The development of a platform for hyperthermia induction in small animal cancer models using MRI guided Focused Ultrasound to test drug delivery of thermosensitive liposomes
Date
2020-12
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Abstract
Focused ultrasound concentrates acoustic energy on a small volume. In tissues, this can have several bioeffects, including hyperthermia. Hyperthermia occurs when the body temperature is raised above its core value to about 43⁰C and is sustained for several tens of minutes. The increased temperature can cause damage to the tumour cells directly by denaturing proteins and DNA. It also leads to an increase in oxygenation, which leads to cell toxicity and can have synergistic effects for radio-sensitization. Localized hyperthermia can also be used to improve drug delivery to tumours using thermosensitive formulations. In particular, a liposome-based encapsulation of the chemotherapeutic drug, doxorubicin, has been used in studies for targeted drug delivery to tumours. Doxorubicin is commonly used to treat soft tissue sarcomas, which make up 4-8% of childhood cancers. The liposome dissolves when reaching hyperthermic temperatures and releases its load in tissues where localized hyperthermia takes place. A challenge when studying tumour response in preclinical models is performing precise localized hyperthermia delivery as tight temporal-spatial control of the temperature distribution is required. For this research project, Magnetic Resonance Imaging-guided Focused Ultrasound (MRIgFUS) is proposed as a method to deliver localized hyperthermia in small animal models. Focused ultrasound can precisely concentrate mechanical energy that is transformed into heat, and MRI can be used to target treatment location and monitor temperature spatially and temporally. This monitoring can be used to control hyperthermic levels in a tumour model. In this study, we present details on a platform to deliver MRIgFUS in small animal models. For a demonstration of MRIgFUS as an effective platform for localized hyperthermia in small animals, we performed two studies. The first study was conducted in healthy mice (n=30, C57BL/6) for technical development to establish the basic guidelines for MRIgFUS-based hyperthermia in small animals. The second study used a murine model of alveolar soft part sarcoma (ASPS) to demonstrate that MRIgFUS can increase thermosensitive liposomal doxorubicin delivery. ASPS is a rare type of soft tissue sarcoma commonly found in children and adolescents, with tumour location usually in the body’s extremities. A current challenge in the treatment of ASPS is that tumour resection is unfeasible in 45% of patients. We first used a small cohort of mice (n=6, CB17 SCID) to perform an MRI assessment of alveolar soft part sarcoma tumour growth in a lower limb. A comparison study was then conducted to test the delivery of a temperature-sensitive, liposome-encapsulated form of doxorubicin (ThermoDXR) to the tumour site using MRIgFUS-based hyperthermia. Drug concentrations were compared between four treatment groups. This study was done in ASPS-bearing mice (n=5 in each of four groups, CB17 SCID) with tumours growing subcutaneously, just below the skin. Mice in the first and second group received free doxorubicin with no hyperthermia and free doxorubicin with hyperthermia using MRIgFUS, respectively. Mice in the third and fourth groups received ThermoDXR with no hyperthermia, and ThermoDXR with hyperthermia, respectively. This study hypothesized that the treatment group with ThermoDXR and hyperthermia would have the greatest drug concentration at the tumour site, thereby indicating an improvement in targeted drug delivery. As ASPS tumours were implanted subcutaneously, special arrangements were implemented to target them correctly using MRIgFUS-based hyperthermia; the tumour’s position and the focal target for heating must be carefully planned. In this project, we demonstrated the delivery of the drug to ASPS tumours in mice was enhanced in the group using MRIgFUS based hyperthermia in combination with ThermoDXR. However, future experiments must be conducted with larger sample sizes to evaluate significant differences between groups. Additional studies for tumour growth and survival must also be conducted to test this treatment’s therapeutic effects.
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Keywords
cancer, preclinical research, focused ultrasound, magnetic resonance imaging, soft tissue sarcoma
Citation
Siddiqui, M. (2020). The development of a platform for hyperthermia induction in small animal cancer models using MRI guided Focused Ultrasound to test drug delivery of thermosensitive liposomes (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.