**2. The anticancer agent PTX**

PTX, an anticancer agent isolated from the trunk bark of the Pacific Yew tree, Taxus brevifolia, shows a wide spectrum of anticancer activity for a variety of human cancers, including breast, ovarian, non-small-cell lung, prostate, head and neck, colon cancers and so on (Rowinsky, 1997). PTX can induce mitotic arrest and apoptosis in proliferating cells by targeting tubulin, which is a component of the mitotic spindle. PTX binds to the N-terminal 31 amino acids of the β-tubulin subunit and prevents depolymerization. As a result, the mitotic spindle is disabled, cell division can not be completed, and the cell replication in the late G2 or M phase of the cell cycle is inhibited. The cancer cells are killed by disrupting the dynamics necessary for cell division (Bhalla, 2003). The anticancer mechanism of PTX is shown in Fig. 1.

The clinical use of PTX is limited by its high hydrophobicity, low solubility, high systemic exposure, poor pharmacokinetic characteristics, and the lack of selective tumor uptake (Parveen & Sahoo, 2008; ten Tije et al., 2003). The clinical use of PTX also leads to many side effects. Side effects of PTX include nausea, vomiting, diarrhea, mucositis, myelosuppression, cardiotoxicity, neurotoxicity and hypersensitivity reactions, and the latter two are mainly owing to polyoxyethylated castor oil (Cremophor® EL) and ethanol used for solubilizing PTX (Rogers, 1993; Sugahara et al., 2007). PTX for injection is supplied in 50% Cremophor® EL and 50% dehydrated ethanol.

Despite premedication with corticosteroids and antihistamines, PTX still induces minor reactions (e.g., flushing and rash) in approximately 40% of patients and major potentially life-threatening reactions in 1.5%−3% of patients (Lemieux et al., 2008; Price & Castells, 2002). Hydrophobicity of PTX is also associated with unfavorable kinetics, high levels of protein binding, and high volumes of distribution often greatly exceeding total body water. Together, all these factors have a negative impact on the therapeutic index because only a small proportion of the drug administered actually reaches the tumor site (Singer, 2005). As mentioned above, the efficacy and tolerability of PTX are limited by its low solubility, high systemic exposure, and the lack of selective tumor uptake.

Fig. 1. Schematic illustration of PTX anticancer mode: heterdimers of α- and β-tubulin assemble to form a highly dynamic microtubule which plays an extremely important role in the process of mitosis (A); microtubule-targeted paclitaxel binds along the interior surface of the microtubule, suppressing its dynamics mitosis (B).

PTX, an anticancer agent isolated from the trunk bark of the Pacific Yew tree, Taxus brevifolia, shows a wide spectrum of anticancer activity for a variety of human cancers, including breast, ovarian, non-small-cell lung, prostate, head and neck, colon cancers and so on (Rowinsky, 1997). PTX can induce mitotic arrest and apoptosis in proliferating cells by targeting tubulin, which is a component of the mitotic spindle. PTX binds to the N-terminal 31 amino acids of the β-tubulin subunit and prevents depolymerization. As a result, the mitotic spindle is disabled, cell division can not be completed, and the cell replication in the late G2 or M phase of the cell cycle is inhibited. The cancer cells are killed by disrupting the dynamics necessary for cell

The clinical use of PTX is limited by its high hydrophobicity, low solubility, high systemic exposure, poor pharmacokinetic characteristics, and the lack of selective tumor uptake (Parveen & Sahoo, 2008; ten Tije et al., 2003). The clinical use of PTX also leads to many side effects. Side effects of PTX include nausea, vomiting, diarrhea, mucositis, myelosuppression, cardiotoxicity, neurotoxicity and hypersensitivity reactions, and the latter two are mainly owing to polyoxyethylated castor oil (Cremophor® EL) and ethanol used for solubilizing PTX (Rogers, 1993; Sugahara et al., 2007). PTX for injection is supplied in 50% Cremophor®

Despite premedication with corticosteroids and antihistamines, PTX still induces minor reactions (e.g., flushing and rash) in approximately 40% of patients and major potentially life-threatening reactions in 1.5%−3% of patients (Lemieux et al., 2008; Price & Castells, 2002). Hydrophobicity of PTX is also associated with unfavorable kinetics, high levels of protein binding, and high volumes of distribution often greatly exceeding total body water. Together, all these factors have a negative impact on the therapeutic index because only a small proportion of the drug administered actually reaches the tumor site (Singer, 2005). As mentioned above, the efficacy and tolerability of PTX are limited by its low solubility, high

Fig. 1. Schematic illustration of PTX anticancer mode: heterdimers of α- and β-tubulin assemble to form a highly dynamic microtubule which plays an extremely important role in the process of mitosis (A); microtubule-targeted paclitaxel binds along the interior surface of

division (Bhalla, 2003). The anticancer mechanism of PTX is shown in Fig. 1.

systemic exposure, and the lack of selective tumor uptake.

the microtubule, suppressing its dynamics mitosis (B).

**2. The anticancer agent PTX** 

EL and 50% dehydrated ethanol.
