Name: Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model (Video) | JoVE Journal
Uploaded: 2023-01-13T14:10:00.000+00:00
Duration: 13 min 41 s
Description: Learn MRI-guided HIFU hyperthermia for targeted sarcoma therapy using a murine rhabdomyosarcoma model. This method enables precise drug delivery with temperature-sensitive liposomes while minimizing systemic toxicity.

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We would like to acknowledge our sources of funding for this project and the personnel involved including: C17 Research Grant, Canada Graduate Scholarship, Ontario Student Opportunity Trust Fund, and James J. Hammond Fund.

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<li>Kok, H. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Heating+technology+for+malignant+tumors%3A+a+review%5BTitle%5D)+AND+%22International+Journal+of+Hyperthermia%22%5BJournal%5D)">Heating technology for malignant tumors: a review.</a> International Journal of Hyperthermia. 37 (1), 711-741 (2020).</li>
<li>Kokuryo, D., Kumamoto, E., Kuroda, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Recent+technological+advancements+in+thermometry%5BTitle%5D)+AND+%22Advanced+Drug+Delivery+Reviews%22%5BJournal%5D)">Recent technological advancements in thermometry.</a> Advanced Drug Delivery Reviews. 163, 19-39 (2020).</li>
<li>Bongiovanni, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((3-T+magnetic+resonance-guided+high-intensity+focused+ultrasound+%283+T-MR-HIFU%29+for+the+treatment+of+pain+from+bone+metastases+of+solid+tumors%5BTitle%5D)+AND+%22Support+Care+Cancer%22%5BJournal%5D)">3-T magnetic resonance-guided high-intensity focused ultrasound (3 T-MR-HIFU) for the treatment of pain from bone metastases of solid tumors.</a> Support Care Cancer. 30 (7), 5737-5745 (2022).</li>
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<li>Dewhirst, M. W., Vujaskovic, Z., Jones, E., Thrall, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Re-setting+the+biologic+rationale+for+thermal+therapy%5BTitle%5D)+AND+%22International+Journal+of+Hyperthermia%22%5BJournal%5D)">Re-setting the biologic rationale for thermal therapy.</a> International Journal of Hyperthermia. 21 (8), 779-790 (2005).</li>
<li>Repasky, E. A., Evans, S. S., Dewhirst, M. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Temperature+matters%21+And+why+it+should+matter+to+tumor+immunologists%5BTitle%5D)+AND+%22Cancer+Immunology+Research%22%5BJournal%5D)">Temperature matters! And why it should matter to tumor immunologists.</a> Cancer Immunology Research. 1 (4), 210-216 (2013).</li>
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<li>Shultz, L. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Human+cancer+growth+and+therapy+in+immunodeficient+mouse+models%5BTitle%5D)+AND+%22Cold+Spring+Harbor+Protocols%22%5BJournal%5D)">Human cancer growth and therapy in immunodeficient mouse models.</a> Cold Spring Harbor Protocols. 2014 (7), 694-708 (2014).</li>
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<li>Dunne, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Heat-activated+drug+delivery+increases+tumor+accumulation+of+synergistic+chemotherapies%5BTitle%5D)+AND+%22Journal+of+Controlled+Release%22%5BJournal%5D)">Heat-activated drug delivery increases tumor accumulation of synergistic chemotherapies.</a> Journal of Controlled Release. 308, 197-208 (2019).</li>
<li>Zhao, Y. X., Hu, X. Y., Zhong, X., Shen, H., Yuan, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((High-intensity+focused+ultrasound+treatment+as+an+alternative+regimen+for+myxofibrosarcoma%5BTitle%5D)+AND+%22Dermatologic+Therapy%22%5BJournal%5D)">High-intensity focused ultrasound treatment as an alternative regimen for myxofibrosarcoma.</a> Dermatologic Therapy. 34 (2), 14816(2021).</li>
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</ol>

The authors have no financial interests or conflicts of interest to disclose.

The protocol developed herein was used to target hind limb tumors using MRgHIFU for mild HT treatment and release encapsulated drugs from liposomes in vivo. Several critical steps were encountered in this protocol during the pilot study, and optimizing these critical steps accounted for the improved treatment success over the pilot study. First is the complete removal of the hair on the area to be sonicated. Any gas trapping within the fur prevents the ultrasound beam from passing and blocks ultrasound passage i...

An erratum was issued for:&#160;<a href="https://www.jove.com/t/64544">Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model </a>. The Authors section was updated from:
Claire Wunker1,2 
Karolina Piorkowska3 
Ben Keunen3 
Yael Babichev2 
Suzanne M. Wong3,4 
Maximilian Regenold5 
Michael Dunne5 
Julia Nomikos1,2 
Maryam Siddiqui6 
Samuel Pichardo6 
Warren Foltz7 
Adam C. Waspe3,8 
Justin T. Gerstle3,9 
Rebecca A. Gladdy1,2,10 
1 Institute of Medical Science, University of Toronto 
2 2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital 
3 The Wilfred and Joyce Posluns Centre for Image-Guided Innovation and Therapeutic Intervention, The Hospital for Sick Children 
4 Institute of Biomedical Engineering, University of Toronto 
5 Leslie Dan Faculty of Pharmacy, University of Toronto 
6 Departments of Radiology and Clinical Neurosciences, University of Calgary 
7 Department of Radiation Oncology, University of Toronto 
8 Department of Medical Imaging, University of Toronto 
9 Department of Pediatric Surgery, University of Toronto 
10 Department of Surgery, University of Toronto
to:
Claire Wunker1,2 
Karolina Piorkowska3 
Ben Keunen3 
Yael Babichev2 
Suzanne M. Wong3,4 
Maximilian Regenold5 
Michael Dunne5 
Julia Nomikos1,2 
Maryam Siddiqui6 
Samuel Pichardo6 
Warren Foltz7 
Adam C. Waspe3,8 
Justin T. Gerstle3,9 
James M. Drake1,3,4,10 
Rebecca A. Gladdy1,2,10 
1 Institute of Medical Science, University of Toronto 
2 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital 
3 The Wilfred and Joyce Posluns Centre for Image-Guided Innovation and Therapeutic Intervention, The Hospital for Sick Children 
4 Institute of Biomedical Engineering, University of Toronto 
5 Leslie Dan Faculty of Pharmacy, University of Toronto 
6 Departments of Radiology and Clinical Neurosciences, University of Calgary 
7 Department of Radiation Oncology, University of Toronto 
8 Department of Medical Imaging, University of Toronto 
9 Department of Pediatric Surgery, University of Toronto 
10 Department of Surgery, University of Toronto

An erratum was issued for:&#160;<a href="https://www.jove.com/t/64544">Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model
</a>. The Authors section was updated.

Erratum: Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model

Rhabdomyosarcoma (RMS) is a skeletal muscle tumor that most commonly occurs in children and young adults1. Localized disease is often treated with multimodal treatment, including chemotherapy, ionizing radiation, and surgery. The use of multi-drug chemotherapy regimens is more prevalent in pediatric patients, with improved outcomes compared to their adult counterparts2; however, despite ongoing research efforts, the 5-year survival rate remains at around 30% in the most aggressive form of the disease3,4. The chemotherapy standard of care is a multidrug regimen that includes vincristine, cyclophosphamide, and actinomycin D. In cases of relapsed or recurrent disease, alternate chemotherapies are used, including standard (free) doxorubicin (FD) and ifosfamide1. While all these chemotherapies have systemic toxicities, the cardiotoxicity of doxorubicin imposes a life-long dose limitation5-7. To increase the amount of the drug delivered to the tumor and to minimize systemic toxicity, alternative formulations have been developed, including liposomal encapsulation. These can be non-thermosensitive doxorubicin, which has been approved for the treatment of breast cancer and hepatocellular carcinoma, or thermosensitive doxorubicin, for which clinical trials are ongoing8,9,10,11,12,13. Alternative methods for delivering liposomal encapsulated drugs such as multi-vesicular liposomes and ligand-targeted liposomes have been evaluated and show promise for the treatment of tumors9. In this study, the addition of heat has multifactorial impacts, including drug release14. The combination of hyperthermia (HT) generated with magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) and thermosensitive liposomal doxorubicin (TLD) is a novel multimodal therapeutic approach for using this toxic yet effective drug to treat RMS, while minimizing dose-limiting toxicity and potentially increasing the immune response to the tumor.
Doxorubicin releases rapidly from TLD at temperatures &#62;39 &#176;C, well above the average human body temperature of 37 &#176;C but not high enough to cause tissue damage or ablation; this starts to occur at 43 &#176;C, but occurs more rapidly as temperatures approach 60 &#176;C15. Various methods have been used to generate HT in vivo, including lasers, microwaves, radiofrequency ablation, and focused ultrasound, many of which are invasive heating methods16. MRgHIFU is a noninvasive, nonionizing heating method that facilitates precise temperature settings within the target tissue in situ. Magnetic resonance (MR) imaging crucially provides real-time imaging, where computer software can be used, to calculate a thermometry measurement of the tissue throughout treatment; subsequently, this data can be used to control the ultrasound therapy in real time to reach and maintain a desired temperature set point17. MRgHIFU has been tested in various tissue types and can be used for a wide range of temperature treatments, from mild HT to ablation, as well as clinically to successfully treat painful bone metastases18. Additionally, HT has been shown to cause tumor cytotoxicity, modulate protein expression, and alter the immune response in the tumor microenvironment19,20,21,22. One study combined mild HT with TLD, followed by ablation with MRgHIFU, in a synergetic R1 rat model23, resulting in necrosis in the tumor core and drug delivery to the periphery. Traditionally, radiotherapy has been used as an adjunct therapy to damage tumor cells and decrease local disease recurrence. However, its use is limited by lifetime dosing and off-target damage1. Thus, HT is unique in that it can cause some of the same effects without the same toxicities or limitations.
Preclinical animal models for RMS include syngeneic immunocompetent models and patient derived xenografts (PDX) in immunocompromised hosts. While the immunocompromised models allow for growth of the human tumors, they lack the appropriate tumor microenvironment and are limited in their ability to study immune response24. FGFR4-activating mutation is a promising marker for poor prognosis and a potential therapeutic target in adult and pediatric RMS1,25. In the syngeneic RMS models developed in the Gladdy lab, the tumors are able to grow in an immunocompetent host, which develops innate and adaptive immune responses to the tumor26. As HT influences the immune response, observation of the change in the murine immune response is a valuable advantage of this tumor model. To test both the tumor response to TLD in comparison to FD, as well as the change in the immune response of the tumor to both chemotherapy and HT, a protocol was developed and employed to treat syngeneic murine RMS tumors in vivo using MRgHIFU and TLD, which is the focus of this study.

<table><tbody><tr><td>1.5mL Eppendorf tubes</td><td>Eppendorf</td><td>22363204</td><td></td></tr><tr><td>1kb plus DNA Ladder</td><td>Froggabio</td><td>DM015-R500</td><td></td></tr><tr><td>2x HS-Red Taq (PCR mix)</td><td>Wisent</td><td>801-200-MM</td><td></td></tr><tr><td>7 Tesla MRI BioSpec</td><td>Bruker</td><td>T184931</td><td>70/30 BioSpec, Bruker, Ettlingen, Germany</td></tr><tr><td>C1000 Thermal cycler</td><td>Biorad</td><td>1851148</td><td></td></tr><tr><td>Clippers</td><td>Whal Peanut</td><td>8655</td><td></td></tr><tr><td>Compressed ultrasound gel</td><td>Aquaflex</td><td>HF54-004</td><td></td></tr><tr><td>Convection heating device</td><td>3M Bair Hugger</td><td>70200791401</td><td></td></tr><tr><td>Depiliatory cream</td><td>Nair</td><td>61700222611</td><td>Shopper&#039;s Drug Mart</td></tr><tr><td>DMEM</td><td>Wisent</td><td>219-065-LK</td><td></td></tr><tr><td>DNeasy extraction kit</td><td>Qiagen&amp;nbsp;</td><td>69504</td><td></td></tr><tr><td>DPBS</td><td>Wisent</td><td>311-420-CL</td><td></td></tr><tr><td>Drug injection system</td><td>Harvard Apparatus</td><td>PY2 70-2131</td><td>PHD 22/2200 MRI compatible Syringe Pump</td></tr><tr><td>Eye lubricant</td><td>Optixcare</td><td>50-218-8442</td><td></td></tr><tr><td>F10 Media</td><td>Wisent</td><td>318-050-CL</td><td></td></tr><tr><td>FBS</td><td>Wisent</td><td>081-105</td><td></td></tr><tr><td>Froggarose</td><td>FroggaBio</td><td>A87</td><td></td></tr><tr><td>Gel Molecular Imager</td><td>BioRad</td><td>GelDocXR</td><td></td></tr><tr><td>Glutamax</td><td>Wisent</td><td>609-065-EL</td><td></td></tr><tr><td>Heat Lamp</td><td>Morganville Scientific</td><td>HL0100&amp;nbsp;</td><td>Similar to this product</td></tr><tr><td>Intravascular Polyethylene tubing (0.015&quot; ID x 0.043&quot; OD, 20G)</td><td>SAI infusion</td><td>PE-20-100</td><td></td></tr><tr><td>Isoflurane</td><td>Sigma</td><td>792632</td><td></td></tr><tr><td>M25FV24C Cell line</td><td>Gladdy Lab</td><td>N/A</td><td></td></tr><tr><td>Microliter Syringe</td><td>Hamilton</td><td>01-01-7648</td><td></td></tr><tr><td>Molecular Imager Gel Doc XR</td><td>Biorad</td><td>170-8170</td><td></td></tr><tr><td>Mouse holder</td><td>The 3D printing material used was ABS-M30i, and it was printed on FDM Fortus 380mc machine&amp;nbsp;</td><td>N/A</td><td>Dimensions: length = 43 mm, outer radius = 15 mm, inner width (where the mouse would sit) = 20.7 mm.&amp;nbsp;</td></tr><tr><td>MyRun Machine</td><td>Cosmo Bio Co Ltd</td><td>CBJ-IMR-001-EX</td><td></td></tr><tr><td>Nanodrop 8000 Spectrophotometer</td><td>Thermo Scientific</td><td>ND-8000-GL</td><td></td></tr><tr><td>p53 primers</td><td>Eurofins</td><td>N/A</td><td>Custom Primers</td></tr><tr><td>PCR tubes</td><td>Diamed</td><td>SSI3131-06</td><td></td></tr><tr><td>Penicillin/Streptomycin</td><td>Wisent</td><td>450-200-EL</td><td></td></tr><tr><td>Proteus software&amp;nbsp;</td><td>Pichardo lab</td><td>N/A</td><td></td></tr><tr><td>Respiratory monitoring system</td><td>SAII</td><td>Model 1030</td><td>MR-compatible monitoring and gating system for small animals</td></tr><tr><td>Small Bore HIFU device, LabFUS</td><td>Image Guided Therapy</td><td>N/A</td><td>LabFUS, Image Guided Therapy, Pessac, France Number of elements 8&lt;br/&gt; frequency 2.5 MHz&lt;br/&gt; diameter&amp;nbsp; 25 mm&lt;br/&gt; radius of curvature 20 mm&lt;br/&gt; Focal spot size 0.6 mm x 0.6 mm x 2.0 mm&lt;br/&gt; &lt;br/&gt; Motor: axes 2&lt;br/&gt; &lt;br/&gt; Generator:&lt;br/&gt; Number of channels 8&lt;br/&gt; Maximum electrical power/channel Wel 4&lt;br/&gt; Maximum electrical power Wel 32&lt;br/&gt; Bandwidth 0.5 - 5 MHz&lt;br/&gt; Control per channel: Freq., Phase and. amplitude&lt;br/&gt; Measurements per channel: Vrms, Irms, cos(theta)&lt;br/&gt; Duty Cycle at 100% power % 100% for 1 min.&lt;br/&gt; &lt;br/&gt; Transducer:&lt;br/&gt; Number of elements 8&lt;br/&gt; frequency&amp;nbsp; 2.5 MHz&lt;br/&gt; diameter 25 mm&lt;br/&gt; radius of curvature 20 mm&lt;br/&gt; Focal spot size&amp;nbsp; 0.6 mm x 0.6 mm x 2.0 mm</td></tr><tr><td>SYBR Safe</td><td>ThermoFisher Scientific</td><td>S33102</td><td></td></tr><tr><td>TAE</td><td>Wisent</td><td>811-540-FL</td><td></td></tr><tr><td>Tail vein catheter (27G 0.5&quot; )</td><td>Terumo Medical Corp</td><td>15253</td><td></td></tr><tr><td>Thermal probes</td><td>Rugged Monitoring</td><td>L201-08</td><td></td></tr><tr><td>Trypan blue</td><td>ThermoFisher Scientific</td><td>15250061</td><td></td></tr><tr><td>Trypsin</td><td>Wisent</td><td>325-052-EL</td><td></td></tr><tr><td>Ultrasound Gel</td><td>Aquasonic</td><td>PLI 01-08</td><td></td></tr></tbody></table>

magnetic resonance-guided high intensity focused ultrasound generated hyperthermia: a feasible treatment method in a murine rhabdomyosarcoma model

Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time imaging and acoustic energy modulation, this modality enables precise temperature control within a defined area. Many thermal applications are being explored with this noninvasive, nonionizing technology, such as hyperthermia generation, to release drugs from thermosensitive liposomal carriers. These drugs can include chemotherapies such as doxorubicin, for which targeted release is desired due to the dose-limiting systemic side effects, namely cardiotoxicity. Doxorubicin is a mainstay for treating a variety of malignant tumors and is commonly used in relapsed or recurrent rhabdomyosarcoma (RMS). RMS is the most common solid soft tissue extracranial tumor in children and young adults. Despite aggressive, multimodal therapy, RMS survival rates have remained the same for the past 30 years. To explore a solution for addressing this unmet need, an experimental protocol was developed to evaluate the release of thermosensitive liposomal doxorubicin (TLD) in an immunocompetent, syngeneic RMS mouse model using MRgHIFU as the source of hyperthermia for drug release.

Using the MRgHIFU-generated hyperthermia protocol, the tumors in the hind limb were able to be consistently heated to the desired set temperature for the duration of the treatment (Figure 4 shows a representative treatment, 10 or 20 min, n = 65). To consider a treatment to be successful, the ROI had to be maintained above 39 °C for the entirety of the treatment, with &lt;6 °C variation throughout the treatment and without heating of off-target tissue. Additionally, the core temperature had t...

Presented here is a protocol to use controlled hyperthermia, generated by magnetic resonance-guided high intensity focused ultrasound, to trigger drug release from temperature-sensitive liposomes in a rhabdomyosarcoma mouse model.

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is an established method for producing localized hyperthermia. Given the real-time ...

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Cancer Research

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Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model (Video) | JoVE Journal

Magnetic Resonance-Guided High Intensity Focused Ultrasound Generated Hyperthermia: A Feasible Treatment Method in a Murine Rhabdomyosarcoma Model

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