Liposomes can be designed to release an entrapped drug preferentially at temperatures attainable by mild local hyperthermia. In a test system in vitro, protein synthesis by Escherichia coli is inhibited and killing of the cells is enhanced by heating neomycin-containing liposomes to their phase transition temperature to maximize drug release. In the presence of serum the ratio of release at 44 degrees C to that at 37 degrees C can be made greater than 100:1, suggesting possible applications in the treatment of tumors or local infection.

http://science.sciencemag.org/content/sci/202/4374/1290.full.pdf

Design of liposomes for enhanced local release of drugs by hyperthermia

Hyperthermia and Cancer

Hyperthermia in the treatment of cancer

Saccharomyces cerevisiae cells grown either aerobically or anaerobically were tested for tolerance to a brief heat stress (52°C, 5 min) or oxidative stress (20 mM H2O2, 15 min). Tolerance was related to growth phase, in that stationary phase cells were intrinsically more resistant to heat or oxidative stress than exponential phase cells. A mild heat shock (37 °C, 30 min) induced thermotolerance and oxidative tolerance in both aerobic and anaerobic cells. However, prior exposure to a low concentration of H2O2 (0.1 mM, 60 min) induced protection against the lethal concentration of H2O2 but not against the lethal temperature. Sensitivity to both heat and oxidative stress was dependent on membrane lipid composition. In the case of anaerobic cells, the most stress resistant had membranes enriched in saturated fatty acids, followed in order by cells enriched in oleic and linolenic acids. Aerobic cells with membranes enriched in palmitoleic and oleic acids showed the highest resistance to stress under all conditions. In both aerobic and anaerobic cells, a mild heat shock or oxidative shock induced markedly increased levels of thiobarbituric acid reactive substance (TBARS), indicative of malondialdehyde formation and lipid damage. Anaerobic cells with membranes enriched in linolenic acid had the highest TBARS, followed by cells enriched in oleic acid, with cells enriched in saturated fatty acids showing the lowest TBARS. The results suggest that heat and oxidative stress may share a common mechanism of damage through induction of oxygen-derived free radicals, resulting in membrane lipid damage. The extent of cellular damage was related to membrane lipid composition and correlated positively with increasing unsaturation of the phospholipid fatty acyl component.

Stress tolerance and membrane lipid unsaturation in Saccharomyces cerevisiae grown aerobically or anaerobically.

Hyperthermia has the potential to modify the cytotoxicity of anticancer drugs and to convert some other drugs to cytotoxic agents having no considerable cytotoxicity at normal temperature. This has been demonstrated by in vitro and in vivo experiments, which are compiled in the first part of this review. The pattern of modification of the dose response curves of the drugs and the degree of change of their effectiveness by heat depends on a great variety of factors; not all these are known at present. In this review an attempt is made to compile as many data as possible on these modifying factors. They will be discussed in the context of each specific drug in order to avoid misleading generalizations, but rather to give a “hyperthermic portrayal” of these drugs.

Hyperthermia and Drugs

SummaryThe mechanism of hyperthermic killing, a component of some cancer therapy, is not known. Cell-survival curves during hyperthermic exposure can be used to elucidate the effects of membrane modifying procedures on cell death. Experiments were designed to test whether procedures that were reported to increase membrane fluidity also resulted in increased killing on hyperthermic exposure. An E. coli K12 mutant, K1060, is used to predictably alter the degree and amount of unsaturated fatty acids incorporated into membranes. Changing from an 18 : 1 to an 18 : 3 unsaturated fatty acid increases killing. Decreasing the amount of unsaturated fatty acid cells incorporated by increasing growth temperature decreases killing. Procaine, a drug known to decrease membrane viscosity, increases heat killing. These data are most simply explained by the hypothesis that membrane disorganization occurs as a result of temperature increasing to a point where a lipid transition causes a membrane structural change, which res...

Milton B. Yatvin

Papers

The influence of membrane lipid composition and procaine on hyperthermic death of cells.