Comparison of drug release and pharmacokinetics after transarterial chemoembolization using diverse lipiodol emulsions and drug-eluting beads (original) (raw)
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Theranostics, 2019
There are currently two methods widely used in clinical practice to perform transarterial chemoembolization (TACE). One is based on mixing an aqueous drug with an iodized oil (Lipiodol) and creating an emulsion that is delivered intraarterially, followed by embolization with a particulate agent. The other is based on a one-step TACE using Drug-eluting Beads (DEBs) loaded with drug. It is not recommended to mix Lipiodol with DEBs due to incompatibility. For the first time, novel DEB: Lipiodol: doxorubicin (Dox) emulsions are identified using lyophilized polyvinyl alcohol (PVA) hydrogels (non-iodinated or iodinated) DEBs. Methods: 15 DEB emulsions (50mg Dox) were assessed for stability and deliverability in vitro and in vivo in a swine model. Dox release from selected formulations was measured in vitro using a vascular flow model and in vivo in a VX2 rabbit tumor model. Results: Both DEB formats were shown to be able to form emulsions, however only Iodinated DEBs consistently met defined handling criteria. Those based on the non-iodinated DEB achieved >99%+ Dox loading in <5 minutes but were generally less stable. Those prepared using iodinated DEBs, which are more hydrophobic, were able to form stable Pickering-like emulsions (separation time ≥ 20 minutes) and demonstrated handling, administration and imaging observations more akin to Lipiodol™ TACE emulsions in both embolization models. Controlled Dox release and hence beneficial in vivo pharmacokinetics associated with DEB-TACE were maintained. Conclusions: This study demonstrates that it is possible to formulate novel DEB emulsions suitable for TACE that combine positive elements of both Lipiodol™ based and DEB-TACE procedures.
European Journal of Gastroenterology & Hepatology, 2011
Objective Lipiodol transcatheter arterial chemoembolization (TACE) is widely used to treat hepatocellular carcinoma (HCC). Recently, a drug-eluting bead (DEB) has been developed to enhance drug delivery to the tumor and reduce its systemic availability. The purpose of this study was to compare the efficacy and safety of intra-arterial injection of DEB loaded with doxorubicin versus conventional, Lipiodol-based TACE regimens in Asian patients with HCC. Methods The study was designed as a case-control, single-institution clinical trial. Twenty patients with HCC who received DEB loaded with 50 mg doxorubicin ('cases') were matched with 20 patients who had undergone conventional TACE ('controls'). The primary efficacy endpoint was tumor response at 1 month according to modified Response Evaluation Criteria in Solid Tumors. The primary safety endpoint was liver toxicity. Results The rate of objective response by modified Response Evaluation Criteria in Solid Tumors was 85% (17 of 20 patients) in the DEB arm versus 30% (six of 20 patients) in the conventional TACE arm (P = 0.001). Subgroup analyses conducted in patients with large (> 5 cm) or multinodular tumor confirmed significantly higher objective response rates in patients receiving DEB as compared with those treated with conventional TACE (P = 0.003 and P = 0.005, respectively). At the dose of 50 mg doxorubicin, there was no statistically significant difference in liver toxicity between DEB and conventional TACE (P > 0.05). Conclusion In Asian patients with HCC, transcatheter treatment with DEB loaded with doxorubicin offers a distinct advantage in objective tumor response rate as compared with conventional, Lipiodol-based TACE regimens.
Biomedical Chromatography, 2012
Because liver cancer is rarely suitable for surgery, transcatheter arterial chemoembolization (TACE) is used for palliative therapy. In this procedure, an emulsion of doxorubicin in iodized oil is injected directly into liver tumors through a catheter positioned within the artery supplying blood flow to the tumor. At present, there is limited understanding of factors affecting the delivery and dispersion of doxorubicin within treated tumors during TACE. This study addresses the development and application of an ultrahigh-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS-MS) method for rapid confirmation of drug delivery after TACE in a rabbit VX2 liver cancer model. Doxorubicin levels in liver tumors were measured using UHPLC-MS-MS and compared with computed tomography measured levels of iodized oil, a metric used clinically to indicate drug delivery. We found that tissue drug levels determined using UHPLC-MS-MS did not correlate with the regional iodized oil concentration (vehicle) within tumors following TACE, suggesting that chemotherapeutic drugs like doxorubicin spread throughout tumors, and that lack of iodized oil staining in portions of a tumor does not necessarily indicate inadequate therapy during TACE.
CardioVascular and Interventional Radiology, 2011
Objectives-To study the pharmacokinetic profile after hepatic arterial embolization with superabsorbent microspheres (QuadraSpheres) loaded with doxorubicin. Materials and Methods-Rabbits with hepatic VX2 tumors were treated with intra-arterial administration of QuadraSpheres loaded with doxorubicin, or transarterial chemoembolization (TACE) using doxorubicin, Lipiodol and Embospheres, or hepatic arterial infusion (HAI) of doxorubicin. Tumor specimens were evaluated by fluorescence microscopy, and plasma and tumor concentrations of doxorubicin were measured. Results-The peak plasma concentration of doxorubicin was lower in the QuadraSphere group (309.9 ng/ml) than in the HAI (673.4 ng/ml) or TACE (360.5 ng/ml) groups, suggesting higher tumor retention in the QuadraSphere group. Intratumoral doxorubicin levels declined to negligible levels at 1 and 3 days after treatment, respectively in the HAI and TACE groups. In the QuadraSphere groups, intratumoral doxorubicin level declined after day 1, but was still detectable at 14 days after treatment and was higher than that in the other groups at 1, 3, and 7 days. Intratumoral doxorubicin fluorescence was detected at all time points in the QuadraSphere group, but only at 1 day after treatment in the TACE group. Conclusions-Hepatic arterial administration of doxorubicin-loaded QuadraSpheres enables the sustained release of doxorubicin to hepatic tumors.
Journal of the Belgian Society of Radiology
Objectives To compare efficacy and safety of super-selective DEB-TACE with doxorubicin-loaded microspheres sized below and above 100 microns for treatment of hepatocellular carcinoma (HCC). Material and methods All consecutive patients with HCC who underwent DEB-TACE were included in this retrospective study. Regarding to microsphere size (>100 microns or <100 microns), patients were determined as Group A (n = 28) and Group B (n = 30), respectively. Results Of the 58 patients (78% males), no statistically significant difference was found between the two groups in terms of age and gender (P = 0.388, P = 0.888, respectively). There were no significant differences between the two groups in terms of BCLC stages, presence of chronic liver disease, and Child-Pugh classes (P = 0.593, P = 0.081, P = 0.391, respectively). Although statistically insignificant, median overall survival (19 months vs 32 months, P = 0.190) and median progression-free survival (13 months vs 20 months (P = 0.574) were longer and 1-3-years objective response rates (7.40% vs 23.33%, P = 0.330) were higher in Group B than in Group A, respectively. No mortality or major complications were observed. Grade I/ II adverse events were detected in all patients. Transient elevations in liver function tests (Grade III adverse events) were similar in both groups (3.57% vs 3.33%; P = 0.980). Conclusion Super-selective DEB-TACE with doxorubicin-loaded microspheres sized <100 microns is an effective and safe method for the HCC treatment. Objective response rates are higher and survival durations are longer after DEB-TACE performed with doxorubicin-loaded microspheres sized below 100 microns. Keywords Chemoembolization Doxorubicin Microspheres Drug-eluting beads Hepatocellular carcinoma
Theranostics
The goal of this study was to investigate the role of Lipiodol as a tumor-specific imaging biomarker to determine therapeutic efficacy of cTACE and investigate its inter-dependency with tumor perfusion using radiological-pathological correlation in an animal model of liver cancer. Methods: A total of N=36 rabbits were implanted in the left lobe of the liver with VX2 tumors, treated with cTACE using doxorubicin suspended in Lipiodol, and randomly sacrificed at 24 h, 7 days, or 20 days post-TACE. Unenhanced and contrast-enhanced CT scans including a perfusion protocol were obtained before cTACE and immediately before sacrifice. Tumor vascularity and Lipiodol deposition within tumors and hepatic tissue (non-target deposits) were quantified using 3D quantitative assessment tools and measurements of arterial flow, portal flow, and perfusion index (PI). After sacrifice histologic staining, including hematoxylin and eosin (H&E), CD31, and Oil Red O (ORO) were performed on tumor and liver samples to evaluate necrosis, microvascular density (MVD), and Lipiodol retention over time. Transmission electron microscopy (TEM) was performed to assess Lipiodol deposition and clearance over time. Results: All cTACE procedures were carried out successfully except for one, which was excluded from further analysis. Twenty-four hours post-TACE, tumor PI (p=0.04) was significantly decreased, which was maintained at 7 days (p=0.003), but not at 20 days (p=0.4). A strong correlation (R 2 = 0.894) was found between the volume of enhancing tumor tissue at baseline and Lipiodol-positive tumor volume post-TACE. Both ORO and TEM showed deposition of Lipiodol across all imaging time points within the VX2 tumors. However, gradual and ultimately near-complete Lipiodol washout was observed over time in the non-tumoral liver. MVD decreased between 24 h and 7 days post-TACE, and then increased 20 days post-TACE (both p<0.01). Conclusions: Our data provide radiology-pathology evidence for the function of Lipiodol as a theranostic, tumor-specific drug delivery agent because it is both imageable and tumor-seeking, whereby it is preferentially taken up and retained by tumor cells. Those tumor-specific functions also enable Lipiodol to act as an imaging biomarker for the therapeutic efficacy of cTACE. Together with volumetric quantification of tumor vascularization on CT, Lipiodol could be used as a predictor of a patient's response to cTACE and contribute to the therapeutic management of patients with liver cancer.
Journal of Vascular and Interventional Radiology, 2010
PURPOSE: To evaluate the local tissue concentrations of the antineoplastic agent doxorubicin and the amount of drug still present inside drug delivery embolization beads at different time points after embolization and to compare doxorubicin levels with histologic modifications around the beads in a pig liver model. It was hypothesized that doxorubicin-eluting beads maintain cytotoxic concentrations of drug locally over a period of several weeks, as suggested by in vitro elution tests.
Korean Journal of Radiology, 2019
Drug-eluting microspheres (DEMs), also called drug-eluting beads (DEBs), are a type of drug delivery system that was introduced in 2006 for the treatment of hepatocellular carcinoma (HCC) (1). Although conventional transcatheter arterial chemoembolization (c-TACE) is considered the firstline palliative treatment for patients with unresectable HCC (2), it has important technical and scheduling drawbacks that have not yet been standardized. Moreover, lipiodol oil used in c-TACE may cause severe pain in some patients. DEM-transcatheter arterial chemoembolization (DEM-TACE) was produced to overcome these drawbacks and ensure