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Temperature-sensitive liposomes were first formulated by Yatvin et al. in 1978 [39], which released a hydrophilic drug at a temperature a few degrees above physiological temperature. The drug release from heat-triggered nanocarriers can be achieved by using thermosensitive polymers. When mild hyperthermia (HT) is applied along with administration of thermosensitive liposomes, the heat increases pore size of tumor vessel, increasing extravasation of liposome into the tumor. Further, hyperthermia facilitates release of drug from thermosensitive liposomes in the tumor vasculature as well as in the tumor interstitium [40].

The release of drugs occurs at the melting phase transition temperature (T_m) of lipid bilayer following a phase transition from solid gel phase (L_β) to a liquid-crystalline phase (L_α) at T_m. Dipalmitoylphosphatidylcholine, with T_m of 41.4°C, is generally used as a major component in TSL. Drug release characteristics can be modified by blending DPPC with small amounts of other phospholipids, such as 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine (DSPC) (Tm = 54.9°C) [41]. Lysolipid-containing low-temperature-sensitive liposomes (LTSLs) were the first TSL formulations used for intravascular delivery of drugs upon heating. Thermodox^®, licensed to Celsion Corporation (Columbia, MD, USA), is an LTSL formulation loaded with doxorubicin, which is currently under clinical investigation [42]. The shortcomings of LTSL have been rectified by development of sterically stabilized TSL formulation (Stealth TSL) by adding DSPE-PEG2000, which has improved stability and better in vivo half-life as compared to LTSL formulation [43]. Further, the safety of patients using TSL can be assured by encapsulating contrast agents to distinguish heated and unheated tissues, and also, absolute temperatures complementing traditional MRI thermometry methods can be quantified [44, 45].