Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies.

PURPOSE: A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD). The primary objectives were to determine the safe maximum tolerated dose (MTD), pharmacokinetic properties, and dose-limiting toxicity (DLT) of LTLD during this combination therapy. MATERIALS AND METHODS: Subjects eligible for percutaneous or surgical radiofrequency (RF) ablation with primary (n = 9) or metastatic (n = 15) tumors of the liver, with four or fewer lesions as large as 7 cm in diameter, were included. RF ablation was initiated 15 minutes after starting a 30-minute intravenous LTLD infusion. Dose levels between 20 mg/m(2) and 60 mg/m(2) were evaluated. Magnetic resonance imaging, positron emission tomography, and computed tomography were performed at predetermined intervals before and after treatment until evidence of recurrence was seen, administration of additional antitumor treatment was performed, or a total of 3 years had elapsed. RESULTS: DLT criteria were met at 60 mg/m(2), and the MTD was defined as 50 mg/m(2). RF ablation was performed during the peak of the plasma concentration-time curve in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia. CONCLUSIONS: LTLD can be safely administered systemically at the MTD (50 mg/m(2)) in combination with RF ablation, with limited and manageable toxicity. Further evaluation of this agent combined with RF ablation is warranted to determine its role in the management of liver tumors.

In vitro and in vivo evaluations of increased effective beam width for heat deposition using a split focus high intensity ultrasound (HIFU) transducer.

PURPOSE: To develop a novel and efficient, in vitro method for characterizing temporal and spatial heat generation of focused ultrasound exposures, and evaluate this method to compare a split focus and conventional single focus high intensity focused ultrasound transducer. MATERIALS AND METHODS: A HIFU tissue-mimicking phantom was validated by comparing respective temperature elevations generated in the phantoms and in murine tumors in vivo. The phantom was then used in combination with IR thermography to spatially and temporally characterize differences in low-level temperature elevation (e.g. 3-5 degrees C) produced by a single focus and split focus HIFU transducer, where the latter produces four simultaneous foci. In vivo experiments with heat sensitive liposomes containing doxorubicin were then carried out to determine if the larger beam width of the split focus transducer, compared to the single focus, could increase overall deployment of the drug from the liposome. RESULTS: Temperature elevations generated in the HIFU phantom were not found to be different from those measured in vivo when compensating for disparities in attenuation coefficient and specific heat, and between the two transducers by increasing the energy deposition. Exposures with the split focus transducer provided significant increases in the area treated compared to the single focus, which then translated to significant increases in drug deposition in vivo. CONCLUSIONS: Preliminary evidence was provided indicating the potential for using this novel technique for characterizing hyperthermia produced by focused ultrasound devices. Further development will be required for its suitability for correlating in vitro and in vivo outcomes.

Pulsed-high intensity focused ultrasound and low temperature-sensitive liposomes for enhanced targeted drug delivery and antitumor effect.

PURPOSE: To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. EXPERIMENTAL DESIGN: Comparisons in vitro and in vivo were carried out between non-thermosensitive liposomes (NTSL) and low temperature-sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. RESULTS: In vitro incubations simulating the pulsed-HIFU thermal dose (42 degrees C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. CONCLUSIONS: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.