A new generation of Doxorubicin-loaded liposomes with improved localization in tumors: preclinical and clinical studies

Abstract

In most instances, liposomes have been used as carriers of cytotoxic drugs with a strategy based on reduction of toxicity and/or passive delivery to liver­ infiltrating tumors. The fast and dominant uptake of most types of liposomes by the reticulo-endothelial system (RES) has prevented so far the adoption of a more direct strategy based on selective homing of liposomes to tumors. Re­ cent developments [I] have shown that the inclusion of some negatively-charged glycolipids in the liposome bilayer coupled with phospholipids of high-phase­ transition temperature, cholesterol, and careful size control result in : I) inhi­ bition of RES uptake, 2) prolonged circulation half-life, 3) minimal leakage of liposome contents during circulation, and 4) concomitant enhancement of tumor uptake. We refer to these liposomes with prolonged circulation time as Stealth liposomes to indicate that they are not recognized by the RES and to differentiate them from conventional liposomes. Although the pharmacological importance of many of the above mentioned liposome attributes (high-phase-transition phospholipids, cholesterol, and small particle size) was identified more than ten years ago by several groups of in­ vestigators, it was not until recently that the contribution of molecules, such as monosialoganglioside and phosphatidylinositol, to liposome circulation half­ life and liposome localization in tumors was recognized. A further refinement of the Stealth technology is the use of a polyethylene-glycol derivatized phos­ phatidylethanolamine which has been shown to confer optimal prolongation of vesicle circulation time in animal models [2]. Although these molecules confer to the vesicles a net negative charge, the uptake by the RES is actually decreased, in contrast to the acceleration of RES uptake commonly observed with the inclusion of other negatively-charged lipids, such as Phosphatidic acid, Phosphatidylserine, and Phosphatidylglycerol [3]. Preclinical studies with Doxorubicin Stealth Iiposomes The development of these new formulations of long-circulating liposomes, with reduced uptake by the RES and enhanced accumulation in tumors, has broa­ dened the potential applications of these carriers in cancer drug delivery. In pharmacological studies in rodents and dogs, DOX encapsulated in Stealth Iipo­ somes has been shown to circulate in liposome-associated form with very long half-lives in the range of 15 to 30 hours [4, 5]. We have investigated the tis­ sue distribution, anti-tumor activity, and toxicity of Stealth liposomal Dox