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Lilienberg, Elsa
Publications (10 of 11) Show all publications
Ahnfelt, E., Degerstedt, O., Lilienberg, E., Sjögren, E., Hansson, P. & Lennernäs, H. (2019). Lipiodol-based emulsions used for transarterial chemoembolization and drug delivery: Effects of composition on stability and product quality. Journal of Drug Delivery Science and Technology, 53, Article ID UNSP 101143.
Open this publication in new window or tab >>Lipiodol-based emulsions used for transarterial chemoembolization and drug delivery: Effects of composition on stability and product quality
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2019 (English)In: Journal of Drug Delivery Science and Technology, ISSN 1773-2247, Vol. 53, article id UNSP 101143Article in journal (Refereed) Published
Abstract [en]

Transarterial chemoembolization with emulsion-based formulations using doxorubicin hydrochloride (DOX) and Lipiodol (R) is the golden standard for the loco-regional treatment of unresectable hepatocellular carcinoma (HCC). However, from a pharmaceutical quality perspective these emulsions are poorly characterized. In this study, clinically relevant Lipiodol (R)-based emulsions were characterized in terms of emulsion stability, continuous phase classification and droplet-size distribution. Also, the solubility of DOX in the different emulsion components and the distribution of DOX to the lipid phase were investigated. These are key features to investigate due to the claimed tumor-seeking properties of Lipiodol (R). The in vitro release of DOX was studied in a miniaturized dialysis method and an empirical release model was applied to adjust for the passage of DOX across the dialysis membrane. The most stable emulsion ( > 72 h) was classified as water-in-oil (w/o), had the highest distribution of DOX to the lipid phase (20%) and an aqueous-to-lipid phase ratio of 1:4. The composition of the aqueous phase was a mixture (v/v) of iohexol (85%) and water (15%). Emulsions containing iohexol and a high aqueousto-lipid phase ratio (1:2-1:4) displayed prolonged in vitro release profiles of DOX. This study further emphasizes the medical need to standardize these emulsion-based drug delivery systems.

Place, publisher, year, edition, pages
ELSEVIER, 2019
Keywords
Emulsion, Lipiodol (R), Miniaturized dialysis method, In vitro release, Pharmaceutical quality, Liver cancer
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-395729 (URN)10.1016/j.jddst.2019.101143 (DOI)000487963600044 ()
Funder
Swedish Research Council, 521-2011-373
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Dubbelboer, I. R., Lilienberg, E., Karalli, A., Axelsson, R., Brismar, T. B., Ebeling Barbier, C., . . . Lennernäs, H. (2018). Reply to "Comment on 'In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma'". Molecular Pharmaceutics, 15(1), 336-340
Open this publication in new window or tab >>Reply to "Comment on 'In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma'"
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 1, p. 336-340Article in journal (Refereed) Published
Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Lipiodol, doxorubicin, drug-eluting beads, hepatocelluar carcinoma, image-guided transarterial tumor therapy, interventional radiology, liver cancer, local therapy, transarterial chemoembolization (TACE)
National Category
Pharmacology and Toxicology Pharmaceutical Sciences Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-335507 (URN)10.1021/acs.molpharmaceut.7b00840 (DOI)000419419800033 ()29185767 (PubMedID)
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2018-05-04Bibliographically approved
Dubbelboer, I. R., Lilienberg, E., Sjögren, E. & Lennernäs, H. (2017). A Model -Based Approach To Assessing the Importance of Intracellular Binding Sites in Doxorubicin Disposition. Molecular Pharmaceutics, 14(3), 686-698
Open this publication in new window or tab >>A Model -Based Approach To Assessing the Importance of Intracellular Binding Sites in Doxorubicin Disposition
2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 3, p. 686-698Article in journal (Refereed) Published
Abstract [en]

Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (K-p,K-t),could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model. Two semi-PBPK models were developed and evaluated using doxorubicin and doxorubicinol concentrations in healthy pig blood, bile, and urine and kidney and liver tissues. In the generic semi-PBPK model, tissue binding was described using the conventional K-p,K-t approach. In the binding-specific semi-PBPK model, tissue binding was described using intracellular binding sites. The best semi-PBPK model was validated against a second data set of healthy pig blood and bile concentrations. Both models could be used for analysis and simulations of biliary and urinary excretion of doxorubicin and doxorubicinol and plasma doxorubicinol concentrations in pigs, but the binding-specific model was better at describing plasma doxorubicin concentrations. Porcine tissue concentrations were 400- to 1250-fold better captured by the binding-specific model. This model adequately predicted plasma doxorubicin concentration time and biliary doxorubicin excretion profiles against the validation data set. The semi-PBPK models applied were similarly effective for analysis of plasma concentrations and biliary and urinary excretion of doxorubicin and doxorubicinol in healthy pigs. Inclusion of intracellular binding in the doxorubicin semi-PBPK models was important to accurately describe tissue concentrations during in vivo conditions.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
Keywords
doxorubicin, physiologically based pharmacokinetic modeling, PBPK, pig
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-320394 (URN)10.1021/acs.molpharmaceut.6b00974 (DOI)000395847000012 ()28182434 (PubMedID)
Available from: 2017-04-20 Created: 2017-04-20 Last updated: 2018-01-13Bibliographically approved
Lilienberg, E., Dubbelboer, I. R., Karalli, A., Axelsson, R., Brismar, T. B., Ebeling Barbier, C., . . . Lennernäs, H. (2017). In vivo Drug Delivery Performance of Lipiodol-based Emulsion or Drug-eluting Beads in Patients with Hepatocellular Carcinoma. Molecular Pharmaceutics, 14(2), 448-458
Open this publication in new window or tab >>In vivo Drug Delivery Performance of Lipiodol-based Emulsion or Drug-eluting Beads in Patients with Hepatocellular Carcinoma
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2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 2, p. 448-458Article in journal (Refereed) Published
Abstract [en]

Doxorubicin (DOX) delivered in a lipiodol-based emulsion (LIPDOX) or in drug-eluting beads (DEBDOX) is used as palliative treatment in patients with intermediate-stage hepatocellular carcinoma (HCC). The primary objective of this study was to evaluate the in vivo delivery performance of DOX from LIPDOX or DEBDOX in HCC patients using the local and systemic pharmacokinetics of DOX and its main metabolite doxorubicinol (DOXol). Urinary excretion of DOX and DOXol, and their short-term safety and anti-tumor effects were also evaluated. In this open, prospective, non-randomized multi-center study, LIPDOX (n=13) or DEBDOX (n=12) were injected into the feeding arteries of the tumor. Local (vena cava/hepatic vein orifice) and systemic (peripheral vein) plasma concentrations of DOX and DOXol were determined in samples obtained up to 6 h and 7 days after treatment. Tumor response was assessed using computed tomography or magnetic resonance imaging. The Cmax and AUC0-24 h for DOX were 5.6-fold and 2.4-fold higher in LIPDOX vs DEBDOX recipients, respectively (p <0.001). After 6 h, the respective mean proportions of the dose remaining in the liver or drug-delivery system (DDS) were 49% for LIPDOX and 88% for DEBDOX. LIPDOX releases DOX faster than DEBDOX in HCC patients and provides more extensive local and systemic exposure (AUC) to DOX and DOXol initially (0-7 days). DEBDOX formulation has a release and distribution of DOX that is more restricted and rate controlled than LIPDOX.

Keywords
doxorubicin, doxorubicinol, drug eluting beads, local delivery, local therapy, hepatocellular carcinoma, liver cancer, lipiodol, transarterial chemoembolization, transarterial infusion chemotherapy
National Category
Social and Clinical Pharmacy
Identifiers
urn:nbn:se:uu:diva-311314 (URN)10.1021/acs.molpharmaceut.6b00886 (DOI)000393630100012 ()27997198 (PubMedID)
Funder
Swedish Research Council, S21-2011-373
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-01-13Bibliographically approved
Lilienberg, E., Dubbelboer, I. R., Sjögren, E. & Lennernäs, H. (2017). Lipiodol does not affect the tissue distribution of intravenous doxorubicin infusion in pigs. Journal of Pharmacy and Pharmacology (JPP), 69(2), 135-142
Open this publication in new window or tab >>Lipiodol does not affect the tissue distribution of intravenous doxorubicin infusion in pigs
2017 (English)In: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 69, no 2, p. 135-142Article in journal (Refereed) Published
Abstract [en]

ObjectivesIn liver cancer treatment, lipiodol is used as a pharmaceutical excipient to improve delivery of the cytostatic drug doxorubicin (DOX). As DOX and its metabolite doxorubicinol (DOXol) cause serious off-target adverse effects, we investigated the effects of drug-free lipiodol or ciclosporin (CsA) on the tissue distribution (K-p) of DOX and DOXol in relevant pig tissues. MethodsFour treatment groups (TI-TIV) all received an intravenous DOX solution at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), lipiodol (TII), CsA (TIII) or lipiodol and CsA (TIV). After 6 h, the pigs were euthanised, and liver, kidney, heart and intestine samples were collected and analysed. Key findingsThe tissue DOX concentrations were highest in the kidney (TI-TIV). All the investigated tissues showed extensive DOX K-p. Lipiodol had no effect on the K-p of DOX to any of the tissues. However, the tissue concentrations of DOX were increased by CsA (in liver, kidney and intestine, P < 0.05). ConclusionLipiodol injected into the portal vein does not affect the tissue distribution of DOX and DOXol.

Keywords
ciclosporin, doxorubicin, K, (p), lipiodol, tissue distribution
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-317962 (URN)10.1111/jphp.12665 (DOI)000393174500003 ()27882559 (PubMedID)
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2018-01-13Bibliographically approved
Lilienberg, E. (2015). Biopharmaceutical Evaluation of Intra-arterial Drug-Delivery Systems for Liver Cancer: Investigations in healthy pigs and liver cancer patients. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Biopharmaceutical Evaluation of Intra-arterial Drug-Delivery Systems for Liver Cancer: Investigations in healthy pigs and liver cancer patients
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There are currently two types of intra-arterial drug-delivery system (DDS) in clinical use in the palliative treatment of primary liver cancer. The chemotherapeutic drug doxorubicin (DOX) can be formulated into a drug-in-lipiodol emulsion (LIPDOX) or a microparticulate drug-eluting bead system (DEBDOX). To facilitate development of future DDSs, we need to understand the release and local distribution of drug from these DDSs into the complex, in vivo, pathological environment.

The overall aim of this project was to assess and improve understanding of the in vivo release of DOX from LIPDOX and DEBDOX and its local disposition in the liver. These processes were investigated in detail in a multisampling-site, healthy pig model and in human patients with liver cancer. The mechanisms involved in DOX disposition were studied by examining potential interactions between DOX and lipiodol and/or cyclosporine A (CsA) in pigs.  

In this project, the main elimination pathway for DOX and its primary metabolite doxorubicinol (DOXol) was via bile; their extensive canalicular carrier-mediated transport (e.g. ATP-binding cassette transporters ABCB1, ABCC1, ABCC2 and ABCG2) was inhibited by CsA. CsA had no effect on the carbonyl and aldo-keto reductases responsible for the metabolism of DOX into DOXol. LIPDOX released DOX more rapidly and to a greater extent into the circulation than DEBDOX, which had only released 15% of the dose in patients after 24 hrs. The systemic exposure to DOX was lower for DEBDOX than for LIPDOX. Greater fractions of DOXol were formed in blood and bile with LIPDOX than with DEBDOX. This may have been because DOX was more widely distributed into regions with increased metabolic capacity or because of increased intracellular uptake when DOX was delivered in LIPDOX. The excipient lipiodol in the LIPDOX formulation did not interact with transporters, enzymes or membranes that would explain the increased cellular uptake of DOX.

In conclusion, the release of DOX from DEBDOX is more controlled in vivo than that from LIPDOX, indicating that DEBDOX is a more robust pharmaceutical product. The formulations for future optimized DDSs should therefore be more similar to DEBDOX than to LIPDOX. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 207
Keywords
in vivo release, drug delivery systems, local delivery, drug disposition, doxorubicin, hepatocellular carcinoma, transarterial chemoembolization, transarterial chemotherapy infusion
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-267396 (URN)978-91-554-9422-3 (ISBN)
Public defence
2016-01-22, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2015-12-22 Created: 2015-11-21 Last updated: 2018-01-10
Lilienberg, E., Ebeling-Barbier, C., Nyman, R., Hedeland, M., Bondesson, U., Axén, N. & Lennernas, H. (2014). Investigation of Hepatobiliary Disposition of Doxorubicin Following Intrahepatic Delivery of Different Dosage Forms. Molecular Pharmaceutics, 11(1), 131-144
Open this publication in new window or tab >>Investigation of Hepatobiliary Disposition of Doxorubicin Following Intrahepatic Delivery of Different Dosage Forms
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2014 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 1, p. 131-144Article in journal (Refereed) Published
Abstract [en]

Unresectable, intermediate stage hepatocellular carcinoma (HCC) is often treated palliatively in humans by doxorubicin (DOX). The drug is administered either as a drug-emulsified-in-Lipiodol (DLIP) or as drug loaded into drug eluting beads (DEB), and both formulations are administered intrahepatically. However, several aspects of their in vivo performance in the liver are still not well-understood. In this study, DLIP and DEB were investigated regarding the local and systemic pharmacokinetics (PK) of DOX and its primary metabolite doxorubicinol (DOXol). An advanced PK-multisampling site acute in vivo pig model was used for simultaneous sampling in the portal, hepatic, and femoral veins and the bile duct. The study had a randomized, parallel design with four treatment groups (TI–TIV). TI (n = 4) was used as control and received an intravenous (i.v.) infusion of DOX as a solution. TII and TIII were given a local injection in the hepatic artery with DLIP (n = 4) or DEB (n = 4), respectively. TIV (n = 2) received local injections of DLIP in the hepatic artery and bile duct simultaneously. All samples were analyzed for concentrations of DOX and DOXol with UPLC-MS/MS. Compared to DLIP, the systemic exposure for DOX with DEB was reduced (p < 0.05), in agreement with a slower in vivo release. The approximated intracellular bioavailability of DOX during 6 h appeared to be lower for DEB than DLIP. Following i.v. infusion (55 min), DOX had a liver extraction of 41 (28–53)%, and the fraction of the dose eliminated in bile of DOX and DOXol was 20 (15–22)% and 4.2 (3.2–5.2)%, respectively. The AUCbile/AUCVP for DOX and DOXol was 640 (580–660) and 5000 (3900–5400), respectively. In conclusion, DLIP might initially deliver a higher hepatocellular concentration of DOX than DEB as a consequence of its higher in vivo release rate. Thus, DLIP delivery results in higher intracellular peak concentrations that might correlate with better anticancer effects, but also higher systemic drug exposure and safety issues.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-210381 (URN)10.1021/mp4002574 (DOI)000329529700012 ()24171458 (PubMedID)
Available from: 2013-11-06 Created: 2013-11-06 Last updated: 2017-12-06Bibliographically approved
Dubbelboer, I. R., Lilienberg, E., Hedeland, M., Bondesson, U., Piquette-Miller, M., Sjögren, E. & Lennernäs, H. (2014). The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs. Molecular Pharmaceutics, 11(4), 1301-1313
Open this publication in new window or tab >>The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs
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2014 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 4, p. 1301-1313Article in journal (Refereed) Published
Abstract [en]

Doxorubicin (DOX) emulsified in Lipiodol (LIP) is used as local palliative treatment for unresectable intermediate stage hepatocellular carcinoma. The objective of this study was to examine the poorly understood effects of the main excipient in the drug delivery system, LIP, alone or together with cyclosporin A (CsA), on the in vivo liver disposition of DOX. The advanced, multi-sampling-site, acute pig model was used; samples were collected from three blood vessels (v. portae, v. hepatica and v. femoralis), bile and urine. The four treatment groups (TI-TIV) all received two intravenous 5 min infusions of DOX into an ear vein: at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), LIP (TII), CsA (TIII) or LIP and CsA (TIV). Concentrations of DOX and its active metabolite doxorubicinol (DOXol) were analyzed using UPLC-MS/MS. A multi-compartment model was developed to describe the distribution of DOX and DOXol in plasma, bile and urine. LIP did not affect the pharmacokinetics of DOX or DOXol. CsA (TIII and TIV) had no effect on the plasma pharmacokinetics of DOX, but a 2-fold increase in exposure to DOXol and a significant decrease in hepatobiliary clearance of DOX and DOXol was observed. Model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism of DOX to DOXol. In conclusion, LIP did not interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-222282 (URN)10.1021/mp4007612 (DOI)000334092700022 ()24558959 (PubMedID)
Available from: 2014-04-09 Created: 2014-04-09 Last updated: 2018-01-11Bibliographically approved
Dubbelboer, I. R., Lilienberg, E., Ahnfelt, E., Sjögren, E., Axén, N. & Lennernäs, H. (2014). Treatment of intermediate stage hepatocellular carcinoma: a review of intrahepatic doxorubicin drug-delivery systems. Therapeutic delivery, 5(4), 447-466
Open this publication in new window or tab >>Treatment of intermediate stage hepatocellular carcinoma: a review of intrahepatic doxorubicin drug-delivery systems
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2014 (English)In: Therapeutic delivery, ISSN 2041-5990, E-ISSN 2041-6008, Vol. 5, no 4, p. 447-466Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-246080 (URN)10.4155/tde.14.11 (DOI)24856170 (PubMedID)
Available from: 2015-03-02 Created: 2015-03-02 Last updated: 2018-01-11Bibliographically approved
Lilienberg, E., Dubbelboer, I. R., Karalli, A., Axelsson, R., Brismar, T. B., Ebeling-Barbier, C., . . . Lennernäs, H.Comparison of drug release, pharmacokinetics and pharmacodynamics after lipiodol-based emulsion or drug-eluting bead delivery to patients with hepatocellular carcinoma.
Open this publication in new window or tab >>Comparison of drug release, pharmacokinetics and pharmacodynamics after lipiodol-based emulsion or drug-eluting bead delivery to patients with hepatocellular carcinoma
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(English)Manuscript (preprint) (Other academic)
Keywords
Doxorubicin, doxorubicinol, drug eluting beads, focal delivery, focal therapy, hepatocellular carcinoma, liver cancer, lipiodol, transarterial chemoembolization, transarterial infusion chemotherapy
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-267395 (URN)
Funder
Swedish Research Council, 521-2011-373
Available from: 2015-11-21 Created: 2015-11-21 Last updated: 2018-01-10
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