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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

Mean (± SEM) plasma concentration of total doxorubicin in pigs in Study A.Pigs (n = 3) received a single, intravenous infusion of LTLD (1.43 mg/kg) over 30 minutes.
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pone.0139752.g001: Mean (± SEM) plasma concentration of total doxorubicin in pigs in Study A.Pigs (n = 3) received a single, intravenous infusion of LTLD (1.43 mg/kg) over 30 minutes.

Mentions: Total plasma doxorubicin for the 3 pigs in study A (each getting 4 sequential, non-overlapping ablations after a 1.43 mg/kg or 50 mg/m2 dose of LTLD) is shown in Fig 1. The mean peak plasma concentration (at the end of infusion) was 26.5 μg/ml (which is similar to the Cmax observed in humans receiving a 50 mg/m2 dose of LTLD [16]) and the estimated half life was 4.83 hours.


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)

Mean (± SEM) plasma concentration of total doxorubicin in pigs in Study A.Pigs (n = 3) received a single, intravenous infusion of LTLD (1.43 mg/kg) over 30 minutes.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139752.g001: Mean (± SEM) plasma concentration of total doxorubicin in pigs in Study A.Pigs (n = 3) received a single, intravenous infusion of LTLD (1.43 mg/kg) over 30 minutes.
Mentions: Total plasma doxorubicin for the 3 pigs in study A (each getting 4 sequential, non-overlapping ablations after a 1.43 mg/kg or 50 mg/m2 dose of LTLD) is shown in Fig 1. The mean peak plasma concentration (at the end of infusion) was 26.5 μg/ml (which is similar to the Cmax observed in humans receiving a 50 mg/m2 dose of LTLD [16]) and the estimated half life was 4.83 hours.

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