ABSTRACT
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Due to their wide spectrum of activity, high potency, and also high toxicity, anthracyclines are probably the most studied family of drugs in the context of liposome encapsulation. 1 Anthracyclines are natural antibiotics which, due to their intercalation into nucleic DNA, kill dividing cells. Selective killing is therefore based on quickly dividing cells. The severe toxic side effects, such as myelosuppression (depletion of blood cells), fever and chills (due to released substances of lysed blood cells), alopecia (hair loss), and vomiting (depletion of lining cells in the digestive tract), are therefore not surprising. Furthermore, the drug action is believed to also involve membrane-related effects and high-affinity binding to cardiolipin makes the drug also cardiotoxic. Most early studies demonstrated the reduced toxicity of liposome-encapsulated doxorubicin (Adriamycin), epirubicin, and daunorubicin, while antitumor efficacy was often not studied in depth. 1-3 At that time many researchers simply believed that reduced toxicity was enough of a benefit to endorse liposome encapsulation. In reality, however, the reduced toxicity was in most cases due to increased liver and spleen uptake of the drug, and this resulted in reduced bioavailability, and in many cases negligible therapeutic efficacy. In other words, drug accumulated in liver could not reach tumors elsewhere. Only few tumors can benefit because of the altered biodistribution and pharmacokinetics. This applies mostly to liver tumors.4·5 In some cases liposomes can also act as a sustained release system and it was speculated that the release of the drug from liposomes as well as from macrophages after liposome digestion resulted in improved efficacy observed in some tumor models.6 In general, however, such examples were rather rare. Imaging techniques have shown reduced marker accumulation even in the case of some liver tumors and metastases
because in "nondiffuse" tumors drug cannot diffuse from Kuppfer cells in the liver (which engulf most of the liposomes carrying drug) to other liver cells. 7 In other words, despite almost two decades of extensive research there is no formulation close to the market.8
