Effects of hepatic artery chemoembolization using cisplatin-lipiodol suspension with gelatin sponge particles on swine liver.

PURPOSE: To define the effects of hepatic artery chemoembolization with cisplatin-lipiodol suspension and gelatin sponge particles on swine liver tissue and estimate the concentration of cisplatin that would have a minimal negative effect on normal liver parenchyma. MATERIALS AND METHODS: Twelve pigs were divided into four groups: group A was the control group in which hepatic arteries were embolized with lipiodol and gelatin sponge particle (n = 3); group B animals were embolized with 10 mg/mL cisplatin-lipiodol suspension plus gelatin sponge particle (n = 3), group C with 20 mg/mL cisplatin-lipiodol suspension plus gelatin sponge particle (n = 3), and group D with 30 mg/mL cisplatin-lipiodol suspension plus gelatin sponge particle (n = 3). Pigs were euthanized 1 week after embolization, and the resected livers were cut into 10-mm-thick sections. The livers and necrotic foci were contoured in each section, and the necrosis volume ratio was calculated. RESULTS: The necrosis volume ratios of the livers in groups A, B, C, and D were 0.832% +/- 0.334, 2.324% +/- 1.126, 8.056% +/- 3.276, and 11.82% +/- 4.921, respectively. Significant differences (P < .05) in necrosis volume ratio were found between groups A and C, groups A and D, groups B and C, and groups B and D; no significant difference was found between groups A and B. CONCLUSIONS: Hepatic artery chemoembolization with higher doses of cisplatin causes greater damage to liver tissue; 10 mg/mL cisplatin-lipiodol suspension causes minimal damage, similar to that without cisplatin, and is related to minimal negative changes in a swine model.

188Re-HDD/lipiodol therapy for hepatocellular carcinoma: a phase I clinical trial.

UNLABELLED: The aim of this study was to investigate the pharmacokinetics, organ dosimetry, and toxicity after the intraarterial administration of (188)Re-labeled 4-hexadecyl-1,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol ((188)Re-HDD/lipiodol) for palliative treatment of hepatocellular carcinoma (HCC). A secondary objective was to document the response. METHODS: A mean activity of 3.60 GBq (188)Re-HDD/lipiodol (range, 1.86-4.14 GBq) was administered to 11 patients (16 treatment sessions) via a transfemoral catheter. The pharmacokinetic and dosimetric data were collected by means of venous blood samples, urine collections, and 4 or 5 gamma-scintigraphies over 76 h. Absorbed doses to the various organs were calculated according to the MIRD formalism, using the MIRDOSE3.1 software. The toxicity was assessed until 6 wk after administration by means of the Common Toxicity Criteria scale. The response was evaluated on MRI and by monitoring of the tumor marker. RESULTS: A fast blood clearance of the injected activity was observed with a calculated effective half-life of 7.6 +/- 2.2 h (+/-SD) in blood. The predominant elimination of the activity was through urinary excretion with a mean renal clearance of 44.1% +/- 11.7% (+/-SD) of the injected activity within the 76 h after administration. Fecal elimination was negligible. The calculated whole-body effective half-life was 14.3 +/- 0.9 h (+/-SD). The absorbed dose to the liver tissue, the lungs, the kidneys, and the thyroid was 4.5 +/- 1.9, 4.1 +/- 1.2, 0.9 +/- 0.7, and 0.3 +/- 0.1 Gy, respectively. Treatment was well tolerated, except in 2 patients. One Child B patient experienced a worsening of his liver dysfunction (hyperbilirubinemia) and another patient experienced dyspnea and coughing. Response assessment on MRI showed 1 case of partial response, disease stabilization in 11 treatments, and progressive disease in 1 treatment. In 5 of 8 treatment sessions with an initially elevated alpha-fetoprotein, a reduction (range, 19%-90%) was observed 6 wk later. CONCLUSION: After the intraarterial administration of 3.60 GBq (188)Re-HDD/lipiodol, a fast clearance of the activity appearing in the blood is observed and the predominant elimination is through urinary excretion. The tolerance as well as the preliminary response rates of the present phase I study are encouraging.

PEGylated polyethylenimine for in vivo local gene delivery based on lipiodolized emulsion system.

Polyethylenimine (PEI) is one of the most efficient vectors for non-viral gene delivery, whereas its poor transfection activity, compared to viral vectors, and cytotoxicity need to be improved for in vivo applications. In this study, we prepared two PEI conjugates with 6 and 10 wt.% of poly(ethylene glycol) (PEG) grafts (referred to PEI-PEG-6 and PEI-PEG-10, respectively) in order to investigate the effects of PEGylation on cytotoxicity and transfection activity in vitro. In addition, their suitability as vectors for local gene delivery in vivo was assessed by injecting lipiodolized emulsions containing polymer/DNA complexes into the femoral artery of Sprague-Dawley (SD) rats, occluded by a surgical suture to block inflow of the blood to the leg. Both PEGylated PEIs showed significantly lower cytotoxicity and higher transfection activity in COS-1 cells than PEI taken as a control; in particular, PEI-PEG-10 produced the most promising results. The stable water-in-oil emulsion, composed of aqueous domains containing the complexes and lipiodol as an oil phase, was formed in the presence of a hydrogenated castor oil. From in vivo experiments, it was found that all the complexes, dispersed in the lipiodolized emulsion, delivered effectively gene to muscle, surrounding the injection site, rather than other organs such as liver, spleen, kidney, heart and lung. The in vivo transfection activity of PEI-PEG-10 was 3-folds higher in muscle than that of PEI. Based on these results, it can be concluded that PEGylated PEIs (based on the lipiodolized emulsion system) hold a promising potential for local gene delivery in vivo.

Transcatheter arterial chemoembolization with paclitaxel-lipiodol solution in rabbit VX2 liver tumor.

PURPOSE: To evaluate the antitumor effects of transcatheter arterial chemoembolization (TACE) with a solution of an anticancer drug (Paclitaxel; Bristol-Myers Squibb, Princeton, NJ) and iodized oil (Lipiodol; Laboratoire Gurerbet, Aulnay-Sous-Bois, France) (hereafter, the solution), as well as intratumor concentration and hepatotoxicity, in experimentally induced liver tumor. MATERIALS AND METHODS: VX2 carcinoma was grown in livers of 30 rabbits. In 18 rabbits, TACE was performed with the high-dose solution (4 mg anticancer drug and 0.4 mL iodized oil, n = 6), the low-dose solution (1 mg anticancer drug and 0.4 mL iodized oil, n = 6), or iodized oil alone (0.4 mL, n = 6) in a control group. One week later, the growth ratio and residual viable proportion of the tumors were calculated on the basis of findings at spiral computed tomography and histopathologic examination. Hepatic and hematologic toxicities were evaluated by means of biochemical analysis. Differences between the three groups were statistically assessed with the Kruskal-Wallace and Mann-Whitney U tests. The remaining 12 animals were treated with the high-dose solution and serially sacrificed for clarification of chronologic change of concentration of the anticancer drug in liver tissues. RESULTS: Growth ratios and residual viable proportions of the tumors were significantly lower in the solution groups (high dose, 3.3% +/- 6.2 [mean +/- SD] and 2.8% +/- 3.6, respectively; low dose, 18.7% +/- 7.4 and 12.7% +/- 6.1, respectively) than in the control group (68.3% +/- 12.7 and 31.1% +/- 8.8, respectively) (P <.05). Hepatotoxicity was transient in all but one rabbit, which died 2 days after TACE with substantial biochemical changes. The anticancer drug accumulated in tumor where the concentration peaked at day 3 and returned to levels comparable to those for normal hepatic parenchyma at 7 days after TACE. CONCLUSION: TACE with the Paclitaxel-Lipiodol solution has dose-dependent antitumor effects without major toxicities in VX2 liver tumor.

Basic study for stabilization of w/o/w emulsion and its application to transcatheter arterial embolization therapy.

Stabilization of w/o/w emulsion and its application to transcatheter arterial embolization (TAE) therapy are reviewed. W/o/w emulsion was stabilized by making inner aqueous phase hypertonic, addition of chitosan in inner phase, and techniques of phase-inversion with porous membrane. Lipiodol w/o/w emulsion for TAE therapy was prepared by using a two-step pumping emulsification procedure. The procedure is so easy that the emulsion could be prepared even during the surgical operation. The deposition after hepatic arterial administration of the emulsion was detected by an X-ray CT scanner. The concentration of epirubicin hydrochloride (EPI) in liver was increased and its residence was prolonged by encapsulating it in the w/o/w emulsion. The toxic effects of EPI and lipiodol on the normal hepatic cells were reduced. The w/o/w emulsion prepared by us is a suitable formulation for the TAE therapy.

Preparation and in vitro evaluation of B-lipiodol as a boron delivery agent for neutron capture therapy of hepatoma.

BACKGROUND: We prepared boron containing lipiodol (B-lipiodol), elucidated the retention of B-lipiodol in hepatoma cells and evaluated the in vitro cellular toxicity of B-lipiodol for neutron capture therapy. MATERIALS AND METHODS: Human hepatoma HepG2 cells were used to examine the uptake and retention of B-lipiodol. Light microscopes were used to examine the interaction and retention of B-lipiodol globules in individual hepatoma cells. Boron and lipiodol concentrations were determined by inductively coupled plasma-atomic emission spectroscopy and neutron activation analysis, respectively. RESULTS: The boron concentration in B-lipiodol drug could reach 2500 ppm. B-lipiodol could be stably retained in serum and culture medium. HepG2 cells appeared proficiently at internalization and persistent retention of B-lipiodol. The boron concentration reached 3.5 micrograms/10(6) cells without approaching saturation at 48 h treatment. CONCLUSION: Hepatoma cells could actively uptake B-lipiodol and a sufficient amount of boron was retained inside the HepG2 cells which could be used for neutron capture therapy.

Hepatic microcirculatory changes induced by hepatic artery embolization in rats: original investigation.

RATIONALE AND OBJECTIVES: To evaluate the effects of hepatic artery embolization (HAE), hepatic microcirculatory changes induced by HAE were assessed quantitatively in rats. METHODS: Using in vivo microscopy, the blood-flow velocity (BFV) through terminal portal venules (TPVs) and terminal hepatic venules (THVs) was measured during HAE with gelatin sponge powder (GSP), iodized oil (Lipiodol, 0.1, 0.2, and 0.4 mL/kg), or 0.1 mL/kg Lipiodol followed by GSP. RESULTS: After HAE with GSP, BFV through TPVs decreased significantly, but BFV through THVs did not decrease. After HAE with Lipiodol (0.2 and 0.4 mL/kg), BFV through TPVs decreased significantly, but BFV through THVs did not. After HAE with Lipiodol followed by GSP, BFV through both TPVs and THVs decreased significantly. CONCLUSIONS: Neither GSP nor Lipiodol adversely affects hepatic microcirculation when administered alone; however, HAE with a combination of Lipiodol and GSP does adversely affect hepatic microcirculation.

Acute toxicity of lipiodol infusion into the hepatic arteries of dogs.

RATIONALE AND OBJECTIVES: The authors studied the acute toxicity of percutaneous transcatheter hepatic artery infusion of iodized poppy oil fatty acid ester (Lipiodol, Laboratoire Guerbet, Aulnay-sous-Bois, France). METHODS: Lipiodol dosages of 0, 0.25, 0.5, 1.0, and 2.0 mL/kg were infused into the hepatic arteries of 10 beagles. Enzymatic and radiographic alterations were assessed. RESULTS: After the infusion of Lipiodol, the dogs showed body weight loss and hypoalbuminemia attributable to decreased food intake, transient elevation of the aspartate transaminase and alanine transaminase, and continuous increase in alkaline phosphatase. The controls did not show any significant change. The radiographs obtained immediately after and 2 weeks after the infusion showed dose-dependent accumulation of Lipiodol in the liver. After 2 weeks, histologic examination of livers and lungs showed dose-dependent (r = .9) retention of oily droplets in sinusoids and pulmonary capillaries. Interlobar pericholangitis was found in four dogs infused with Lipiodol. Pulmonary inflammatory reaction was observed with capillary oil embolism. Oil droplets also were found in the pancreas and the brain. CONCLUSIONS: Lipiodol infusion of the hepatic artery resulted in dose-dependent circulation and embolism of Lipiodol droplets via sinusoids and via pulmonary capillaries into the systemic circulation.

Effects of hepatic artery embolization with Lipiodol and gelatin sponge particles on normal swine liver.

In order to evaluate the effects of hepatic artery embolization (HAE) with Lipiodol (Lp) and gelatin sponge particles (GSP) on swine liver tissue, we embolized the hepatic arteries of 3 pigs with GSP, 9 with Lp, and 9 with Lp + GSP. None of the pigs embolized with GSP died spontaneously during the 4-week experimental period. One pig embolized with 1 ml/kg Lp and three pigs with 2 ml/kg Lp died within 2 h. Two pigs embolized with 0.5 ml/kg Lp + GSP died the following day. The portal vein pressure (PVP) and wedge hepatic vein pressure (WHVP) values before HAE, immediately after, 1 h after, and 4 weeks after HAE showed no remarkable change in the GSP group. Remarkable and temporary elevation was observed in the more than 0.2 ml/kg Lp group. Remarkable and continuous elevation was observed in the 0.2 ml/kg Lp + GSP and 0.5 ml/kg Lp + GSP groups. Gross and histological studies demonstrated no liver damage in the GSP and Lp group. Liver infarction, circular coagulation necrosis with pseudocapsule, and liver atrophy were found in the Lp + GSP group 4 weeks after HAE. The incidence of infarction, circular coagulation necrosis, and liver atrophy in the livers embolized with 0.2 ml/kg Lp + GSP and 0.5 ml/kg Lp + GSP were 67%, 100%, and 75%, respectively. In conclusion, when the hepatic artery is embolized with Lp + GSP, the volume of Lp should be limited to less than 0.1 ml/kg.

[Percutaneous injection of cisplatin lipiodol suspension (CLS) in rabbit lung, aiming at intratumoral injection therapy for lung cancer].

Cisplatin lipiodol suspension (CLS: cisplatin 20 mg/ml) was percutaneously injected (cisplatin dose, 2, 4 or 6 mg/kg) in normal lungs of 10 rabbits (1.9-2.3 kg) to assess the safety and feasibility of intratumoral injection of CLS for lung cancer. Histological study revealed acute and chronic infiltrates with bronchiolitis and immature fibrosis at the injected lung tissue even at four weeks after injection. Intrathoracic leaks of CLS produced mild and focal fibrinous pleuritis. Intrabronchial leaks of CLS produced peripheral bronchiolitis with regenerative epithelia. However, no noxious parenchymal damage in the lung and surrounding tissues was noted. Neither oil embolism in brain nor renal toxicity was demonstrated. Seven of eight rabbits showed an increase in body weight. Concentration levels of plasma platinum were lower when compared with intravenous injection of cisplatin in the rabbit: highest at 30 minutes and unmeasurable one week after injection. Lipiodol accumulation in mediastinal lymph nodes was demonstrated in two of nine rabbits by X-ray examination, suggesting intralymphatic drainage of CLS. Intratumoral injection of CLS is safe even with CLS leaks in surrounding normal lung tissues and may be a potent therapy for controlling mediastinal lymph nodes metastasized from lung cancer as well as the primary tumor.

Intraarterial adriamycin and lipiodol for inoperable hepatocellular carcinoma: a comparison with intravenous adriamycin.

The technique of 'targeting' cytotoxic drugs by mixing them with the contrast medium lipiodol is now widely used in Japan and the Far East where it has been reported to enhance response rates in patients with hepatocellular carcinoma. In the present study 19 patients with this tumour were treated with intra-(hepatic) arterial adriamycin (60 mg/m2), at least one course of which was combined with lipiodol (10-20 ml). Two patients (11%) had a remission as indicated by a significant fall in serum alphafetoprotein and there was a reduction of tumour size in one of these. The median survival period was 3 months (range 1-18) with the two responding patients surviving 8 and 12 months. This response rate was no better than the figure of 14% seen in 31 consecutive patients treated with intravenous adriamycin at the same dose, and the survival curves of the two groups of patients were not significantly different. Lipiodol in combination with adriamycin is not superior to intravenous adriamycin administered alone.

[Effects of experimental hepatic artery embolization with lipiodol and gelatin sponge on liver tissue].

The effect of hepatic artery embolization with Lipiodol (Lp) and Gelatin sponge particles (GSP) on liver tissue was evaluated in 17 dogs embolized with GSP, 12 dogs with Lp and 19 dogs with Lp + GSP. Survival rate and extent of liver damage were used as evaluation criteria. None of the dogs with GSP died during the 4 week period, two exhibited small liver infarctions. Of the dogs with 0.2 to 5 ml/kg Lp, two dogs with 4 ml/kg or 5 ml/kg Lp died of cardiac failure. Gross liver examination did not show any liver infarction. Eight of the 19 dogs with Lp + GSP died of liver failure. Gross examination of the surviving dogs demonstrated infarction in 9 of the 11 livers with 100% incidence in those with 0.2 ml/kg or 0.5 ml/kg Lp. Liver infarction increased in size with the increase of Lp volume. In combination with Lp + GSP, the Lp volume should be less than 0.1 ml/kg.

[Contrast material for CT of the liver and spleen--an experimental study on the safety of lipiodol-iopamidol emulsion].

Iodinated oil (Lipiodol Ultra-Fluid) emulsified by non-ionic contrast material (Iopamidol) featuring much iodine and surface activity, was developed for computed tomography (CT) of the liver and spleen. The stability study revealed that Lipiodol-Iopamidol Emulsion (LIE, 1-6 microns in diameter) stored 2 weeks under refrigeration showed no visible change in globule size distribution. The biodistribution study in six rabbits revealed that LIE injected into the vein was accumulated in the liver, spleen, and lung, which have reticuloendothelial cells, however not accumulated in the brain, kidney, and serum, which have no reticuloendothelial cells. The disruption to the blood brain barrier (BBB) was assessed using Evans' Blue dye as a visual marker. After the coarse emulsion (larger than 8 microns in diameter) was injected into the internal carotid artery of three rats, the permeability of BBB increased. However, after the injection of LIE, no increased permeability of BBB was noted. Our results suggest that LIE will have a clinical application in the detection of focal hepatic and splenic lesions.

Experimental investigation of a new iodinated lipid emulsion for computed tomography of the liver.

Iodinated lipid emulsions are highly efficient macrophage imaging agents. Nevertheless, none of them has been accepted for clinical use because of adverse reactions. We have tested a new iodinated lipid emulsion, Intraiodol. The size and surface properties of the particles of this emulsion are similar to those of Intralipid which in turn closely resemble the naturally occurring chylomicrons. Using computed tomography (CT) of the rabbit liver as well as vital microscopy and electron microscopy of the rat liver we found that Intraiodol has low efficiency as a liver-specific contrast medium because its particles are predominantly taken up by the hepatocytes and to a less extent by the Kupffer cells, as is Intralipid. The low efficiency of Intraiodol could be fully compensated by an increase in dosage without any significant effect on sinusoidal blood flow. This in turn suggests that the likelihood of release of toxic mediators (and thereby related adverse reactions from activated macrophages) is reduced. We believe that this new way of delivering iodinated lipid particles to the liver represents an important advance in the search for a non-toxic lipid emulsion for CT of the liver.

In vivo microscopy of the liver after injection of Lipiodol into the hepatic artery and portal vein in the rat.

The route, distribution and clearance of intraarterially administered Lipiodol in the liver has been the subject of much speculation. The hepatic microcirculation was therefore studied by in vivo microscopy after injection of Lipiodol into the hepatic artery and the portal vein in rats. After intraarterial injection, Lipiodol rapidly entered the portal branches through arterio-portal communications. Lipiodol also passed through the sinusoids from the portal into the hepatic veins and then into the systemic circulation. Sinusoidal congestion occurred when the oil droplets filled the liver microcirculation and resolved as the oil was cleared. It is of clinical significance to note the passage of the oil into the systemic circulation after arterial injection.

Effect of intravenously injected iodinated lipid emulsion on the liver. An experimental study correlating computed tomography findings with in vivo microscopy and electron microscopy findings.

Iodinated lipid emulsions have been shown to have great potential as site specific contrast media for the liver and spleen. Because of unacceptable adverse reactions none of these emulsions has been adopted for clinical use. In an attempt to find an explanation for these adverse reactions we tested three iodinated lipid emulsions, EOE-13, AG 60.99 and AG 66.18. The following models were used: Computed tomography (CT) of the rabbit liver, in vivo microscopy and electron microscopy of the rat liver. The emulsions contained particles of different sizes and were used in varying doses. We found that the larger the emulsion particles, the more likely they were to be taken up by the Kupffer cells and thereby the higher the opacification of the liver achieved at CT. We also observed changes in the microcirculation of the liver when the emulsions were given in doses required to secure satisfactory opacification of the liver at CT. The main changes were 1) a marked increase in the size of the Kupffer cells, and 2) damage to the sinusoidal endothelium, both contributing to sinusoidal congestion. These changes strongly suggest activation of the macrophages and this in turn probably results in the release of toxic mediators. We suspect that the adverse reactions observed in patients when using iodinated lipid emulsions are due to these toxic mediators.

[Cytogenetic effect of iodized radiocontrast media in human blood lymphocytes]. / Tsitogeneticheskii éffekt iodirovannykh rentgenokontrastnykh sredstv v limfotsitakh krovi cheloveka.

Triombrast (60%) iodamide-380, free verografin and verografin incorporated in liposomes in commonly used amounts produce no significant cytogenetic effect on peripheral blood lymphocytes. An increase in the concentration of these drugs results in a decrease in the lymphocytic mitotic index and structural chromosomal disorders which are marked at the most in a 10- and 20-fold increase in a clinical dose.

Experimental data on the problem of specific hepatosplenography with radiodense lipomicrons.

Investigations into specific hepatosplenography performed with the aid of radiodense lipomicrons of different size ranges and various surface layers are presented. It is concluded that certain synthetic neutral and/or negatively charged amphiphilic substances may enhance hepatic and splenic uptake of small lipomicrons. Kinetics concerning clearance of lipid globules from the blood and hepatic concentration as well as elimination rates are studied. Furthermore, circulatory reactions following the intravenous administration of lipid emulsions and interactions between lipid globules and plasma proteins or synthetic polymeric substances are discussed.