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Temperature-Triggered Nanotechnology for Chemotherapy: Rapid Release From Lysolipid Temperature-Sensitive Liposomes

J.K. Mills and D. Needham
Duke University; presently Sterne, Kessler, Goldstein & Fox, P.L.L.C., US

Keywords:
liposome, drug delivery, temperature-sensitive, doxorubicin, cancer

Abstract:
Despite advances in drug retention and evasion of the body’s defenses, the therapeutic efficacy of many liposomes has been limited by low drug bioavailability within the tumor. Developed in this laboratory in 1996, lysolipid temperature sensitive liposomes (LTSLs) demonstrate enhanced release of encapsulated drug contents via grain boundary permeabilization when heated at their phase transition temperature, resulting in dramatic in vivo tumor toxicity. To characterize and attempt to determine the mechanism behind the lysolipid-generated permeability enhancement, dithionite permeability and doxorubicin release were measured for lysolipid and non-lysolipid containing membranes. Results indicate that a dramatic enhancement in the permeability rate constant begins about two degrees below the calorimetric peak of the thermal transition of the liposomes, and extends several degrees past it. Release rates of encapsulated doxorubicin are enhanced more than ten-fold over that of the pure bilayers by the inclusion of 10 mol% lysolipid. Lysolipid appears to not desorb from the liposomes during heating as previously hypothesized, but remains in the membranes stabilizing long lasting pores. This is the basis for the temperature-triggered nanotechnology for drug release.

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