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Increased Duration of Heating Boosts Local Drug Deposition during Radiofrequency Ablation in Combination with Thermally Sensitive Liposomes (ThermoDox) in a Porcine Model.

Swenson CE, Haemmerich D, Maul DH, Knox B, Ehrhart N, Reed RA - PLoS ONE (2015)

Bottom Line: This may reduce recurrence and be more effective than thermal ablation alone.Each pig received a single, 50 mg/m2 dose of the clinical LTLD formulation (ThermoDox®).The mean Cmax of plasma total doxorubicin was 26.5 μg/ml at the end of the infusion.

View Article: PubMed Central - PubMed

Affiliation: Celsion Corporation, Lawrenceville, NJ, United States of America.

ABSTRACT

Introduction: Radiofrequency ablation (RFA) is used for the local treatment of liver cancer. RFA is effective for small (<3 cm) tumors, but for tumors > 3 cm, there is a tendency to leave viable tumor cells in the margins or clefts of overlapping ablation zones. This increases the possibility of incomplete ablation or local recurrence. Lyso-Thermosensitive Liposomal Doxorubicin (LTLD), is a thermally sensitive liposomal doxorubicin formulation for intravenous administration, that rapidly releases its drug content when exposed to temperatures >40°C. When used with RFA, LTLD releases its doxorubicin in the vasculature around the zone of ablation-induced tumor cell necrosis, killing micrometastases in the ablation margin. This may reduce recurrence and be more effective than thermal ablation alone.

Purpose: The purpose of this study was to optimize the RFA procedure used in combination with LTLD to maximize the local deposition of doxorubicin in a swine liver model. Pigs were anaesthetized and the liver was surgically exposed. Each pig received a single, 50 mg/m2 dose of the clinical LTLD formulation (ThermoDox®). Subsequently, ablations were performed with either 1, 3 or 6 sequential, overlapping needle insertions in the left medial lobe with total ablation time of 15, 45 or 90 minutes respectively. Two different RFA generators and probes were evaluated. After the final ablation, the ablation zone (plus 3 cm margin) was dissected out and examined for doxorubicin concentration by LC/MS and fluorescence.

Conclusion: The mean Cmax of plasma total doxorubicin was 26.5 μg/ml at the end of the infusion. Overall, increased heat time from 15 to 45 to 90 minutes shows an increase in both the amount of doxorubicin deposited (up to ~100 μg/g) and the width of the ablation target margin to which doxorubicin is delivered as determined by tissue homogenization and LC/MS detection of doxorubicin and by fluorescent imaging of tissues.

No MeSH data available.


Related in: MedlinePlus

Plain and fluorescent images of ablation zone in pigs in Study B, group 1.Each pig received a single 12 minutes ablation and 3 minute cool down (total time = 15 minutes) with the Covidien device. Scale is μg/g doxorubicin.
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pone.0139752.g003: Plain and fluorescent images of ablation zone in pigs in Study B, group 1.Each pig received a single 12 minutes ablation and 3 minute cool down (total time = 15 minutes) with the Covidien device. Scale is μg/g doxorubicin.

Mentions: Slices of the ablation zones were also imaged for fluorescent signal attributed to free doxorubicin. Figs 3, 4 and 5 show plain and fluorescent images of the ablations zones from pigs in groups 1, 2 and 3 respectively. The actual ablation zone surrounding the probe tracks shows coagulation necrosis. This tissue is non-viable and is not perfused, thus doxorubicin from LTLD does not diffuse into these areas and these areas are dark in the fluorescent images. When used with RFA, intravenously administered LTLD takes advantage of the tissue surrounding the ablation where the temperature exceeds 40°C but is still well perfused and viable, resulting in triggered intravascular release (TIR) of drug in the tumor margins where micrometastases may occur.


Increased Duration of Heating Boosts Local Drug Deposition during Radiofrequency Ablation in Combination with Thermally Sensitive Liposomes (ThermoDox) in a Porcine Model.

Swenson CE, Haemmerich D, Maul DH, Knox B, Ehrhart N, Reed RA - PLoS ONE (2015)

Plain and fluorescent images of ablation zone in pigs in Study B, group 1.Each pig received a single 12 minutes ablation and 3 minute cool down (total time = 15 minutes) with the Covidien device. Scale is μg/g doxorubicin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592068&req=5

pone.0139752.g003: Plain and fluorescent images of ablation zone in pigs in Study B, group 1.Each pig received a single 12 minutes ablation and 3 minute cool down (total time = 15 minutes) with the Covidien device. Scale is μg/g doxorubicin.
Mentions: Slices of the ablation zones were also imaged for fluorescent signal attributed to free doxorubicin. Figs 3, 4 and 5 show plain and fluorescent images of the ablations zones from pigs in groups 1, 2 and 3 respectively. The actual ablation zone surrounding the probe tracks shows coagulation necrosis. This tissue is non-viable and is not perfused, thus doxorubicin from LTLD does not diffuse into these areas and these areas are dark in the fluorescent images. When used with RFA, intravenously administered LTLD takes advantage of the tissue surrounding the ablation where the temperature exceeds 40°C but is still well perfused and viable, resulting in triggered intravascular release (TIR) of drug in the tumor margins where micrometastases may occur.

Bottom Line: This may reduce recurrence and be more effective than thermal ablation alone.Each pig received a single, 50 mg/m2 dose of the clinical LTLD formulation (ThermoDox®).The mean Cmax of plasma total doxorubicin was 26.5 μg/ml at the end of the infusion.

View Article: PubMed Central - PubMed

Affiliation: Celsion Corporation, Lawrenceville, NJ, United States of America.

ABSTRACT

Introduction: Radiofrequency ablation (RFA) is used for the local treatment of liver cancer. RFA is effective for small (<3 cm) tumors, but for tumors > 3 cm, there is a tendency to leave viable tumor cells in the margins or clefts of overlapping ablation zones. This increases the possibility of incomplete ablation or local recurrence. Lyso-Thermosensitive Liposomal Doxorubicin (LTLD), is a thermally sensitive liposomal doxorubicin formulation for intravenous administration, that rapidly releases its drug content when exposed to temperatures >40°C. When used with RFA, LTLD releases its doxorubicin in the vasculature around the zone of ablation-induced tumor cell necrosis, killing micrometastases in the ablation margin. This may reduce recurrence and be more effective than thermal ablation alone.

Purpose: The purpose of this study was to optimize the RFA procedure used in combination with LTLD to maximize the local deposition of doxorubicin in a swine liver model. Pigs were anaesthetized and the liver was surgically exposed. Each pig received a single, 50 mg/m2 dose of the clinical LTLD formulation (ThermoDox®). Subsequently, ablations were performed with either 1, 3 or 6 sequential, overlapping needle insertions in the left medial lobe with total ablation time of 15, 45 or 90 minutes respectively. Two different RFA generators and probes were evaluated. After the final ablation, the ablation zone (plus 3 cm margin) was dissected out and examined for doxorubicin concentration by LC/MS and fluorescence.

Conclusion: The mean Cmax of plasma total doxorubicin was 26.5 μg/ml at the end of the infusion. Overall, increased heat time from 15 to 45 to 90 minutes shows an increase in both the amount of doxorubicin deposited (up to ~100 μg/g) and the width of the ablation target margin to which doxorubicin is delivered as determined by tissue homogenization and LC/MS detection of doxorubicin and by fluorescent imaging of tissues.

No MeSH data available.


Related in: MedlinePlus