Ultrasound drug targeting to tumors with thermosensitive liposomes

Induction of local tissue hyperthermia is emerging as a valuable tool in cancer therapy, as temperatures between 39-43°C are sufficient to trigger release of drug from thermosensitive liposomes (TSL), but is not harmful to normal tissue. Despite significant advances in spatial and dynamic control of ultrasound, temperature profiles in heated tissues are never homogenous, and an ideal TSL should achieve complete local release over the entire hyperthermia range. We have developed a TSL exhibiting a sensitive temperature release profile (39-43°C) with excellent stability at 37°C. We prepared a TSL composed of DPPC lipid and Brij78 surfactant, and loaded this hyperthermia-activated-cytotoxic (HaT) TSL with doxorubicin (DOX). EMT-6 breast tumors located on a Balb/c mouse footpad were instantaneously heated to 42-43°C using a 3.9 MHz planar transducer: body temperature did not elevate above 37°C, and complete remission of the EMT-6 breast cancer tumors was observed. Mice treated with standard DOX chemotherapy (at same 10 mg/kg dose as HaT) did not exhibit any tumor inhibition effects compared to control mice. By histological examination, no physiological damage to normal tissues was induced by ultrasound heating, and mice treated with HaT DOX regained normal tissue appearance and function posttreatment. This study confirms the benefit of coupling ultrasound induced hyperthermia with a sensitive TSL formulation.