UBC Theses and Dissertations
Triggered drug release from thermosemsitive liposomes Ickenstein, Ludger Markus
Targeted delivery of anticancer drugs by delivery devices such as thermosensitive liposomes promises to increase the efficacy of drugs while decreasing their side effects. The objectives of the present thesis were to characterize a lysolipid-containing thermosensitive liposomal formulation (LTSL) of the antineoplastic agent doxorubicin (DOX) and to determine its drug release mechanisms and efficacy in mice bearing multidrug resistant (MDR) tumors. It was hypothesized that lysolipids accumulate at membrane grain boundaries leading to physical alterations of the membrane and rapid drug release at the liposome's phase transition temperature (T[sub C]). This property was hypothesized to be beneficial in the use of LTSL encapsulated with DOX (LTSL-DOX) in combination with tumor hyperthermia against MDR tumors overexpressing Pglycoprotein (PGP) by overcoming PGP-mediated drug efflux from tumor cells. At temperatures of 41 and 42 °C, drug release rates of LTSL were approximately 100-times faster than those of traditional thermosensitive liposomes. Membrane redistribution patterns of a fluorescent label resembling lysolipid and the membrane retention of radiolabeled lysolipids indicated that lysolipids accumulated in LTSL membrane regions over time and lysolipids did not dissociate from LTSL after phase transition in vitro. Cryogenic electron microscopy images revealed the formation of membrane discs in heated LTSL and this process was dependent on the degree of phospholipid hydrolysis. The mean plasma half-life of DOX in mice after LTSL-DOX administration was 0.67 h and lysolipids dissociated rapidly from LTSL after in vivo exposure. In mice bearing MDA435/LCC6[sup MDR1] tumors, the efficacy of LTSL-DOX in combination with hyperthermia was similar to that of free DOX with or without tumor hyperthermia treatment. It was concluded that the velocity of drug release from LTSL at temperatures close to their T[sub C] was unsurpassed by any other known triggered drug release mechanism. After intravenous administration however, DOX retention in LTSL was insufficient to allow for tumor drug accumulation and the rapid dissociation of lysolipids from LTSL compromized their superior drug release properties observed in vitro. These shortcomings of the LTSL-DOX formulation and the choice of the DOX-insensitive tumor model were considered responsible for the lack of improved efficacy of the LTSL-DOX treatment in mice bearing MDA435/LCC6[sup MDR1] tumors as compared to free DOX administration.
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