Reversed Lipid-Based Nanoparticles Dispersed in Iodized Oil for Transarterial Chemoembolization.

Transarterial chemoembolization (TACE) is a promising treatment for patients suffering from unresectable liver malignancy. A coarse emulsion of doxorubicin solution and iodized oil is widely used in clinical practice. However, this coarse emulsion lacks sufficient physical stability and can split into water and oil very quickly. Furthermore, most chemotherapeutics are quickly released into systematic circulation, causing serious adverse effects. In this study, we aimed to prepare reversed lipid-based nanoparticles (RLBNs) dispersed in iodized oil as nanocarriers for the delivery of hydrophilic chemotherapeutics. Unlike a simple mixture of drug solution and oil, RLBN is a homogenous system and possesses a hydrophobic nanostructure that has high dispersibility in oils. Hydrophilic chemotherapeutics were entrapped in the polar core juxtaposed by highly biocompatible lipid materials, such as egg phospholipids. A sustained drug-release profile was observed in both in vitro and in vivo pharmacokinetics studies. The results of computed tomography showed that RLBN-doxorubicin-iodized oil could remain in the tumor region for more than 14 days and that the growth of tumors was effectively suppressed. Thus, the current results suggest that RLBN is a promising drug delivery system and is compatible with TACE treatment.

Ultraselective conventional transarterial chemoembolization: When and how?

Ultraselective conventional transarterial chemoembolization (cTACE), defined as cTACE at the most distal portion of the subsubsegmental hepatic artery, is mainly performed for hepatocellular carcinoma (HCC) ≤5 cm. Distal advancement of a microcatheter enables injection of a larger volume of iodized oil into the portal vein in the limited area under non-physiological hemodynamics. As a result, the reversed portal flow into the tumor through the drainage route of the tumor that occurs when the hepatic artery is embolized is temporarily blocked. By adding gelatin sponge slurry embolization, both the hepatic artery and portal vein are embolized and not only complete necrosis of the tumor but also massive peritumoral necrosis can be achieved. Ultraselective cTACE can cure small HCCs including less hypervascular tumor portions and replace surgical resection and radiofrequency ablation in selected patients.

In Vitro Evaluation of the Polymerization Properties of N-Butyl Cyanoacrylate/Iodized Oil Mixtures for Lymphatic Interventions.

PURPOSE: To evaluate polymerization of N-butyl cyanoacrylate (NBCA)/iodized oil mixtures for lymphatic interventions in vitro. MATERIALS AND METHODS: Polymerization times of different NBCA/iodized oil mixtures (ratios of 1:0-1:7) were investigated in a static and dynamic experimental setup (performed in a lymph flow model in a silicone tube). Eight lymphatic samples with different triglyceride (TG) concentrations (low TGs, < 50 mg/dL; medium TGs, approximately 100-400 mg/dL; high TGs, > 700 mg/dL) were investigated. Morphologic changes during NBCA polymerization were monitored and recorded by video. Statistical analysis was performed with intergroup comparisons (Kruskal-Wallis test) and multiple regression analysis. RESULTS: Static experiments showed increasing polymerization times with increasing concentrations of iodized oil as well as increasing concentrations of TGs. In the low-TG group, polymerization time increased from 14 s at a 1:1 ratio of NBCA to iodized oil to 1,336 s at a 1:7 ratio; times in the medium-TG group increased from 21 s (1:1) to 2,546 s (1:7), and those in the high TG group increased from 168 s (1:1) to 16,530 s (1:7). In dynamic experiments, prolongation of polymerization time was less pronounced. For low- and medium-TG groups, total occlusion of the silicon tube was observed in all cases during the embolization procedure at between 26 seconds (1:1 ratio) and 52 seconds (1:7). In the high-TG group, polymerization took considerably longer (between 43 s [1:1] and 467 s [1:7]) or failed completely. CONCLUSIONS: Polymerization time of NBCA/iodized oil in lymph seems to be prolonged by increasing iodized oil and TG concentrations.

Comparison of Combined Therapy Using Conventional Chemoembolization and Radiofrequency Ablation Versus Conventional Chemoembolization for Ultrasound-Invisible Early-Stage Hepatocellular Carcinoma (Barcelona Clinic Liver Cancer Stage 0 or A).

Objective: To compare the therapeutic efficacy between conventional transarterial chemoembolization (cTACE) and combined therapy using cTACE and radiofrequency ablation (RFA) in ultrasound (US)-invisible early stage hepatocellular carcinoma (HCC). Materials and Methods: From January 2008 to June 2016, 167 patients with US-invisible early stage HCCs were treated with cTACE alone (cTACE group; n = 85) or cTACE followed by immediate fluoroscopy-guided RFA targeting intratumoral iodized oil retention (combined group; n = 82). Procedure-related complications, local tumor progression (LTP), time to progression (TTP), and overall survival (OS) were compared between the two groups. Multivariate analyses were performed to identify prognostic factors. Results: There was no major complication in either group. The cTACE group showed higher 1-, 3-, and 5-year LTP rates than the combined group; i.e., 12.5%, 31.7%, and 37.0%, respectively, in the cTACE group; compared to 7.3%, 16.5%, and 16.5%, respectively, in the combined group; p = 0.013. The median TTP was 18 months in the cTACE group and 24 months in the combined group (p = 0.037). Cumulative 1-, 3-, and 5-year OS rates were 100%, 93.2%, and 87.7%, respectively, in the cTACE group and 100%, 96.6%, and 87.4%, respectively, in the combined group (p = 0.686). Tumor diameter > 20 mm and cTACE monotherapy were independent risk factors for LTP and TTP. Conclusion: Combined therapy using cTACE followed by fluoroscopy-guided RFA is a safe and effective treatment in US-invisible early stage HCCs. It provides less LTP and longer TTP than cTACE alone.

An Imaging and Histological Study on Intrahepatic Microvascular Passage of Contrast Materials in Rat Liver.

Background. Lipiodol has been applied for decades in transarterial chemoembolization to treat liver malignancies, but its intrahepatic pathway through arterioportal shunt (APS) in the liver has not been histologically revealed. This rodent experiment was conducted to provide evidence for the pathway of Lipiodol delivered through the hepatic artery (HA) but found in the portal vein (PV) and to elucidate the observed unidirectional APS. Methods. Thirty rats were divided into 5 groups receiving systemic or local arterial infusion of red-stained iodized oil (RIO) or its hydrosoluble substitute barium sulfate suspension (BSS), or infusion of BSS via the PV, monitored by real-time digital radiography. Histomorphology of serial frozen and paraffin sections was performed and quantified. Results. After HA infusion, RIO and BSS appeared extensively in PV lumens with peribiliary vascular plexus (PVP) identified as the responsible anastomotic channel. After PV infusion, BSS appeared predominantly in the PV and surrounding sinusoids and to a much lesser extent in the PVP and HA (P < 0.001). Fluid mechanics well explains the one-way-valve phenomenon of APS. Conclusions. Intravascularly injected rat livers provide histomorphologic evidences: (1) the PVP exists in between the HA and PV, which is responsible to the APS of Lipiodol; and (2) the intrahepatic vascular inflow appears HA-PVP-PV unidirectional without a physical one-way valve, which can be postulated by the fluid mechanics.

Embolization of Arteriovenous Malformations: Effect of Flow Control and Composition of n-Butyl-2 Cyanoacrylate and Iodized Oil Mixtures with and without Ethanol in an in Vitro Model.

Purpose To elucidate the effect of flow control (ie, balloon occlusion) and the composition of various mixtures of n-butyl-2 cyanoacrylate (NBCA) and iodized oil, with and without the addition of ethanol, for the treatment of arteriovenous malformations in an in vitro model. Materials and Methods A simulation circuit device that featured an artificial nidus was filled with heparinized swine blood obtained during exsanguination from another Institutional Animal Care and Use Committee-approved protocol and was constructed to generate pulsatile flow. Mixtures of NBCA and iodized oil (NL) at a 1:1 ratio (NL 1:1); NL and ethanol (NLE) at a 1:1:3 ratio (NLE 1:1:3) with or without flow control; and NL at 1:3, 1:5, and 1:10 ratios without flow control were injected six times each for a total of 42 trials. Embolization was classified as complete filling, proximal occlusion, pass through, or distal overpenetration after occlusion balloon deflation, and the trial results were compared. The results of the embolization test were evaluated by using the Fisher exact probability test to compare optimal and suboptimal embolization groups. Results NLE 1:1:3 with flow control completely filled the nidus in all six trials. NL 1:1 delivered with flow control achieved complete nidus filling in three of six injections, as did the NL 1:5 ratio trial without flow control. Complete embolization with NLE 1:1:3 with flow control was more feasible to achieve complete nidus filling than was NL 1:1 with flow control or NL 1:5 without flow control, although there was no statically significant difference (all, P = .09). None of the other mixtures produced complete embolization. Conclusion NLE 1:1:3 showed consistent and reproducible complete embolization with flow control and was stable after balloon deflation, making it an acceptable material for embolization in an in vitro arteriovenous malformation model. Further study should be performed before the NLE 1:1:3 mixture is used in routine clinical practice. (©) RSNA, 2015.

Preparation and therapeutic evaluation of (188)Re-thermogelling emulsion in rat model of hepatocellular carcinoma.

Radiolabeled Lipiodol(®) (Guerbet, Villepinte, France) is routinely used in hepatoma therapy. The temperature-sensitive hydrogel polyethylene glycol-b-poly-DL-lactic acid-co-glycolic acid-b-polyethylene glycol triblock copolymer is used as an embolic agent and sustained drug release system. This study attempted to combine the polyethylene glycol-b-poly-DL-lactic acid-co-glycolic acid-b-polyethylene glycol hydrogel and radio-labeled Lipiodol to form a new radio-thermogelling emulsion, rhenium-188-N,N'-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride-Lipiodol/hydrogel ((188)Re-ELH). The therapeutic potential of (188)Re-ELH was evaluated in a rodent hepatoma model. Rhenium-188 chelated with N,N'-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride was extracted with Lipiodol to obtain rhenium-188-N,N'-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride-Lipiodol ((188)Re-EL), which was blended with the hydrogel in equal volumes to develop (188)Re-ELH. The (188)Re-ELH phase stability was evaluated at different temperatures. Biodistribution patterns and micro-single-photon emission computed tomography/computed tomography images in Sprague Dawley rats implanted with the rat hepatoma cell line N1-S1 were observed after in situ tumoral injection of ~3.7 MBq (188)Re-ELH. The therapeutic potential of (188)Re-EL (48.58±3.86 MBq/0.1 mL, n=12) was evaluated in a 2-month survival study using the same animal model. The therapeutic effects of (188)Re-ELH (25.52±4.64 MBq/0.1 mL, n=12) were evaluated and compared with those of (188)Re-EL. The responses were assessed by changes in tumor size and survival rates. The (188)Re-ELH emulsion was stable in the gel form at 25°C-35°C for >52 hours. Biodistribution data and micro-single-photon emission computed tomography/computed tomography images of the (188)Re-ELH group indicated that most activity was selectively observed in hepatomas. Long-term (188)Re-ELH studies have demonstrated protracted reductions in tumor volumes and positive effects on the survival rates (75%) of N1-S1 hepatoma-bearing rats. Conversely, the 2-month survival rate was 13% in the control sham group. Therapeutic responses differed significantly between the two groups (P<0.005). Thus, the hydrogel enhanced the injection stability of (188)Re-EL in an animal hepatoma model. Given the synergistic results, direct (188)Re-ELH intratumoral injection is a potential therapeutic alternative for hepatoma treatment.

Iodinated oil-loaded, fluorescent mesoporous silica-coated iron oxide nanoparticles for magnetic resonance imaging/computed tomography/fluorescence trimodal imaging.

In this study, a novel magnetic resonance imaging (MRI)/computed tomography (CT)/fluorescence trifunctional probe was prepared by loading iodinated oil into fluorescent mesoporous silica-coated superparamagnetic iron oxide nanoparticles (i-fmSiO4@SPIONs). Fluorescent mesoporous silica-coated superparamagnetic iron oxide nanoparticles (fmSiO4@SPIONs) were prepared by growing fluorescent dye-doped silica onto superparamagnetic iron oxide nanoparticles (SPIONs) directed by a cetyltrimethylammonium bromide template. As prepared, fmSiO4@SPIONs had a uniform size, a large surface area, and a large pore volume, which demonstrated high efficiency for iodinated oil loading. Iodinated oil loading did not change the sizes of fmSiO4@SPIONs, but they reduced the MRI T2 relaxivity (r2) markedly. I-fmSiO4@SPIONs were stable in their physical condition and did not demonstrate cytotoxic effects under the conditions investigated. In vitro studies indicated that the contrast enhancement of MRI and CT, and the fluorescence signal intensity of i-fmSiO4@SPION aqueous suspensions and macrophages, were intensified with increased i-fmSiO4@SPION concentrations in suspension and cell culture media. Moreover, for the in vivo study, the accumulation of i-fmSiO4@SPIONs in the liver could also be detected by MRI, CT, and fluorescence imaging. Our study demonstrated that i-fmSiO4@SPIONs had great potential for MRI/CT/fluorescence trimodal imaging.

Improved drug targeting to liver tumors after intra-arterial delivery using superparamagnetic iron oxide and iodized oil: preclinical study in a rabbit model.

PURPOSE: The purpose of this study was to evaluate the feasibility and the therapeutic efficacy of a novel drug-delivery system that uses superparamagnetic iron oxide (SPIO) and iodized oil (IO) to improve the selective intra-arterial (IA) drug delivery to an experimentally induced hepatic tumor. MATERIALS AND METHODS: This animal study was approved by our institutional animal care and use committee. Fifteen rabbits with hepatic VX2 carcinomas were treated with IA delivery of 4 different agents: doxorubicin alone (group A, n = 3), doxorubicin/IO (group B, n = 3), a doxorubicin/SPIO complex (group C, n = 4), and a doxorubicin/SPIO/IO complex (group D, n = 5). The infused doxorubicin dose was 1 mg for all groups. The serum doxorubicin concentration was measured at 0, 5, 30, 60, and 120 minutes after the delivery. To assess the distribution of the SPIO, magnetic resonance (MR) scans were performed at day 7 after the delivery, when computed tomographic scans were performed in addition to MR in group B and D to assess the distribution of IO. After the completion of follow-up imaging, all the animals were euthanized to measure the intratumoral doxorubicin concentration and to assess tumor viability through pathologic examination. RESULTS: Groups C and D demonstrated significantly lower MR signal intensities, which inversely corresponded to SPIO deposition, in the tumor areas than did groups A and B. Group D exhibited the lowest serum doxorubicin concentration at all time points up to 180 minutes after the delivery, suggesting minimal passage of doxorubicin into the systemic circulation. The intratumoral doxorubicin concentrations were 72.4 ng/g for group A, 142.0 ng/g for group B, 264.1 ng/g for group C, and 679.6 ng/g for group D. The proportion of viable tumor cells were 65.3% for group A, 1.3% for group B, 17.0% for group C, and 0.1% for group D. CONCLUSIONS: The drug-delivery system developed using SPIO and IO can result in better drug targeting when it is used for IA delivery to liver cancer. The results of this study warrant further investigation of this potential clinical treatment of advanced liver cancer.

Iodinated nano-emulsions as contrast agents for preclinical X-ray imaging: Impact of the free surfactants on the pharmacokinetics.

This study presents new important aspects in the design of contrast agents for X-ray preclinical imaging. The first one is a new simple formulation of long circulating contrast agents, formulated from a commercial iodinated oil, and resulting in CT contrast agents containing more than twice the iodine concentration commercial contrast agents. The second point is a methodological aspect, utilizing tangential filtration for reducing the residual surfactants in the bulk phase and serving as well for concentrating droplets (and iodine) in the suspension. The last point is a more general aspect regarding the influence of the free surfactant on the pharmacokinetics and biodistribution of the nano-emulsion droplets on mice. We showed that cross-flow filtration is efficient for concentrating the droplets and reducing the concentration of free surfactant from 10wt.% to 1wt.%, without any changes in the nano-emulsion droplet morphologies or surface properties. We also showed that the presence of free surfactant has a significant impact on the elimination way of the nano-emulsion droplets, shared between liver and kidneys. The purified nano-emulsions are preferentially eliminated by the kidneys in contrast to raw nano-emulsions, predominantly eliminated by the liver. In practice, for two similar suspensions, half-life decreases from 4.1±1.10h to 2.5±0.77h before and after purification. Since the design and development of long circulating systems are critical in numerous domains, and not for preclinical CT imaging, this study presents important results in that field, taken under a formulation and technical point of view.

Comparison of epirubicin-iodized oil suspension and emulsion for transcatheter arterial chemoembolization in VX2 tumor.

To compare the antitumor efficacy and safety of transcatheter arterial chemoembolization (TACE) by epirubicin suspension (epirubicin suspension: epirubicin-iodized oil mixture without solution) to that by epirubicin emulsion (epirubicin emulsion: epirubicin-iodized oil mixture with solution), the efficacy of treatment by administration of either an epirubicin suspension or emulsion was examined in an animal model. Changes in plasma epirubicin concentration were compared over 24 h immediately after treatment, and enhanced ultrasonographic and histopathological analysis subsequently conducted 7 days after treatment to determine the growth ratio and proportion of viable tumor cells. The growth ratio and proportion of viable tumor cells were found to be significantly lower in the suspension group than in the emulsion group while the plasma epirubicin concentration was found to be significantly higher in the suspension group than in the emulsion group. These results indicate that administration of an epirubicin suspension is a superior form of TACE compared to that of administration of an epirubicin emulsion.

Radiopaque drug-eluting beads for transcatheter embolotherapy: experimental study of drug penetration and coverage in swine.

PURPOSE: To determine local doxorubicin levels surrounding radiopaque drug-eluting beads (DEBs) in normal swine liver and kidney following transcatheter arterial chemoembolization. The influence of bead size (70-150 µm or 100-300 µm) was compared with regard to tissue penetration and spatial distribution of the bead, as well as eventual drug coverage (ie, amount of tissue exposed to drug). MATERIALS AND METHODS: Radiopaque DEBs were synthesized by suspension polymerization followed by incorporation of iodized oil and doxorubicin. Chemoembolization of swine liver and kidney was performed under fluoroscopic guidance. Three-dimensional tissue penetration of "imageable" DEBs was investigated ex vivo with micro-computed tomography (microCT). Drug penetration from the bead surface and drug coverage was evaluated with epifluorescence microscopy, and cellular localization of doxorubicin was evaluated with confocal microscopy. Necrosis was evaluated with hematoxylin and eosin staining. RESULTS: MicroCT demonstrated that 70-150-µm DEBs were present in more distal arteries and located in a more frequent and homogeneous spatial distribution. Tissue penetration of doxorubicin from the bead appeared similar (∼300 µm) for both DEBs, with a maximum tissue drug concentration at 1 hour coinciding with nuclear localization of doxorubicin. The greater spatial frequency of the 70-150-µm DEBs resulted in approximately twofold improved drug coverage in kidney. Cellular death is predominantly observed around the DEBs beginning at 8 hours, but increased at 24 and 168 hours. CONCLUSIONS: Smaller DEBs penetrated further into targeted tissue (ie, macroscopic) with a higher spatial density, resulting in greater and more uniform drug coverage (ie, microscopic) in swine.

Novel intraarterial therapy for liver cancer using ethylbromopyruvate dissolved in an iodized oil.

RATIONALE AND OBJECTIVES: In spite of various therapies developed, hepatocellular carcinoma still shows poor prognosis. In this study, we introduced ethylbromopyruvate (EBrP), a hydrophobic derivative of 3-bromopyruvate, as an agent for intraarterial therapy of hepatocellular carcinoma. MATERIALS AND METHODS: In in vitro study, we evaluated whether EBrP induced apoptotic cell death in Huh-BAT cells. Chemical degradation products of EBrP were identified by performing proton nuclear magnetic resonance spectroscopy and thin layer chromatography. VX2 carcinoma was implanted and grown in the liver of 25 rabbits for in vivo study. By transfemoral intraarterial approach, 0.4 mL of 10 mM and 40 mM EBrP dissolved in an iodized oil (Lipiodol) was infused into the proper hepatic artery in 8 and 10 rabbits, respectively. In the remaining seven rabbits, 0.4 mL of Lipiodol alone was intraarterially injected as a control. One week later, tumor necrosis rate was calculated with histopathologic examination and hepatotoxicity was evaluated with biochemical analysis. RESULTS: EBrP induced apoptosis in human HCC cells via mitochondrial apoptotic signaling cascades. EBrP dissociated into 3-bromopyruvate and ethanol in the aqueous environment. In VX2 liver tumor models, the group of intraarterial delivery of 40 mM EBrP/Lipiodol solution showed higher tumor necrosis rates (96.1% ± 3.8) than the other groups (38.9% ± 15.9 of a control, 90.5% ± 2.9 in 10 mM) (P < .05). There was transient elevation of AST and ALT enzyme levels without any mortality. CONCLUSIONS: Intraarterial infusion of EBrP/Lipiodol solution is a feasible intraarterial therapy for liver tumors with potent antitumor effects and transient hepatotoxicity.

Block-copolymer-stabilized iodinated emulsions for use as CT contrast agents.

The objective of this study was to develop radiopaque iodinated emulsions for use as CT blood pool contrast agents. Three hydrophobic iodinated oils were synthesized based on the 2,3,5-triiodobenzoate moiety and formulated into emulsions using either phospholipids or amphiphilic polymers, i.e. Pluronic F68 and poly(butadiene)-b-poly(ethylene glycol) (PBD-PEO), as emulsifiers. The size, stability and cell viability was investigated for all stabilized emulsions. Three emulsions stabilized with either lipids or PBD-PEO were subsequently tested in vivo as a CT blood pool contrast agent in mice. While the lipid-stabilized emulsions turned out unstable in vivo, polymer-stabilized emulsions performed well in vivo. In blood, a contrast enhancement of 220 Hounsfield Units (HU) was measured directly after intravenous administration of 520 mg I/kg. The blood circulation half-life of a PBD-PEO stabilized emulsion was approximately 3 h and no noticeable in vivo toxicity was observed. These results show the potential of above emulsions for use as blood pool agents in contrast enhanced CT imaging.

Feasibility of interstitial CT lymphography using optimized iodized oil emulsion in rats.

OBJECTIVES: To formulate an iodine-based contrast agent with an oil-in-water emulsion and to evaluate the feasibility of the agent for use as an interstitial computed tomographic (CT) lymphographic agent in a normal rat model. MATERIALS AND METHODS: The effect of iodized oil (lipiodol) content and the type of surfactant/cosurfactant on the resultant emulsion size and polydispersity was investigated to obtain an optimized lipiodol emulsion for CT lymphography. Optimized emulsions (144 mg/mL) were injected in the hind paws of 6 rats, using 0.5 mL per paw. As control groups, iopamidol solution and lipiodol diluted with squalene to adjust the injection volume with iodine concentration equivalent to the emulsions were used. Precontrast and postcontrast CT images up to 1 week after contrast agent injection were obtained. Time-enhancement curves of the popliteal lymph nodes were obtained. Analysis of variance and post hoc analysis with the Dunn procedure were used for comparing mean peak enhancement, time to peak enhancement, and sustained duration of contrast enhancement. RESULTS: Optimized emulsion formulations composed of 30% lipiodol and 282 mg/mL of 9:1 surfactant mixture (Tween 80:TPGS [alpha-tocopheryl polyethylene glycol succinate], Tween 80:Kollidon 12 PF, or Tween 80:Span 85) exhibited mean particle size less than 120 nm, and they were stable without significant particle size change up to 1 month. Targeted lymph nodes in all emulsion groups showed continuously increasing enhancement until 4 or 8 hours after injection, followed by continuous washout. Peak enhancement (time to peak enhancement) was 172.4 +/- 54.5 HU (Hounsfield unit) (384.0 +/- 131.5 minutes) for Tween 80:TPGS; 172.8 +/- 28.0 HU (432.0 +/- 107.3 minutes) for Tween 80:Kollidon 12 PF, and 177.2 +/- 68.9 HU (294.0 +/- 190.2 minutes) for Tween 80:Span 85. For iopamidol, peak enhancement of 153.0 +/- 46.1 HU (0.5 +/- 0.5 minutes) occurred early with rapid washout. For lipiodol as a reference agent, contrast enhancement continuously increased even 1 week after injection without washout (peak enhancement, 486.0 +/- 97.4 HU). Peak enhancement among the emulsion groups and the iopamidol group was not statistically different (P = 0.95). All emulsion groups showed more prolonged enhancement than the iopamidol group; enhancement duration for the emulsion groups was 534.0 +/- 481.1 minutes for Tween 80:TPGS; 957.0 +/- 524.8 minutes for Tween 80:Kollidon 12 PF; and 750.0 +/- 566.0 minutes for Tween 80:Span 85, and enhancement duration for iopamidol was 8.2 +/- 12.3 minutes (all P < 0.05 in multiple comparisons). However, there was no significant difference in enhancement duration among the 3 emulsion groups (P > 0.05). CONCLUSIONS: Iodized oil emulsion made with a surfactant mixture (Tween 80 as the main surfactant and TPGS, Kollidon 12 PF, or Span 85 as the cosurfactant) provided sufficient and sustained contrast enhancement on CT of targeted lymph nodes with washout on delayed phase.

Transcatheter arterial infusion chemotherapy with cisplatin-lipiodol suspension in patients with hepatocellular carcinoma.

PURPOSE: The aim of this study was to investigate the antitumor efficacy of treatment, identify prognostic factors, and construct a prognostic index in patients with hepatocellular carcinoma treated by transcatheter arterial infusion chemotherapy (TAI) using cisplatin suspended in lipiodol. METHODS: We analyzed the outcomes in a total of 94 consecutive patients with previously untreated hepatocellular carcinoma who were treated by TAI using cisplatin suspended in lipiodol. RESULTS: Twenty-seven patients (29%) showed complete response and 21 patients (22%) showed partial response, with an overall response rate of 51% (95% confidence interval, 41-61%). The median survival time was 2.5 years and the proportions of survivors at 1, 2, and 5 years were 81.6, 65.2, and 18.3%, respectively. The results of multivariate analysis indicated a significant association of serum albumin > or =3.0 g/dL, maximum tumor size < or =3.0 cm, absence of ascites, and unilateral distribution of the tumors with a favorable survival. For clinical application, we also propose a prognostic index based on a combination of these prognostic factors. Based on this index, the patients were classified into three groups: those with good, intermediate, and poor prognosis. The median survival times in these three groups were 4.3, 2.7, and 1.1 years, respectively (p < 0.01). CONCLUSIONS: TAI with cisplatin suspended in lipiodol exhibited favorable tumor efficacy and survival in patients with hepatocellular carcinoma. The prognostic factors identified and the index proposed based on these factors may be useful for predicting life expectancy, determining treatment strategies, and designing future clinical trials.

Preparation and evaluation of 99mTc(CO)3-labeled pentadecanoic acid derivative and its suspension in lipiodol.

Abstract Transarterial embolization by the intra-arterial administration of 131I-lipiodol is a modality used in the treatment of liver cancer. Long-chain fatty acids, being highly lipophilic, are also known to localize in the liver, thus constituting favorable vectors for this modality of treatment. Toward this, we envisaged the derivatization of 15-bromopentadecanoic acid, rendering it suitable for incorporation of a tridentate chelating moiety, for radiolabeling with the [99mTc(CO)3(H2O)3]+ precursor. The complex prepared, being lipophilic, was expected to behave as a lipiodol surrogate. The radiolabeled complex could be obtained in >95% radiochemical yield, as characterized by high-performance liquid chromatography. The intravenous injection of the radiolabeled complex in mice resulted in 23.5% +/- 4.3% uptake of injected dose (ID) organ in the liver at 3 hours postinjection. However, the uptake of the lipiodol suspension of the complex at 3 hours postinjection in the liver was found to be 43.8 +/- 13.4% ID/organ, when injected via the portal vein.

Formulation considerations of gadolinium lipid nanoemulsion for intravenous delivery to tumors in neutron-capture therapy.

The effects of the formulation and particle composition of gadolinium (Gd)-containing lipid nanoemulsion (Gd-nanoLE) on the biodistribution of Gd after its intravenous (IV) injection in D(1)-179 melanoma-bearing hamsters were evaluated for its application in cancer neutron-capture therapy. Gd-nanoLEs whose particles had an oily core (soybean oil, ethyl oleate, lipiodol, or triolein) and a surface layer of hydrogenated phosphatidylcholine, gadolinium-diethyl-enetriaminepentaacetic acid-distearylamide, and a cosurfactant (Myrj 53, Brij 700, or HCO-60) were prepared by a thin-layer hydration-sonication method. Biodistribution data revealed that Brij 700 and HCO-60 prolonged the retention of Gd in the blood and enhanced its accumulation in tumors. Among the core components employed, soybean oil yielded the highest Gd concentration in the blood and tumor and the lowest in the liver and spleen. Gd-nanoLEs with a Gd content of 1.5-4.5 mg/ml could be formulated by using HCO-60 and soybean oil at a constant oil-to-water ratio, and by enriching Gd in the surface layer with the particle size maintained below 100 nm. When each Gd-nanoLE was IV injected once or twice at a 24-h interval, the Gd concentration in the tumor correlated well with the total dose of Gd, and it reached a maximum of 189 microg/g wet tumor. This maximum Gd level was greater than the limit required for significantly suppressing tumor growth in neutron-capture therapy.

[Pharmacokinetics of doxorubicin alginate microspheres and evaluation of its hepatic arterial embolization in vivo].

AIM: To investigate the pharmacokinetics of doxorubicin alginate microspheres (DOX-AM) in vivo after hepatic arterial embolization. METHODS: China miniature pigs were chosen as the experimental animals. Transcatheter hepatic arterial chemoembolization (TACE) with DOX-AM (experimental group), lipiodol and DOX (DOX-lipiodol, control group 1), and infusion with DOX (control group 2) were performed after angiography and superselection of an intrahepatic branch of hepatic artery. After chemoembolization or infusion, the blood was collected at different time intervals. Drug concentration in plasma was measured by HLPC and the parameters of pharmacokinetics were calculated. RESULTS: The values of T1/2, AUC, Cmax, and MRT of the DOX-AM were significantly different from those of control group 1 and control group 2. After embolization, the DOX-AM embolized in the vessel and still retained there at 8 weeks. The digital subtraction arteriography (DSA) and computerized tomography (CT) showed the reliable embolization results. The histological examination indicated that the liver damnifications were changed transitorily in all groups (P < 0.05) and were recovered within two weeks. The liver damnifications increased in following order: DOX < DOX-AM < DOX-lipiodol. CONCLUSION: DOX-AM showed definite property of delayed release of drug in liver, and increased the retention time and concentration of DOX after embolization in vivo.