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

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dc.contributor.advisorPichardo, Samuel
dc.contributor.authorSiddiqui, Maryam
dc.contributor.committeememberPichardo, Samuel
dc.contributor.committeememberCuriel, Laura
dc.contributor.committeememberRobbins, Stephen M.
dc.contributor.committeememberDunn, Jeff F.
dc.contributor.committeememberYanushkevich, Svetlana N.
dc.contributor.committeememberPike, G. Bruce
dc.date2021-02
dc.date.accessioned2020-12-22T20:52:00Z
dc.date.available2020-12-22T20:52:00Z
dc.date.issued2020-12
dc.description.abstractFocused 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.en_US
dc.identifier.citationSiddiqui, 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.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/38491
dc.identifier.urihttp://hdl.handle.net/1880/112897
dc.language.isoengen_US
dc.publisher.facultySchulich School of Engineeringen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectcanceren_US
dc.subjectpreclinical researchen_US
dc.subjectfocused ultrasounden_US
dc.subjectmagnetic resonance imagingen_US
dc.subjectsoft tissue sarcomaen_US
dc.subject.classificationEducation--Sciencesen_US
dc.subject.classificationEducation--Tests and Measurementsen_US
dc.subject.classificationSociology--Theory and Methodsen_US
dc.subject.classificationAnimal Physiologyen_US
dc.subject.classificationBiophysics--Medicalen_US
dc.subject.classificationMedicine and Surgeryen_US
dc.subject.classificationRadiologyen_US
dc.subject.classificationChemistry--Analyticalen_US
dc.subject.classificationBiochemistryen_US
dc.subject.classificationAcousticsen_US
dc.subject.classificationEngineering--Biomedicalen_US
dc.titleThe development of a platform for hyperthermia induction in small animal cancer models using MRI guided Focused Ultrasound to test drug delivery of thermosensitive liposomesen_US
dc.typemaster thesisen_US
thesis.degree.disciplineEngineering – Biomedicalen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameMaster of Science (MSc)en_US
ucalgary.item.requestcopytrueen_US
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