Radio-frequency Ablation Increases Intratumoral Liposomal Doxorubicin Accumulation in a Rat Breast Tumor Model

Monsky, Wayne L.; Kruskal, Jonathan B.; Lukyanov, Anatoly N.; Girnun, Geoffrey D.; Ahmed, Muneeb; Gazelle, G. Scott; Huertas, Juan Carlos; Stuart, Keith; Torchilin, Vladimir P.; Goldberg, S. Nahum

doi:10.1148/radiol.2243011421

Cited by 83 publications

(76 citation statements)

References 33 publications

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“…The uptake of liposomal, but not free, doxorubicin was improved in rodent tumors after hyperthermia (34,35). Intratumoral injection of hyaluronidase before Caelyx administration in the OHS xenografts induced similar improvements in tumor distribution and uptake as found in the present study (36).…”

Section: Discussionsupporting

confidence: 75%

Radiation Improves the Distribution and Uptake of Liposomal Doxorubicin (Caelyx) in Human Osteosarcoma Xenografts

et al. 2004

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Liposomal drug delivery appears to improve the antitumor effect and reduce toxicity compared with the free drug. The therapeutic index may be improved further by combining cytotoxic drugs and radiotherapy. Successful therapy requires that the cytotoxic agents reach the tumor cells. Therefore, we studied tumor growth and the microdistribution of liposomal doxorubicin (Caelyx) with and without additional ionizing radiation in human osteosarcoma xenografts in athymic mice. Caelyx was injected i.v. 1 day before single or fractionated radiotherapy. Both chemoirradiation regimens induced significant tumor growth delays and worked synergistically. Confocal laser scanning microscopy showed that intact liposomes were located in close proximity to endothelial cells, and the distribution of released doxorubicin was heterogeneous. Before radiotherapy, hardly any doxorubicin was localized in the central parts of the tumor. Radiotherapy increased the tumor uptake of doxorubicin by a factor of two to four, with drug being redistributed farther from the vessels in the tumor periphery and located around vessels in the central parts of the tumor. Colocalization of doxorubicin and hypoxic cells showed no distribution of drug into hypoxic areas. Dynamic contrastenhanced magnetic resonance imaging (MRI) 1 day before the injection of Caelyx and 2 days after treatment start showed that the combined treatment reduced the vascular volume and the vascular transfer rate of the MRI tracer. The results show that chemoirradiation with Caelyx induces synergistic treatment effects. Improved intratumoral drug uptake and distribution are responsible to some extent for the enhanced antitumor effect.

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Section: Discussionsupporting

confidence: 75%

Radiation Improves the Distribution and Uptake of Liposomal Doxorubicin (Caelyx) in Human Osteosarcoma Xenografts

et al. 2004

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“…This limitation has led to the development of combination therapies that aim to increase coagulation by modulating biophysical properties such as tumor electrical and thermal conductivity as well as blood fl ow (7)(8)(9)(10) or through coupling the effect of RF ablation with that of chemotherapeutic agents (11)(12)(13)(14). Along these lines, Monsky et al ( 15 ) fi rst reported increased intratumoral drug accumulation in tissues treated with RF…”

Section: Experiments Overviewmentioning

confidence: 99%

Liposomal Doxorubicin Increases Radiofrequency Ablation–induced Tumor Destruction by Increasing Cellular Oxidative and Nitrative Stress and Accelerating Apoptotic Pathways

Solazzo

Ahmed²,

Schor-Bardach³

et al. 2010

Radiology

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Purpose:To determine if oxidative and nitrative stress and/or apoptosis contribute to increased coagulation when combining radiofrequency (RF) ablation with liposomal doxorubicin. Materials and Methods:Animal care committee approval was obtained. R3230 mammary adenocarcinomas in Fischer rats were treated with either RF ablation ( n = 43), 1 mg of intravenously injected liposomal doxorubicin ( n = 26), or combined therapy ( n = 30) and were compared with control subjects ( n = 11). A subset of animals receiving combination therapy ( n = 24) were treated in the presence or absence of N -acetylcysteine (NAC) administered 24 hours and 1 hour before RF ablation. Tumors were analyzed 2 minutes to 72 hours after treatment to determine the temporal range of response by using immunohistochemical staining of the apoptosis marker cleaved caspase-3, phosphorylated g H2AX , and Results:By 4 hours after RF ablation alone, a 0.48-mm 6 0.13 (standard deviation ) peripheral band with 57.0% 6 7.3 cleaved caspase-3 positive cells was noted at the ablation margin, whereas a 0.73-mm 6 0.18 band with 77.7% 6 6.3 positivity was seen for combination therapy ( P , .03 for both comparisons). Combination therapy caused increased and earlier staining for 4-HNE-modifi ed proteins, 8-OHdG, NT, and g H2AX with colocalization to cleaved caspase-3 staining. A rim of increased HSP70 was identifi ed peripheral to the area of cleaved caspase-3. Parameters of oxidative and nitrative stress were signifi cantly inhibited by NAC 1 hour following RF ablation, resulting in decreased cleaved caspase-3 positivity (0.28-mm 6 0.09 band of 25.9% 6 7.4 positivity vs 0.59-mm 6 0.11 band of 62.9% 6 6.0 positivity, P , .001 for both comparisons). Conclusion:Combining RF ablation with liposomal doxorubicin increases cell injury and apoptosis in the zone of increased coagulation by using a mechanism that involves oxidative and nitrative stress that leads to accelerated apoptosis.q RSNA, 2010

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“…RF current was applied for 5 minutes with the generator output titrated to maintain a designated mean tip temperature (70°C 6 2), with a mean current of 90.2 mA 6 22.8 and a range of 49-157 mA. This standardized method of RF ablation application has been demonstrated previously to provide reproducible coagulation volumes with use of this conventional RF ablation system ( 17,30 ).…”

Section: Rf Applicationmentioning

confidence: 99%

“…For this study, we purposefully used the taxol derivative formulation that could be maximally concentrated into liposomal vehicles similar to previously used liposomal doxorubicin. The paclitaxel liposomes were prepared such that the lipid composition in these liposomes was identical to that of liposomal doxorubicin, as has been described in previous work ( 30 ). Briefl y, 0.12 mg of paclitaxel (10 mg/mL solution in methanol) was added to a mixture of egg phosphatidylcholine, cholesterol, and PEG2000-PE…”

Section: Liposomal Agent Preparationmentioning

confidence: 99%

Do Liposomal Apoptotic Enhancers Increase Tumor Coagulation and End-Point Survival in Percutaneous Radiofrequency Ablation of Tumors in a Rat Tumor Model?

Yang

Ahmed²,

Elian³

et al. 2010

Radiology

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Purpose:To characterize effects of combining radiofrequency (RF) ablation with proapoptotic intravenous liposome-encapsulated paclitaxel and doxorubicin on tumor destruction, apoptosis and heat-shock protein (HSP) production, intratumoral drug accumulation, and end-point survival. Materials andMethods:R3230 mammary adenocarcinomas ( n = 177) were implanted in 174 rats in this animal care committee-approved study. Tumors received (a) no treatment, (b) RF ablation, (c) paclitaxel, (d) RF ablation followed by paclitaxel (RF ablation-paclitaxel), (e) paclitaxel before RF ablation (paclitaxel-RF ablation), (f) RF ablation followed by doxorubicin (RF ablation-doxorubicin), (g) paclitaxel followed by doxorubicin without RF ablation (paclitaxel-doxorubicin), or (h) paclitaxel before RF ablation, followed by doxorubicin (paclitaxel-RF ablation-doxorubicin). Tumor coagulation area and diameter were compared at 24-96 hours after treatment. Intratumoral pacli taxel uptake with and without RF ablation were compared. Immunohistochemical staining revealed cleaved caspase-3 and 70-kDa HSP (HSP70 ) expression. Tumors were randomized into eight treatment arms for Kaplan-Meier analysis of defi ned survival end-point (3.0-cm diameter). Results:Paclitaxel-RF ablation increased tumor coagulation over RF ablation or paclitaxel (mean, 14.0 mm 6 0.9 [standard deviation ], 6.7 mm 6 0.6, 2.5 mm 6 0.6, respectively; P , .001). Paclitaxel-RF ablation-doxorubicin had similar tumor coagulation ( P , .05), compared with paclitaxel-RF ablation, at 24 and 96 hours. Mean intratumoral paclitaxel accumulation for paclitaxel-RF ablation (6.76 m g/g 6 0.35) and RF ablation-paclitaxel (9.28 m g/g 6 0.87) increased over that for paclitaxel (0.63 m g/g 6 0.25, P , .001). Paclitaxel substantially increased apoptosis and decreased HSP70 expression at coagulation margin. Mean endpoint survival for paclitaxel-RF ablation-doxorubicin (56.8 days 6 25.3) was greater, compared with that for paclitaxel-RF ablation or RF ablation-paclitaxel (17.6 days 6 2.5), RF ablationdoxorubicin (30.3 days 6 4.9, P , .002), or paclitaxel-doxorubicin (27.9 days 6 4.1, P , .001). Conclusion:Selecting adjuvant liposomal chemotherapies (paclitaxel, doxorubicin) to target cellular apoptosis and HSP production effectively increases RF ablation-induced tumor coagulation and end-point survival, and combined multidrug approach results in even better outcomes.q RSNA, 2010 Supplemental material: http://radiology.rsna.org/lookup/suppl

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Radio-frequency Ablation Increases Intratumoral Liposomal Doxorubicin Accumulation in a Rat Breast Tumor Model

Abstract: RF ablation augments the delivery of systemic antineoplastic agents such as liposomal doxorubicin.

Cited by 83 publications

References 33 publications

Radiation Improves the Distribution and Uptake of Liposomal Doxorubicin (Caelyx) in Human Osteosarcoma Xenografts

Radiation Improves the Distribution and Uptake of Liposomal Doxorubicin (Caelyx) in Human Osteosarcoma Xenografts

Liposomal Doxorubicin Increases Radiofrequency Ablation–induced Tumor Destruction by Increasing Cellular Oxidative and Nitrative Stress and Accelerating Apoptotic Pathways

Do Liposomal Apoptotic Enhancers Increase Tumor Coagulation and End-Point Survival in Percutaneous Radiofrequency Ablation of Tumors in a Rat Tumor Model?

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