Hyperthermia induces doxorubicin release from long-circulating liposomes and enhances their anti-tumor efficacy

• Published in: International journal of radiation oncology, biology, physics Vol. 29; no. 4; pp. 827 - 834
• Main Authors: Ning, Shoucheng, Macleod, Karen, Abra, Robert M., Huang, Anthony H., Hahn, George M.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.07.1994; Elsevier
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Combined Modality Therapy; Disease Models, Animal; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Doxorubicin - pharmacology; Drug Carriers; Drug release; Fibrosarcoma - blood supply; Fibrosarcoma - drug therapy; Fibrosarcoma - metabolism; Hyperthermia; Hyperthermia, Induced; Liposomes; Long-circulating liposomes; Male; Medical sciences; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Neoplasms, Radiation-Induced - blood supply; Neoplasms, Radiation-Induced - drug therapy; Neoplasms, Radiation-Induced - metabolism; Pharmacology. Drug treatments; RIF-1 tumor; Thermochemotherapy; Long-circulating liposomes; Drug release; Thermochemotherapy; RIF-1 tumor; Hyperthermia; Doxorubicin; Antineoplastic agent; Controlled release form; Rodentia; Liposome; Malignant tumor; In vitro; Result; In vivo; Vertebrata; Chemotherapy; Mammalia; Mouse; Animal; Dosage form; Anthracyclins; Combined treatment; Pharmacokinetics; Induced hyperthermia; Release
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/0360-3016(94)90572-X

Purpose : To examine the possibility that hyperthermia would accelerate drug release from long-circulating liposomes, and enhance their antitumor activity. Methods and Materials : Liposomes were prepared by thin film hydration technique. Hyperthermia was induced by ultrasound apparatus and a water bath heating system. The antitumor efficacy of treatment against RIF-1 tumor in C3H mice was evaluated by the tumor growth delay assay. Results : In vitro drug release experiments demonstrated that increase in temperature from 37°C to 41°C resulted in about a sixfold increase in doxorubicin (DOX) release in a 1-h period. Increasing the temperature to 43°C, resulted in only a modest additional drug release. Drug uptake studies showed that local hyperthermic treatment immediately following the drug administration dramatically enhanced Stealth liposome-encapsulated doxorubicin (S-DOX) uptake by tumors, but did not do so for free DOX. At 42°C and at a dose of 10 mg/kg, the accumulation of S-DOX was about 10-fold and 2.5-fold higher than that with free drug and S-DOX at 37°C, respectively. The antitumor efficacy study confirmed our hypothesis that the addition of hyperthermia to the treatment of RIF-I tumors with doxorubicin encapsulated in long-circulating liposomes would enhance antitumor effects. Two hyperthermia treatments given at 24-h intervals appeared to be the most promising method of combining heat and long-circulating liposomes. The increased antitumor activity was not accompanied by increased toxicity, as determined by the body weight of the mice. Conclusion : Local hyperthermic treatment is able to accelerate DOX release from long-circulating liposomes, increase tumor uptake, and enhance their antitumor efficacy. The combination of local hyperthermia and long-circulating liposomes appears to show considerable promise in the treatment of localized diseases.