Thermally enhanced liposomal drug delivery

Abstract

Background The purpose of this article is to review the concept of using heat to augment thermally sensitive liposomal drug delivery to tumors. If one loads a water soluble drug into the liposome below the lipid melting temperature, the drug will exhibit very slow release, which is dependent upon the solubility of the drug in lipid (1). A thermally sensitive liposome is designed to take advantage of changes in permeability when lipids melt. The mechanism leading to enhanced content release is thought to be related to opening of pores between plates of solid lipid, during the melting process (1). Details of the material science that leads to enhanced drug release will not be reviewed here; further details can be found in other reports (1-4). Historical Perspective Milton Yatvin was the first to use hyperthermia with drug loaded thermally sensitive liposomes to enhance drug delivery to tumors (5, 6), but some of the performance characteristics of this liposome were not optimized. Gaber, et al., examined liposomal accumulation and drug release from a pegylated version of the Yatvin liposome (7). Hyperthermia augmented liposome accumulation and drug release in tumors at 42-45 C, but the liposome did not fully release drug and the drug release kinetics were relatively slow (8) (Fig. 1). The slow release was particularly problematic because a liposome would pass through the vasculature of a tumor well before it released drug. To more efficiently capture released drug within the heated tumor, a liposome with faster drug release was sought. Drs. Dewhirst and Needham collaborated in the development of a temperature sensitive liposome that releases drug at a lower temperature (phase transition ¼ 41.3 C) (9, 10). Upon reaching its transition temperature, doxorubicin was nearly completely released in less than 20s (10). This formulation resulted in 25-30 and fivefold increase in drug delivery to a heated volume vs. free drug or non-thermally sensitive liposomes containing doxorubicin, respectively (11). Several other liposomal formulations have been reported that also exhibit rapid drug release between 41-42 C (3, 4, 12, 13). The acronym "LTSL," which stands for "lowtemperature sensitive liposome" is a generic term for this type of formulation. Drug Delivery Characteristics of LTSL and Clinical Implications Manzoor and Lindner, et al., used skin-fold window chambers to prove that drug delivery with LTSLs was purely the result of intravascular drug release in the heated tissue (14) (Fig. 2). Thermally mediated drug delivery to a local tumor has advantages and disadvantages, however. For example, it is difficult to justify giving neoadjuvant doxorubicin-LTSL to a woman with