Celsion Announces Publication of Research on Fluorescence Imaging of ThermoDox® Uptake in International Journal of Hyperthermia
Independent Analysis Confirms Increasing Heating Time + ThermoDox® Improves Tumor Uptake of Drug, which may be visualized by real-time fluorescence imaging
Study Confirms that ThermoDox® Can Deliver Doxorubicin in Unprecedented Concentrations Directly into a Targeted Tumor
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The study, titled, “Real-time fluorescence imaging for visualization and drug uptake prediction during drug delivery by thermosensitive liposomes,” may be found here.
Anjan Motamarry, Department of Drug Discovery & Biomedical Sciences, and Department of Pediatrics, Medical University of South Carolina Ayele H. Negussie, Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health Christian Rossmann, Department of Pediatrics, Medical University of South Carolina James Small, Department of Public Health Sciences, Medical University of South Carolina Marissa Wolfe, Department of Comparative Medicine, Medical University of South Carolina Bradford J. Wood, Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health
- Dieter Haemmerich,
Department of Pediatrics, Medical University of South Carolinaand Department of Bioengineering, Clemson University
Both Dr. Wood and Dr. Haemmerich have worked extensively with
This group used a LTSL-Dox to perform their experiments and confirmed several characteristics of the compound and its delivery mechanism that support the use of ThermoDox plus radiofrequency ablation in the treatment of HCC, as visualized by fluorescent imaging. Researchers used a custom designed hyperthermal (HT) probe to heat the tumors in nude mice carrying
- Fluorescence Intensity Tumor Region of Interest (ROI) of heated tumors was enhanced:
- 4.6-fold (at 15 mins)
- 9.3-fold (at 30 mins)
- 13.2-fold (at 60 mins)
- Tumor doxorubicin concentration of heated tumors was enhanced:
- 1.9-fold (at 15 mins)
- 2.9-fold (at 30 mins)
- 5.2-fold (at 60 mins)
- Fluorescence intensity of LTSL-Dox increased by:
- 6% when heated to 40°C
- 11% when heated to 43°C
- There was a good correlation between fluorescence of tumor and tumor drug uptake
- Heat duration predicted tumor drug uptake (drug concentration) (p=0.02)
Commenting on the study, Dr. Haemmerich said, “This study provides visual proof of the power of heating LTSL-Dox and its ability to target tumors with increased concentration of doxorubicin delivered by a thermally sensitive liposomal formulation. Following infusion of LTSL-Dox, we found that the duration of hyperthermia dictated the tumor drug uptake, with each additional minute of hyperthermia enhancing drug uptake by 0.31 ug/g. We also demonstrated that fluorescence intensity was predictive of tumor drug concentrations, which may enable methods for real-time monitoring of drug uptake in patients in the future.”
“This study appears to support previously announced findings published by researchers at the NIH based on ThermoDox® and the HEAT study. There, in a prospective subgroup of 285 patients where RFA was applied for more than 45 minutes, a clinical benefit greater than two years was found for patients treated with ThermoDox® plus RFA, compared to RFA alone. These analyses in combination with our published study summarized above lend support to the hypothesis underpinning the OPTIMA Study, Celsion’s Phase III study in newly diagnosed HCC patients,” Dr. Haemmerich concluded.
- An independent computational model developed by Dr. Haemmerich’s group at the
Medical University of South Carolina. The results unequivocally indicate that longer RFA heating times correlate with significant increases in doxorubicin concentration around the RFA treated tissue.
- A prospective preclinical study in 22 pigs conducted at
Colorado State University Animal Cancer Centerusing two different manufacturers of RFA and human equivalent doses of ThermoDox® that clearly support the relationship between increased heating duration and doxorubicin concentrations.
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Celsion’s most advanced program is a heat-mediated drug delivery technology that employs a novel heat-sensitive liposome engineered to address a range of difficult-to-treat cancers. The first application of this platform is ThermoDox®, a lyso-thermosensitive liposomal doxorubicin (LTLD), whose novel mechanism of action delivers high concentrations of doxorubicin to a region targeted with the application of localized heat at 40°C, just above body temperature. ThermoDox® is positioned for use with multiple heating technologies and has the potential to treat of a broad range of cancers including metastatic liver, recurrent chest wall (RCW) breast cancer and non-muscle invading bladder cancers.
Celsion’s LTLD technology leverages two mechanisms of tumor biology to deliver higher concentrations of drug directly to the tumor site. In the first mechanism, rapidly growing tumors have leaky vasculature, which is permeable to liposomes and enables their accumulation within tumors. Leaky vasculature influences a number of factors within the tumor, including the access of therapeutic agents to tumor cells. Administered intravenously, ThermoDox® is engineered with a half-life to allow significant accumulation of liposomes at the tumor site as these liposomes recirculate in the blood stream. In the second mechanism, when an external heating device heats tumor tissue to a temperature of 40°C or greater, the heat-sensitive liposome rapidly changes structure and the liposomal membrane selectively dissolves, creating openings that can release a chemotherapeutic agent directly into the tumor and into the surrounding vasculature. Drug concentration increases as a function of the accumulation of liposomes at the tumor site, but only where the heat is present. This method damages only the tumor and the area related to tumor invasion, supporting more precise drug targeting.
About the OPTIMA Study
The Phase III OPTIMA Study has enrolled 556 patients in over 60 clinical sites in
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