These temperature-sensitive liposomes are designed to be stable at the normal physiological temperature of 37°C but become significantly destabilized at slightly higher temperatures (Figure 1). The use of liposomes as the nanocarrier in these formulations is a particularly attractive option with respect to both enhanced tumor site accumulation, as well as facilitated release of the encapsulated drug. This is attributed to the fact that a local increase in temperature has been shown

to enhance extravasation Inhibitors,research,lifescience,medical of liposomes out of circulation resulting in their preferential accumulation to the heated tumor [21], and that liposomes are known to become destabilized at elevated temperatures [1, 2]. For example, we and others have previously shown that liposomes composed of various phospholipids are much Inhibitors,research,lifescience,medical leakier at 37°C than those stored at 4°C [1, 3, 22]. Thus, the use of temperature-sensitive liposomes to deliver encapsulated chemotherapeutics to solid tumors such as breast cancer is an area of promising research, and many Inhibitors,research,lifescience,medical successful constructs have previously been reported. For example, liposomes composed of dipalmitoylphosphatidylcholine (DPPC), monostearoylphosphatidylcholine (MSPC), and distearoylphosphatidylethanolamine (DSPE)-PEG 2000 are currently in Phase II clinical trials for the treatment of recurrent breast cancer (http://www.celsion.com).

These lyso-lipid temperature-sensitive liposomes encapsulate doxorubicin and have previously been shown to exhibit enhanced drug release rates under mild hyperthermic conditions while remaining relatively stable at normal physiological temperature Inhibitors,research,lifescience,medical [23]. More recently, Tagami et al. have reported a similar liposome-based system in which the minor component MSPC is replaced with a nonionic surfactant Brij78 [24]. This new formulation outperformed the lyso-lipid temperature-sensitive liposomes when tested in mice inoculated with a

mammary carcinoma cell line (EMT-6). Chen et al. have also reported promising Inhibitors,research,lifescience,medical results using thermosensitive liposomes prepared with DPPC, 1-myristoyl-2-palmitoyl phosphatidylcholine much (MPPC), and ROCK inhibitor DSPE-PEG 2000 [25]. Figure 1 Temperature-sensitive liposomes designed to remain stable while in circulation at 37°C and become significantly destabilized in the tumor microenvironment at slightly higher temperatures 39–42°C. 2.2. Targeted Liposome-Based Chemotherapeutics Another strategy employed in order to potentially increase the overall therapeutic index of liposome-based drugs involves improving the colocalization between the chemotherapeutic and breast cancer cells. In some cases, this strategy may also involve improvement of cellular internalization of the whole liposome-based drug, particularly when cell-surface receptors known to undergo receptor-mediated endocytosis is concerned.