The efficacy of novel thermosensitive liposomes (40 degrees C) containing doxorubicin (Dox-Lip) together with local hyperthermia (HT) was studied on solid growing rat rhabdomyosarcomas. Tumor response and systemic toxicity were evaluated by comparing to free doxorubicin (Free Dox) with or without hyperthermia. Tumors were heated with infrared-A-radiation and drugs were infused intravenously after preheating the tumors followed by a further 60 min of heating at 42.5 degrees C. Recorded temperatures at various locations in the tumors indicated that all intratumoral temperatures, especially at the back rim, were definitely >40 degrees C. After single doses, tumor growth was further inhibited by Dox-Lip+HT compared to Free Dox+HT or Free Dox alone. Repeated treatments with Dox-Lip+HT (2x2.5 mg/kg+HT/2 weeks) resulted in a statistically significant tumor growth delay and was associated with a much lower systemic toxicity. Uptake studies of drugs in blood, tumor and normal tissues showed that Dox-liposomes (40 degrees C) are long circulating liposomes in the blood. However, the enhanced tumor response did not correlate with an increased uptake of Dox-Lip+HT in the tumor. The findings suggest that repeated applications of thermosensitive liposomal doxorubicin (40 degrees C) and local hyperthermia can control primary rat rhabdomyosarcomas while reducing the systemic toxicity of free doxorubicin.
