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Title: Targeted release from lyso-thermosensitive liposomal doxorubicin (ThermoDox®) using focused ultrasound in patients with liver tumours
Author: Lyon, P. C.
ISNI:       0000 0004 6499 0955
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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The TARDOX study is a Phase I first-in-man proof-of-concept study which aims to demonstrate the safety and feasibility of targeted delivery of a thermo-sensitive liposome in combination with mild hyperthermia induced using an extracorporeal Focused Ultrasound (FUS) device. ThermoDox® is a specially formulated long-circulating and thermosensitive liposome, activated by conditions of mild hyperthermia, to release its cytotoxic doxorubicin content. FUS offers non-invasive and non-ionising approach to tumour therapy, classically by the mechanism of thermal ablation (High Intensity Focused Ultrasound, HIFU) rather than hyperthermia. Nine patients have received intervention; a single treatment cycle of ThermoDox® combined with FUS to a single target primary or secondary liver tumour using an ultrasound-guided extracorporeal FUS device (Model JC200 Focused Ultrasound Tumor Therapeutic System, Haifu Medical). Five cases proceeded with real-time thermometry and four without. In those with thermometry, optimal hyperthermia (T > 39.5°C for over 300 cumulative and 60 continuous seconds, and CEM43 < 60 minutes) was achieved in 4/5. Core tumour biopsies were used for drug quantification studies using high performance liquid chromatography. In an interim analysis, of the evaluable tissue samples analysed to date, an average of 8.41 μg/g ± 4.37 SD of intratumoral doxorubicin was demonstrated in those receiving optimal hyperthermia under real-time thermometry (n=2) and 6.75 μg/g ± 0.13 SD in those whose intervention proceed without thermometry (n=2). Overall, an aver- age of 7.58 μg/g ± 2.70 SD of doxorubicin was seen in the included post-delivery samples analysed to date (n=4). This compares to an average of 2.48 μg/g ± 1.26 SD in evaluable samples taken immediately prior to FUS-mediated delivery (n=4). Microscopic analysis of post-delivery biopsies demonstrated intercalation of doxorubicin in the nuclei of tumour cells in 6/6 patients with adequate tissue samples, evidencing that release of bioavailable drug from the administered liposomes has been achieved. Radiological follow-up at two weeks with 18F-FDG PET-CT demonstrated unequivocal localised response in 3/4 evaluable patients receiving optimal hyperthermia and 2/4 without real-time thermometry (subjective response in 1 of the remaining 2), despite only receiving a single standard dose treatment cycle of doxorubicin. Serious adverse events were limited to transient neutropenia in 4/9 patients, in line with the adverse event profile for doxorubicin, and prolonged hospital stay due to confusion in 1/9. We have demonstrated that combined treatment with ThermoDox® and extracorporeal targeted FUS hyperthermia is feasible, safe and can enhance intratumoral drug delivery, providing localised response in human liver tumours refractory to standard chemotherapy. This study, which builds on decades of research efforts in targeted liposome delivery using FUS, is one of the earliest studies to translate ultrasound-mediated tumour targeting into the clinic. The use of chemotherapy in combination with FUS devices, as a non-invasive targeting method, has the potential to transform future clinical treatments for solid organ cancers.
Supervisor: Coussios, C. C. ; Gleeson, F. V. ; Carlisle, R. Sponsor: Celsion Corporation, USA ; NIHR Oxford Biomedical Research Centre
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Ultrasound-targeted drug delivery ; Liposomal drug delivery systems ; HIFU ; LTLD ; Lyso-thermosensitive liposomal doxorubicin ; Targeted drug delivery ; Hyperthermia ; Thermodox ; Focused ultrasound