Hyperthermia-enhanced targeted drug delivery using magnetic resonance-guided focussed ultrasound: a pre-clinical study in a genetic model of pancreatic cancer

Abstract

Purpose: The lack of effective treatment options for pancreatic cancer has led to a 5-year survival rate of just 8%. Here, we evaluate the ability to enhance targeted drug delivery using mild hyperthermia in combination with the systemic administration of a low-temperature sensitive liposomal formulation of doxorubicin (LTSL-Dox) using a relevant model for pancreas cancer. Materials and methods: Experiments were performed in a genetically engineered mouse model of pancreatic cancer (KPC mice: LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre). LTSL-Dox or free doxorubicin (Dox) was administered via a tail vein catheter. A clinical magnetic resonance-guided high intensity focussed ultrasound (MR-HIFU) system was used to plan treatment, apply the HIFU-induce hyperthermia and monitor therapy. Post-therapy, total Dox concentration in tumour tissue was determined by HPLC and confirmed with fluorescence microscopy. Results: Localized hyperthermia was successfully applied and monitored with a clinical MR-HIFU system. The mild hyperthermia heating algorithm administered by the MR-HIFU system resulted in homogenous heating within the region of interest. MR-HIFU, in combination with LTSL-Dox, resulted in a 23-fold increase in the localised drug concentration and nuclear uptake of doxorubicin within the tumour tissue of KPC mice compared to LTSL-Dox alone. Hyperthermia, in combination with free Dox, resulted in a 2-fold increase compared to Dox alone. Conclusion: This study demonstrates that HIFU-induced hyperthermia in combination with LTSL-Dox can be a non-invasive and effective method in enhancing the localised delivery and penetration of doxorubicin into pancreatic tumours.

Heating technology for malignant tumors: a review

“…HIFU guided by noninvasive MR thermometry is presently pursued primarily to induce local mild hyperthermia as a trigger for localized tumor-specific drug release from drugs encapsulated in thermosensitive liposomes [268]. Phantom tests with the ExAblate 2100 HIFU ablation system (InSightec Ltd, Haifa, Israel) [269,270] and preclinical tests with the Sonalleve system (Profound Medical Inc., Mississauga, Canada) have demonstrated the feasibility of inducing a stable MR controlled temperature rise [271][272][273] resulting in significantly enhanced ThermoDox delivery in mouse [274], rat [275], rabbit [276] and pig models [277]. Using the electronic beam steering of a single HIFU focus limits the size of the maximum volume with a stable elevated temperature level to a few cubic centimeters.…”

“…Thermal ablation is now more popular than application of hyperthermia as radiosensitizer or chemosensitizer, and the rapid rise of HIPEC and hyperthermic chemotherapy for NMIBC testify that combination of hyperthermia with chemotherapy is growing faster than combination of hyperthermia with radiotherapy, which is also associated with a different focus in device development. A breakthrough in heat-triggered tumor targeted drug delivery is one trend that would further strengthen popularity of the combination with chemotherapy [70,268,[274][275][276][277]. Finally, the recent trend to combine thermal therapies with immunotherapies has demonstrated significant potential to address recurrence and metastasis in preclinical and clinical pilot studies [425][426][427][428].…”

Steering Capabilities of an Acoustic Lens for Transcranial Therapy: Numerical and Experimental Studies

“…Steering capabilities of an acoustic lens for transcranial therapy: numerical and experimental studies Guillaume Maimbourg 1,2,3,4 , Alexandre Houdouin 1,2,3 , Thomas Deffieux 1,2,3 , Mickael Tanter 1,2,3 and Jean-François Aubry A single-element transducer with a 61mm radius of curvature and a 67mm aperture (H101 MR, Sonic Concepts, Bothell, USA) was used to achieve transcranial focusing. It was operated at its resonance frequency (914kHz), which was determined from the analysis of its complex impedance against frequency, using a vector network analyzer (ZVL, Rohde & Schwarz, Munich, Germany).…”

“…Focused ultrasound therapies have seen clinical applications for a growing number of pathologies: prostate [1,2] or pancreatic [3,4] cancers, bone metastases [5,6], uterine fibroids [7][8][9], or essential tremor [10][11][12]. It complements or even advantageously replaces surgery-based conventional methods.…”

High‐frequency (20‐MHz) high‐intensity focused ultrasound (HIFU) system for dermal intervention: Preclinical evaluation in skin equivalents

“…Both preclinical and clinical results have demonstrated clinical efficiency of direct ablation and treatment by HIFU in areas such as prostate cancer, uterine fibroids, breast cancer, thyroid cancer, bone metastasis, essential tremor, brain tumors, pancreas cancer, and liver cancer . In these applications, HIFU systems are often combined with magnetic resonance imaging systems (MR) as integrated therapeutic systems, with MR guiding the positioning of the HIFU focal point in the organ being target for treatment, so‐called magnetic resonance‐guided focused ultrasound (MRgFUS).…”