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Dubbelboer, Ilse R
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Publications (10 of 10) Show all publications
Dubbelboer, I. R., Pavlovic, N., Heindryckx, F., Sjögren, E. & Lennernäs, H. (2019). Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile. Cancers, 11(7), Article ID 1024.
Open this publication in new window or tab >>Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 7, article id 1024Article in journal (Refereed) Published
Abstract [en]

Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC50. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 mu M doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
IC50, doxorubicin, liver cancer, cell lines, hypoxia, normoxia
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-395927 (URN)10.3390/cancers11071024 (DOI)000479322800134 ()31330834 (PubMedID)
Funder
Swedish Cancer Society, CAN2018/602Swedish Cancer Society, CAN2017/518Swedish Cancer Society, CAN2013/1273Swedish Research Council, 2018-03301Swedish Society for Medical Research (SSMF), S17-0092
Available from: 2019-10-30 Created: 2019-10-30 Last updated: 2019-10-30Bibliographically approved
Dubbelboer, I. R., Dahlgren, D., Sjögren, E. & Lennernäs, H. (2019). Rat intestinal drug permeability: A status report and summary of repeated determinations. European journal of pharmaceutics and biopharmaceutics, 142, 364-376
Open this publication in new window or tab >>Rat intestinal drug permeability: A status report and summary of repeated determinations
2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 364-376Article in journal (Refereed) Published
Abstract [en]

Intestinal permeability is a key biopharmaceutical variable in pharmaceutical research and development, and regulatory assessment. In situ rat models are often used to predict the corresponding human intestinal permeability data. The rat single-pass intestinal perfusion (SPIP) and intestinal closed loop (ICL) models are commonly applied. The primary objective of this study was to collect, summarize, and evaluate all the available intestinal permeability data for drugs that have been obtained using these two in-situ rat models. The permeability data were also investigated for variability between the experimental designs. The literature survey found 635 permeability determinations for 90 drugs. The studies were performed on the jejunum (n = 284), whole small intestine (n = 111), colon (n = 108), ileum (n = 101), and duodenum (n = 30). All the SPIP (n = 484) and ICL (n = 147) permeability values were summarized in an easily accessible database. There was wide variability in the intestinal permeability to each drug between studies, which was unrelated to the permeability class of the drug. There was no relationship between rat intestinal permeability and luminal pH, luminal drug concentration, rat strain, experimental method, or intestinal region. There was, however, a correlation between permeability values determined in the same laboratory. This report showed that the SPIP and ICL methods are important in situ models for understanding and predicting intestinal drug absorption. However, conclusions based on permeability values sourced from different laboratories may not be reliable. Because each permeability study is unique and because between- and even within-laboratory variability can be substantial, data from individual studies should preferably be interpreted separately.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396542 (URN)10.1016/j.ejpb.2019.07.005 (DOI)000488654000038 ()31283980 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Dubbelboer, I. R., Sjögren, E. & Lennernäs, H. (2018). Porcine and Human In Vivo Simulations for Doxorubicin-Containing Formulations Used in Locoregional Hepatocellular Carcinoma Treatment. AAPS Journal, 20(6), Article ID 96.
Open this publication in new window or tab >>Porcine and Human In Vivo Simulations for Doxorubicin-Containing Formulations Used in Locoregional Hepatocellular Carcinoma Treatment
2018 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 6, article id 96Article in journal (Refereed) Published
Abstract [en]

It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.

Keywords
DC bead, doxorubicin, hepatocellular carcinoma, in vitro-in vivo correlation, Lipiodol, physiologically based pharmacokinetic modeling, physiologically based biopharmaceutical modeling, TACE
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-364156 (URN)10.1208/s12248-018-0251-4 (DOI)000443459100001 ()30167825 (PubMedID)
Available from: 2018-11-07 Created: 2018-11-07 Last updated: 2018-11-20Bibliographically 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
Dubbelboer, I. R. (2017). Biopharmaceutical investigations of doxorubicin formulations used in liver cancer treatment: Studies in healthy pigs and liver cancer patients, combined with pharmacokinetic and biopharmaceutical modelling. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Biopharmaceutical investigations of doxorubicin formulations used in liver cancer treatment: Studies in healthy pigs and liver cancer patients, combined with pharmacokinetic and biopharmaceutical modelling
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There are currently two types of drug formulation in clinical use in the locoregional treatment of intermediate hepatocellular carcinoma (HCC). In the emulsion LIPDOX, the cytostatic agent doxorubicin (DOX) is dissolved in the aqueous phase, which is emulsified with the oily contrast agent Lipiodol® (LIP). In the microparticular system DEBDOX, DOX is loaded into the drug-eluting entity DC Bead™.

The overall aim of the thesis was to improve pharmaceutical understanding of the LIPDOX and DEBDOX formulations, in order to facilitate the future development of novel drug delivery systems. In vivo release of DOX from the formulations and the disposition of DOX and its active metabolite doxorubicinol (DOXol) were assessed in an advanced multisampling-site acute healthy pig model and in patients with HCC. The release of DOX and disposition of DOX and DOXol where further analysed using physiologically based pharmacokinetic (PBPK) and biopharmaceutical (PBBP) modelling. The combination of in vivo investigations and in silico modelling could provide unique insight into the mechanisms behind drug release and disposition.

The in vivo release of DOX from LIPDOX is not extended and controlled, as it is from DEBDOX. With both formulations, DOX is released as a burst during the early phase of administration. The in vivo release of DOX from LIPDOX was faster than from DEBDOX in both pigs and patients. The release from DEBDOX was slow and possibly incomplete. The in vivo release of DOX from LIPDOX and DEBDOX could be described by using the PBBP model in combination with in vitro release profiles.

The disposition of DOX and DOXol was modelled using a semi-PBPK model containing intracellular binding sites. The contrast agent Lipiodol® did not affect the hepatobiliary disposition of DOX in the pig model. The control substance used in this study, cyclosporine A, inhibited the biliary excretion of DOX and DOXol but did not alter metabolism in healthy pigs. The disposition of DOX is similar in healthy pigs and humans, which was shown by the ease of translation of the semi-PBPK pig model to the human PBBP model.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 70
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 240
Keywords
drug delivery system, in vivo release, PBPK modelling, hepatocellular carcinoma, doxorubicin, transarterial chemoembolization, drug disposition
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics; Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-330953 (URN)978-91-513-0124-2 (ISBN)
Public defence
2017-12-08, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-11-16 Created: 2017-10-21 Last updated: 2018-03-07
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: 2020-02-05Bibliographically 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
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
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