Dataset Information

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

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 ?g/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 ?g/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.

SUBMITTER: Swenson CE

PROVIDER: S-EPMC4592068 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Swenson Christine E CE Haemmerich Dieter D Maul Donald H DH Knox Bridget B Ehrhart Nicole N Reed Robert A RA

PloS one 20151002 10

<h4>Introduction</h4>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 ...[more]

PMID: 26431204

Similar Datasets

Project description:BackgroundTemperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug at hyperthermic temperatures, typically above ~40°C. TSL have been combined with various heating modalities, but there is no consensus on required hyperthermia duration or ideal timing of heating relative to TSL administration. The goal of this study was to determine changes in drug uptake when heating duration and timing are varied when combining TSL with radiofrequency ablation (RF) heating.MethodsWe used computer models to simulate both RF tissue heating and TSL drug delivery, to calculate spatial drug concentration maps. We simulated heating for 5, 12 and 30 min for a single RF electrode, as well as three sequential 12 min ablations for 3 electrodes placed in a triangular array. To support simulation results, we performed porcine in vivo studies in normal liver, where TSL filled with doxorubicin (TSL-Dox) at a dose of 30 mg was infused over 30 min. Following infusion, RF heating was performed in separate liver locations for either 5 min (n = 2) or 12 min (n = 2). After ablation, the animal was euthanized, and liver extracted and frozen. Liver samples were cut orthogonal to the electrode axis, and fluorescence imaging was used to visualize tissue doxorubicin distribution.ResultsBoth in vivo studies and computer models demonstrate a ring-shaped drug deposition within ~1 cm of the visibly coagulated tissue. Drug uptake directly correlated with heating duration. In computer simulations, drug concentration increased by a factor of 2.2x and 4.3x when heating duration was extended from 5 to either 12, or 30 minutes, respectively. In vivo, drug concentration was by a factor of 2.4x higher at 12 vs 5 min heating duration (7.1 μg/g to 3.0 μg/g). The computer models suggest that heating should be timed to maximize area under the curve of systemic plasma concentration of encapsulated drug.ConclusionsBoth computer models and in vivo study demonstrate that tissue drug uptake directly correlates with heating duration for TSL based delivery. Computational models were able to predict the spatial drug delivery profile, and may serve as a valuable tool in understanding and optimizing drug delivery systems.

Project description:BACKGROUND:Pulsed field ablation (PFA) can be myocardium selective, potentially sparing the esophagus during left atrial ablation. In an in vivo porcine esophageal injury model, we compared the effects of newer biphasic PFA with radiofrequency ablation (RFA). METHODS:In 10 animals, under general anesthesia, the lower esophagus was deflected toward the inferior vena cava using an esophageal deviation balloon, and ablation was performed from within the inferior vena cava at areas of esophageal contact. Four discrete esophageal sites were targeted in each animal: 6 animals received 8 PFA applications/site (2 kV, multispline catheter), and 4 animals received 6 clusters of irrigated RFA applications (30 W×30 seconds, 3.5 mm catheter). All animals were survived to 25 days, sacrificed, and the esophagus submitted for pathological examination, including 10 discrete histological sections/esophagus. RESULTS:The animals weight increased by 13.7±6.2% and 6.8±6.3% (P=0.343) in the PFA and RFA cohorts, respectively. No PFA animals (0 of 6, 0%) developed abnormal in-life observations, but 1 of 4 RFA animals (25%) developed fever and dyspnea. On necropsy, no PFA animals (0 of 6, 0%) demonstrated esophageal lesions. In contrast, esophageal injury occurred in all RFA animals (4 of 4, 100%; P=0.005): a mean of 1.5 mucosal lesions/animal (length, -21.8±8.9 mm; width, -4.9±1.4 mm) were observed, including one esophago-pulmonary fistula and deep esophageal ulcers in the other animals. Histological examination demonstrated tissue necrosis surrounded by acute and chronic inflammation and fibrosis. The necrotic RFA lesions involved multiple esophageal tissue layers with evidence of arteriolar medial thickening and fibrosis of periesophageal nerves. Abscess formation and full-thickness esophageal wall disruptions were seen in areas of perforation/fistula. CONCLUSIONS:In this novel porcine model of esophageal injury, biphasic PFA induced no chronic histopathologic esophageal changes, while RFA demonstrated a spectrum of esophageal lesions including fistula and deep esophageal ulcers and abscesses.

Dataset Information

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

Introduction

Purpose

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets