Hyperthermia Potentiates Antitumor Effect of Thermosensitive-Liposome- Encapsulated Melphalan and Radiation in Murine Melanoma

Abstract

Malignant melanoma are chemoresistant tumors with poor prognosis. The aim of this study was to determine whether multimodality therapy of murine melanoma involving a combination of radiation with thermosen-sitive-liposome-encapsulated melphalan and local hyperthermia would result in enhancement of therapeutic efficacy for a more effective management of melanoma. Melphalan was entrapped in thermosensitive liposomes prepared from natural lipids: egg phosphatidyl choline, cholesterol and ethanol to show phase transition at 42 ± 0.5° C and used in combination with localized heating of B16F10 murine melanoma transplanted into the legs of C57B1/6 mice for selective drug targeting at the tumors and/or radiation for treatment of melanoma. Murine melanoma transplanted into C57B1/6 mice were subjected to bimodality treatments involving a combination of radiation, hyperthermia or melphalan. Partial tumor regression was observed in mice receiving a combination of hyperthermia and radiation (median tumor volume 427.3 mm³) or a combination of free melphalan and radiation (512.1 mm³) as compared to untreated controls (630.9 mm³). Each group consisted of 18 animals, and the results are expressed as median tumor volume ± SD. Animals receiving multimodality therapy comprising irradiation followed by injection of thermosensitive liposomal melphalan and hyperthermic treatment of the tumor-bearing leg at 42 ± 0.5°C for 1 h showed marked tumor regression in comparison with untreated controls or animals treated with a combination of radiation and hyperthermia or radiation and free-drug melphalan. Animals receiving thermoradiochemotherapy also showed prolonged survival; 70% of animals survived for more than 3 months. The study shows greater tumor cell killing, tumor growth delay and prolonged survival produced by a combination of radiation, thermosensitive-liposome-entrap-ped melphalan and hyperthermia compared with animals receiving single-modality or bimodality treatments. It is concluded that this multimodality approach will be potentially useful for more effective management of melanoma.

Nanoscale Drug Delivery and Hyperthermia: The Materials Design and Preclinical and Clinical Testing of Low Temperature-Sensitive Liposomes Used in Combination with Mild Hyperthermia in the Treatment of Local Cancer

“…Other drugs including taxol [146], melphalan [147, 148], methotrexate [141, 149], plumbagin [150], dacarbazine [151], mitomycin C [152] and tumor necrosis factor [153], have also been encapsulated (see review by Kong and Dewhirst [154]). Currently only the LTSL-doxorubicin is in clinical trials, but an optimized formulation for cisplatin and other drugs may be possible for the near future.…”

A Mathematical Model for Thermosensitive Liposomal Delivery of Doxorubicin to Solid Tumour

“…Some animal experiments have shown that liposomal doxorubicin delivery offers better effectiveness of anticancer treatments than bolus injection, but no obvious advantage over continuous infusion was reported [4]. The development of thermosensitive liposomes to enhance the effectiveness of anticancer treatment has been reported in many studies (e.g., [5–8]).…”

Thermosensitive Liposomes for the Delivery of Cancer Therapeutics

“…In addition, in order to further expand the applicability of the heat triggered drug delivery approach to a wider range of solid tumors or possible combination treatments, novel TSL drug formulations should be developed. Examples of other interesting drugs formulated thus far in TSL are cisplatin [51,52], melphalan [53], taxol [54] and miltefosine [55]. These formulations are still in preclinical stages of development and need extensive testing before being applied in the clinic.…”