LIPOSOME LONGEVITY AND STABILITY IN CIRCULATION - EFFECTS ON THE IN-VIVO DELIVERY TO TUMORS AND THERAPEUTIC EFFICACY OF ENCAPSULATED ANTHRACYCLINES

The effect of liposome composition on drug delivery to tumors and ther apeutic efficacy of liposome-encapsulated anthracyclines was investiga ted in two murine tumor models: an ascitic tumor (J6456 lymphoma) and a solid carcinoma (M-109). Longevity in circulation correlated positiv ely with high drug levels in the extracellular (ascitic) tumor fluid a nd with delayed peak tumor levels. Using polyethylene-glycol(PEG)-coat ed liposomes, liposome stability (drug retention) was found to be an i mportant determinant of therapeutic efficacy, as indicated by the supe rior survival conferred by high T-m phosphatidylcholines (hydrogenated , dipalmitoyl) over low T-m (egg phosphatidyl-choline). Replacing PEG with another negatively-charged surface headgroup (phosphatidyl-glycer ol, phosphatidyl-inositol) resulted in relatively shorter longevity in circulation of the liposome-associated drug, but no detectable differ ences in anti-tumor efficacy. When neither the surface charged headgro up nor the PEG coating are present, the resulting drug formulation was significantly less effective than PEG and phosphatidylinositol-based formulations in both tumor models. In conclusion, longevity in circula tion, as obtained with PEG coating, tends to improve the therapeutic e fficacy of liposome-encapsulated anthracyclines. The current therapeut ic models were however unable to detect differences between the therap eutic activity of PEG and other liposome formulations with relatively small differences in circulation longevity.