Drug-eluting Beads for Liver Embolization: Concentration of Doxorubicin in Tissue and in Beads in a Pig Model

Namur, Julien; Wassef, Michel; Millot, Jean-Marc; Lewis, Andrew L.; Manfait, Michel; Laurent, Alexandre

doi:10.1016/j.jvir.2009.10.026

Cited by 108 publications

(112 citation statements)

References 37 publications

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“…For this, two different human HCC cell lines were incubated with doxorubicin at a concentration that killed >80% of the tumor cells within 48 h. The applied concentration of doxorubicin was in the range of tissue drug concentrations found in experimental TACE models in vivo, as well as in HCC explants of patients after the administration of TACE (33,34). After 2 days, cell culture of surviving HCC cells was continued without doxorubicin exposure to mimic the situation of a single doxorubicin dose application during TACE.…”

Section: Discussionmentioning

confidence: 99%

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Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

et al. 2018

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Abstract. Transarterial chemoembolization (TACE) is an established therapeutic approach for the treatment of hepatocellular carcinoma (HCC). Although patients who undergo TACE may have prolonged survival, there are indications that the malignancy of residual HCC tissue can increase subsequent to the procedure. Although hypoxia, which occurs during TACE due to ischemia, is known to contribute to angiogenesis, little is known with regard to the undesirable effects of chemotherapeutic agents on residual HCC cells. Doxorubicin is one of the most commonly used drugs in TACE. The aim of the present study was to analyze alterations in Hep3B and HepG2 human HCC cell lines surviving doxorubicin treatment in vitro. Initially, the toxic concentration range was determined, and doxorubicin was subsequently applied in concentrations that killed >80% of the HCC cells. During the first days subsequent to treatment, surviving cells had higher expression levels of the epithelial-mesenchymal transition marker SNAIL, and exhibited increased migratory activity compared with control cells. At 3 weeks after the first doxorubicin treatment, surviving HCC cells tolerated significantly higher doxorubicin concentrations compared with control cells. As a potential explanation for this doxorubicin resistance, significantly increased mRNA expression levels of ATP-binding cassette ABCB1 (multidrug resistance protein 1) and ABCC1 (multidrug resistance-associated protein 1) were observed by reverse transcription-quantitative polymerase chain reaction. In summary, these findings indicate that, following TACE treatment, hypoxia as well as doxorubicin may induce a more malignant phenotype in surviving HCC cells and decrease susceptibility to further chemotherapeutic treatment.

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Section: Discussionmentioning

confidence: 99%

“…1C). For the next in vitro model that was designed to mimic the circumstances of TACE, doxorubicin was used at a concentration of 1 µM, which was in the range of doxorubicin concentrations found in human HCC explants following the administration of TACE (33,34 Fig. 2A).…”

Section: Selection Of Hcc Cells Surviving Doxorubicin Treatmentmentioning

confidence: 99%

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

et al. 2018

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“…Unfortunately, this three-arm trial was prematurely stopped because TACE was demonstrated to be more efficient than best supportive care. Although there is currently no level 1 evidence on the benefit of chemotherapy in TACE, the recent introduction of drug-eluting beads has helped demonstrate a clear activity of chemotherapy in both animal [7,8] and human [9,10] studies, thanks to the comparison between loaded and unloaded beads.…”

Section: Introductionmentioning

confidence: 99%

Lipiodol Trans-arterial Chemoembolization of Hepatocellular Carcinoma with Idarubicin: First Experience

Favelier

Boulin

Hamza

et al. 2012

Cardiovasc Intervent Radiol

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Background There is still no consensus about the best chemotherapeutic agent for transarterial chemoembolization (TACE). A recent in vitro study demonstrated that idarubicin, an anthracycline, was by far the most cytotoxic drug on human hepatocellular carcinoma (HCC) cell lines. Idarubicin is much more lipophilic than doxorubicin, leading to higher cell penetration through lipidic membranes and greater accumulation of the drug in the lipiodol. Furthermore, idarubicin has the ability to overcome multidrug resistance. Therefore, we designed this pilot human study to evaluate the safety and efficacy of lipiodol TACE using idarubicin. Methods In 21 consecutive patients treated by lipiodol TACE with idarubicin (10 mg) for HCC, safety data, tumor response (Response Evaluation Criteria in Solid Tumors, mRECIST), time to treatment failure (TTTF), and overall survival were evaluated. Results Postembolization syndrome was observed after 30.9 % (17 of 55) of sessions. No patient died from a TACE-related complication. No hematological grade 3-5 adverse event was observed. At least one grade 3 or higher adverse event occurred in 19 % (4 of 21) of patients. On imaging, no progression was encountered; four patients (24 %) exhibited stable disease, 12 (57 %) exhibited a partial response, and five (19 %) exhibited a complete response. Median TTTF was 16.7 months (Kaplan-Meier analysis). At 6 months, 94.7 % (95 % confidence interval [CI] 68.1-99.2) of patients did not reach treatment failure, whereas treatment failure was not reached in 50.6 % (95 % CI 21.6-73.9) of patients at 1 year. Overall survival was 83.5 % (95 % CI 57-94.4) at 1 year. Conclusion Idarubicin seems safe and effective in lipiodol TACE of HCC. This warrants further study to determine the potential of this drug to replace doxorubicin for TACE.

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“…The in vivo performance of DCBDOX has been investigated in both nonclinical models and patients [12,96,[104][105][106][107][108][109]. A study investigating liver tissue from a single transplanted HCC patient, resected 8 h after treatment with a transarterial infusion of DCBDOX 100-300μm ( Table 4), found that DCB was distributed both within and outside of the tumor, with a range of 13 mm from the tumor surface [109].…”

Section: In Vivo Release Of and Tissue Exposure To Dox From Dcbdoxmentioning

confidence: 99%

“…A study investigating liver tissue from a single transplanted HCC patient, resected 8 h after treatment with a transarterial infusion of DCBDOX 100-300μm ( Table 4), found that DCB was distributed both within and outside of the tumor, with a range of 13 mm from the tumor surface [109]. In pig liver and kidney, smaller DCBDOX penetrated further into the tissue from the injection site than larger beads [108,110]. For instance, DCBDOX 700-900μm occluded large vessels in portal spaces whereas DCBDOX 100-300μm were located in the arterial branches closer to the hepatic lobules and sinusoids.…”

Section: In Vivo Release Of and Tissue Exposure To Dox From Dcbdoxmentioning

confidence: 99%

Treatment of Intermediate Stage Hepatocellular Carcinoma: A Review of Intrahepatic Doxorubicin Drug-Delivery Systems

Dubbelboer

Lilienberg

Ahnfelt

et al. 2014

Therapeutic Delivery

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The biopharmaceutical properties of doxorubicin delivered via two drug-delivery systems (DDSs) for the palliative treatment of unresectable hepatocellular carcinoma were reviewed with relation to the associated liver and tumor (patho)physiology. These two DDSs, doxorubicin emulsified with Lipiodol ® and doxorubicin loaded into DC Bead ® are different regarding tumor delivery, release rate, local bioavailability, if and how they can be given repeatedly, biodegradability, length of embolization and safety profile. There have been few direct head-to-head comparisons of these DDSs, and in-depth investigations into their in vitro and in vivo performance is warranted.The global incidence of liver cancer is increasing and this type of cancer has a poor prognosis and is ranked as the third most common lethal cancer form [1,2]. The recommended treatment for hepatocellular carcinoma (HCC), a primary liver cancer, is dependent on the stage of the disease [3]. For unresectable, intermediate stage HCC, transarterial chemoembolization (TACE) is recommended. TACE involves the delivery of the cytostatic agent(s) in a drug-delivery system (DDS) to the tumor via the hepatic artery (HA) [3]. In contrast to normal liver tissue, which has a dual blood supply from the HA and the portal vein [4], HCC is typically mainly vascularized by the HA. Local drug administration by the TACE DDS is expected to increase the specificity of the tumor response while reducing the frequency of side effects and morbidity compared with systemic dosed treatments [4]. Embolization, caused by the DDS, obstructs the blood flow in the tumor, induces hypoxia, and results in increased drug concentrations and prolonged residence times in the tumortarget area [4]. Patients with untreated HCC that has not invaded the portal vein or spread extrahepatically have an expected median survival of approximately 16 months. With current palliative TACE strategies, the expected median survival is prolonged by approximately 4 months [3].To date, several DDSs delivering various chemotherapeutic drug(s) and pharmaceutical excipients have been developed and clinically evaluated for TACE therapy [5]. A review of these options of TACE DDSs is warranted in that it would form the basis for optimizing tumor-targeted therapy for HCC treatment, and subsequent development of novel, tumor-targeted DDSs and dosing strategies. Two common DDSs used for TACE therapy for intermediate stage HCC involve cytostatic agents emulsified in Lipiodol ® (LIP) or loaded into drugeluting beads. LIP is an iodized poppy seed oil derivative visible on x-ray, and after administration, the contrast is preferentially retained in tumor tissue [6,7]. The combination of the cytostatic agent emulsified in LIP can be administered with or without additional embolizing materials, generating complete or partial embolization of the targeted tumor-feeding vessel(s) [3,8]. DC Bead ® (DCB) is one of several commercially available drug-eluting embolizing bead systems [9]. Positively charged chemotherapeutic drugs can be ...

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Drug-eluting Beads for Liver Embolization: Concentration of Doxorubicin in Tissue and in Beads in a Pig Model

Cited by 108 publications

References 37 publications

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

Hepatocellular carcinoma cells surviving doxorubicin treatment exhibit increased migratory potential and resistance to doxorubicin re-treatment inï¿½vitro

Lipiodol Trans-arterial Chemoembolization of Hepatocellular Carcinoma with Idarubicin: First Experience

Treatment of Intermediate Stage Hepatocellular Carcinoma: A Review of Intrahepatic Doxorubicin Drug-Delivery Systems

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