04754nas a2200469 4500008004100000022001400041245017300055210006900228260001300297300001100310490000800321520331600329653001203645653002203657653002703679653003003706653001603736653001903752653002403771653003003795653001103825653001003836653002103846653001303867653002903880653003203909653001203941653000903953653002203962653002603984653002604010653002404036100001804060700001804078700002504096700002304121700001804144700002104162700002704183700002004210856005404230 2005 eng d a0033-841900aCombination radiofrequency ablation with intratumoral liposomal doxorubicin: effect on drug accumulation and coagulation in multiple tissues and tumor types in animals.0 aCombination radiofrequency ablation with intratumoral liposomal  c2005 May a469-770 v2353 a

PURPOSE: To determine whether use of radiofrequency (RF) ablation combined with intravenously (IV) administered liposomal doxorubicin, as compared with use of RF ablation or doxorubicin alone, facilitates increased tissue coagulation and interstitial drug accumulation in animal models.

MATERIALS AND METHODS: The institutional animal care and use committee approved this study. In experiment 1, multiple canine sarcomas were implanted in seven mildly immunosuppressed dogs and grown to a mean diameter of 4.8 cm. Tumors were assigned to three treatment groups: internally cooled RF ablation (12 minutes, 2000-mA pulsed technique) followed by IV liposomal doxorubicin (10 mg per animal) (n = 6), RF ablation alone (n = 6), and liposomal doxorubicin alone (n = 4). In experiment 2, the livers and kidneys of 10 rabbits and the thigh muscles of 10 rats were randomly assigned to one of two treatment groups: conventional RF ablation (90 degrees C +/- 2, 5 minutes) followed by IV liposomal doxorubicin (5 mg per rabbit, 1 mg per rat) or RF ablation alone (n = 5, each). Coagulation diameter and interstitial doxorubicin concentration (tissues were homogenized in acid alcohol, with doxorubicin extracted for 24 hours at 5 degrees C and quantified with fluorimetry) were measured 48 hours after treatment and compared. Multivariate analysis of variance and subsequent pairwise t tests (alpha = .05, two-tailed test) were performed.

RESULTS: Data are means +/- standard errors of the mean. A larger diameter of tumor destruction was observed in canine sarcomas treated with RF ablation-liposomal doxorubicin (3.7 cm +/- 0.6) compared with that in tumors treated with RF ablation (2.3 cm +/- 0.1) or liposomal doxorubicin (0.0 cm +/- 0.0) alone (P < .01). A new finding was a completely necrotic red zone (1.6 cm +/- 0.7) surrounding the central RF ablation-induced white coagulation zone. Greater but nonuniform drug uptake was observed particularly in this red zone (77.0 ng/g +/- 18.2) compared with uptake in the central zone (15.1 ng/g +/- 3.2), peripheral area of untreated tumor (38.9 ng/g +/- 8.0), and tumors treated with liposomal doxorubicin alone (43.9 ng/g +/- 6.7 for all regions) (P < .01 for all individual comparisons). In experiment 2, use of combined therapy led to increased coagulation in all tissues (liver: 17.6 mm +/- 3.1, P = .03; kidney: 11.0 mm +/- 3.1, P = .03; muscle: 13.1 mm +/- 1.3, P < .01) compared with use of RF ablation alone (liver, 13.4 mm +/- 1.5; kidney, 7.9 mm +/- 0.7; muscle, 8.6 mm +/- 0.5). Combined therapy, as compared with liposomal doxorubicin therapy alone, was also associated with increased doxorubicin accumulation in liver, kidney, and muscle (1.56 microg/g +/- 0.34, 4.36 microg/g +/- 1.78, and 3.63 microg/g +/- 1.43, respectively, vs 1.00 microg/g +/- 0.18, 1.23 microg/g +/- 0.32, and 0.87 microg/g +/- 0.53, respectively) (P < or = .01 for all individual comparisons).

CONCLUSION: Use of RF ablation combined with liposomal doxorubicin facilitates increased tissue coagulation and interstitial doxorubicin accumulation in multiple tissues and tumor types and may be useful for treatment of large tumors and achieving an ablative margin within the untreated tissue surrounding RF ablation-treated tumors.

10aAnimals10aCatheter Ablation10aChemotherapy, Adjuvant10aCombined Modality Therapy10aDoxorubicin10aDrug Synergism10aExtracellular Fluid10aInjections, Intralesional10aKidney10aLiver10aMuscle, Skeletal10aNecrosis10aNeoplasm Transplantation10aNeoplasms, Multiple Primary10aRabbits10aRats10aRats, Inbred F34410aSarcoma, Experimental10aSoft Tissue Neoplasms10aTissue Distribution1 aAhmed, Muneeb1 aLiu, Zhengjun1 aLukyanov, Anatoly, N1 aSignoretti, Sabina1 aHorkan, Clare1 aMonsky, Wayne, L1 aTorchilin, Vladimir, P1 aGoldberg, Nahum uhttp://microfluidicsciences.com/drupal/?q=node/1503346nas a2200421 4500008004100000022001400041245014900055210006900204260001300273300001200286490000700298520204300305653001902348653001202367653003202379653003602411653002602447653002202473653002702495653001402522653003002536653001602566653001702582653003602599653001902635653001302654653000902667653002202676653001702698653002202715100001802737700002502755700002402780700002002804700002602824700002002850856005402870 2005 eng d a1051-044300aCombined radiofrequency ablation and adjuvant liposomal chemotherapy: effect of chemotherapeutic agent, nanoparticle size, and circulation time.0 aCombined radiofrequency ablation and adjuvant liposomal chemothe c2005 Oct a1365-710 v163 a

PURPOSE: To evaluate the effects of liposomal chemotherapeutic agent, nanoparticle size, and liposome circulation time on tissue coagulation and intratumoral drug uptake when radiofrequency (RF) ablation is combined with adjuvant intravenous liposomal chemotherapy in an animal breast tumor model.

MATERIALS AND METHODS: Ninety-one R3230 mammary adenocarcinoma nodules were implanted in 48 Fischer rats. First, standardized RF ablation was combined with intravenous liposomal doxorubicin, cisplatin, or 5-fluorouracil (35 tumors each). Second, three different-sized doxorubicin-containing nanoparticle preparations were combined with standardized RF ablation. Last, two doxorubicin-containing liposome preparations with different blood elimination half-lives were combined with RF ablation. Coagulation diameter and interstitial doxorubicin concentration were measured 48 hours after treatment and compared with use of statistical analysis.

RESULTS: All combinations of RF with liposomal chemotherapy caused significantly greater tumor necrosis than RF alone (P<.05). Significantly increased necrosis was observed with intravenous liposomal RF/doxorubicin and RF/cisplatin compared with intravenous liposomal RF/5-fluorouracil (P<.01). Greater coagulation was observed with RF combined with 100-nm nanoparticles compared with 20-nm or 250-nm nanoparticles (P=.01 and P=.04, respectively). Additionally, greater intratumoral doxorubicin uptake was observed in the group treated with 20-nm nanoparticles compared with those treated with other sizes of nanoparticles (P<.05). RF plus liposomal doxorubicin produced greater coagulation and intratumoral doxorubicin uptake than RF plus 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid (P<.05).

CONCLUSION: When combined with RF ablation, modification of adjuvant intravenous liposomal chemotherapy, including nanoparticle size, circulation time, and chemotherapeutic agent, can influence intratumoral drug accumulation and tissue coagulation.

10aAdenocarcinoma10aAnimals10aAntibiotics, Antineoplastic10aAntimetabolites, Antineoplastic10aAntineoplastic Agents10aCatheter Ablation10aChemotherapy, Adjuvant10aCisplatin10aCombined Modality Therapy10aDoxorubicin10aFluorouracil10aMammary Neoplasms, Experimental10aNanostructures10aNecrosis10aRats10aRats, Inbred F34410aTime Factors10aTreatment Outcome1 aAhmed, Muneeb1 aLukyanov, Anatoly, N1 aTorchilin, Vladimir1 aTournier, Herve1 aSchneider, Anatoly, N1 aGoldberg, Nahum uhttp://microfluidicsciences.com/drupal/?q=node/1403541nas a2200469 4500008004100000022001400041245015800055210006900213260001300282300001200295490000800307520208900315653001202404653002602416653002202442653003002464653001602494653001102510653002702521653001402548653003602562653001302598653002902611653002502640653000902665653002202674653002602696653002602722100002002748700002402768700002502792700001802817700002102835700001902856700002602875700002102901700002002922700002802942700002202970700002502992856005403017 2002 eng d a0033-841900aPercutaneous tumor ablation: increased necrosis with combined radio-frequency ablation and intravenous liposomal doxorubicin in a rat breast tumor model.0 aPercutaneous tumor ablation increased necrosis with combined rad c2002 Mar a797-8040 v2223 a

PURPOSE: To determine whether a combination of intravenous liposomal doxorubicin and radio-frequency (RF) ablation increases tumor destruction compared with RF alone in an animal tumor model.

MATERIALS AND METHODS: R3230 mammary adenocarcinoma 1.4-1.8-cm- diameter nodules were implanted subcutaneously in 132 female Fischer rats. Initially, tumors were treated with (a) conventional, monopolar RF (mean, 250 mA +/- 25 [SD] at 70 degrees C +/- 1 for 5 minutes) ablation alone, (b) RF ablation followed by intravenous administration of 1 mg of liposomal doxorubicin, (c) RF ablation followed by intravenous administration of 1 mg of empty liposomes, (d) RF ablation and direct intratumoral administration of liposomal doxorubicin, or (e) no treatment. Subsequently, the dose (0.06-2.00 mg) of liposomal doxorubicin, the timing of administration (3 days before to 3 days after RF ablation), and the time of pathologic examination (0-72 hours after treatment) were varied.

RESULTS: Mean coagulation diameter for treated tumors follows: 6.7 mm +/- 0.6, RF ablation alone; 11.1 mm +/- 1.5, RF ablation and intravenous administration of empty liposomes (P <.05, compared with RF ablation alone); and 8.4 mm +/- 1.1, RF ablation with intratumoral administration of liposomal doxorubicin (P <.05, compared with RF ablation alone). Maximal increased mean coagulation diameter (13.1 mm +/- 1.5) was observed with a combination of liposomal doxorubicin and RF ablation (P <.001, for all comparisons). The increased coagulation for combination therapy developed over 48 hours after therapy. Coagulation diameter did not vary with the doxorubicin concentration range and was not dependent on the timing of administration of liposomal doxorubicin from 3 days before to 24 hours after RF ablation.

CONCLUSION: Intravenous administration of liposomal doxorubicin can improve RF ablation, since it increases coagulation diameter in solid tumors compared with RF ablation alone or a combination of RF ablation with administration of empty liposomes.

10aAnimals10aAntineoplastic Agents10aCatheter Ablation10aCombined Modality Therapy10aDoxorubicin10aFemale10aInfusions, Intravenous10aLiposomes10aMammary Neoplasms, Experimental10aNecrosis10aNeoplasm Transplantation10aPolyethylene Glycols10aRats10aRats, Inbred F34410aSurface-Active Agents10aTumor Cells, Cultured1 aGoldberg, Nahum1 aGirnan, Geoffrey, D1 aLukyanov, Anatoly, N1 aAhmed, Muneeb1 aMonsky, Wayne, L1 aGazelle, Scott1 aHuertas, Juan, Carlos1 aStuart, Keith, E1 aJacobs, Timothy1 aTorchillin, Vladimir, P1 aHalpern, Elkan, F1 aKruskal, Jonathan, B uhttp://microfluidicsciences.com/drupal/?q=node/2903377nas a2200397 4500008004100000022001400041245011600055210006900171260001300240300001000253490000800263520219300271653001902464653001202483653002602495653002002521653002202541653001602563653001102579653002802590653001402618653003602632653000902668653002202677100002102699700002502720700002502745700002402770700001802794700001902812700002602831700002102857700002702878700002002905856005402925 2002 eng d a0033-841900aRadio-frequency ablation increases intratumoral liposomal doxorubicin accumulation in a rat breast tumor model.0 aRadiofrequency ablation increases intratumoral liposomal doxorub c2002 Sep a823-90 v2243 a

PURPOSE: To determine whether intratumoral accumulation of liposomal doxorubicin or free unencapsulated doxorubicin is increased when combined with radio-frequency (RF) ablation.

MATERIALS AND METHODS: Two 1.2-1.5-cm R3230 mammary adenocarcinomas were grown within the mammary fat pads of 19 female Fischer rats. One tumor of each pair was treated with RF ablation (tip temperature, 70 degrees C +/- 2 [SD]; 120 mA +/- 75) for 5 minutes, whereas the other tumor was a control. Intravenous liposomal doxorubicin (1 mg in 500 micro L, n = 6) or intravenous free unencapsulated doxorubicin (n = 7) was administered immediately following RF ablation. Doxorubicin was extracted in acid alcohol from tumors 24 hours following RF ablation, and fluorescent spectrophotometry was used to quantify extracted doxorubicin. Comparisons of intratumoral doxorubicin accumulation in tumors treated with RF ablation and in untreated tumors were analyzed with parametric (paired Student t test) and nonparametric (Wilcoxon rank sum test) statistics. Findings at autoradiography with densitometry (six additional tumors) demonstrated the spatial distribution of the intratumoral accumulation of liposomal doxorubicin.

RESULTS: When RF ablation preceded administration of liposomal doxorubicin, mean intratumoral doxorubicin concentration was 5.6 micro g/g +/- 2.1 (range, 1.9-7.7 micro g/g), whereas 1.0 micro g/g +/- 0.4 (range, 0.5-1.5 micro g/g) was present in control tumors not treated with RF ablation (P <.05). Thus, there was a mean 7.1-fold +/- 4.9 increase in intratumoral doxorubicin accumulation following RF ablation (range, 2.1-14.5-fold) compared with the amount without RF pretreatment (P <.05). Increased intratumoral accumulation was not seen in animals receiving free doxorubicin with (mean, 0.4 micro g/g +/- 0.1) or without (mean, 0.8 micro g/g +/- 0.4) RF pretreatment (P =.07). Autoradiographic findings demonstrated accumulation of liposomal doxorubicin in a peripheral rim of tumor adjacent to the zone of coagulation.

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

10aAdenocarcinoma10aAnimals10aAntineoplastic Agents10aAutoradiography10aCatheter Ablation10aDoxorubicin10aFemale10aInjections, Intravenous10aLiposomes10aMammary Neoplasms, Experimental10aRats10aRats, Inbred F3441 aMonsky, Wayne, L1 aKruskal, Jonathan, B1 aLukyanov, Anatoly, N1 aGirnun, Geoffrey, D1 aAhmed, Muneeb1 aGazelle, Scott1 aHuertas, Juan, Carlos1 aStuart, Keith, E1 aTorchilin, Vladimir, P1 aGoldberg, Nahum uhttp://microfluidicsciences.com/drupal/?q=node/27