and hydrophobic (Y) nucleophiles in cis-nongeminal way. In particular, the tripodal amphiphiles with a methoxy poly(ethylene glycol) as a hydrophilic group and a linear oligopeptide as a hydrophobic group have been found to self-assemble into very stable spherical micelles with a mean diameter less than 10 nm and a CMC value of 5 mg/L in aqueous solution. Docetaxel micelle-encapsulated by a tripodal amphiphilile [NP(PEG750)(GlyPheLeu)2Et]3 (CP750) exhibited outstanding drug-loaded micelle stability in aqueous solution compared with the polymeric micelles assembled from linear block copolymers. Furthermore, docetaxel micelle-encapsulated by CP750 is obtainable in solvent free powder form, which is immediately soluble in any aqueous media including saline and PBS and very stable to photo-degradation even in the room light at room temperature. Docetaxel micelle-encapsulated by CP750 displayed significantly improved pharmacokinetic profile compared with Taxotere currently in clinical use. Furthermore, its in vivo xenograft trials exhibited outstanding antitumor efficacy by showing complete tumor regression against the breast cancer cells (MDA-MB-231) at a low dose of 5 mg/kg, which is only 1/3 of the optimum dose of Taxotere. Furthermore, according to the acute toxicity study, docetaxel micelle-encapsulated by CP750 exhibited a much higher LD50 value of 75 mg/kg compared with 28 mg/kg of docetaxel in Taxotere. Thus docetaxel micelle-encapsulated by CP750 has entered the stage of preclinical studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A116.