Publications by authors named "Zainab Bascal"

10 Publications

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Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib.

Cancers (Basel) 2020 Jul 13;12(7). Epub 2020 Jul 13.

University College London Cancer Institute, University College London, London WC1E 6BT, UK.

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models.

Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown and . In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC.

Results: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion . , combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment.

Conclusion: In 2D and 3D studies and in a syngeneic model , the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.
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http://dx.doi.org/10.3390/cancers12071878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408860PMC
July 2020

Handling and performance characteristics of a new small caliber radiopaque embolic microsphere.

J Biomed Mater Res B Appl Biomater 2020 Oct 23;108(7):2878-2888. Epub 2020 Jun 23.

Biocompatibles UK Ltd., a BTG International Group Company, Camberley, Surrey, UK.

The in vitro and in vivo handling and performance characteristics of a small caliber radiopaque embolic microsphere, 40-90 μm DC Bead LUMI™ (LUMI40-90), were studied. Microsphere drug loading and elution and effects on size, suspension, and microcatheter delivery were evaluated using established in vitro methodologies. In vivo evaluations of vascular penetration (rabbit renal artery embolization), long-term biocompatibility and X-ray imaging properties, pharmacokinetics and local tissue effects of both doxorubicin (Dox) and irinotecan (Iri) loaded microspheres (swine hepatic artery embolization) were conducted. Compared to 70-150 μm DC Bead LUMI (LUMI70-150), LUMI40-90 averaged 70 μm versus 100 μm, which was unchanged upon drug loading. Handling, suspension, and microsphere delivery studies were successfully performed. Dox loading was faster (20 min) and Iri equivalent (<10 min) while drug elution rates were similar. Contrast suspension times were longer with no delivery complications. Vascular penetration was statistically greater (rabbit) with no unexpected adverse safety findings (swine). Microspheres ± drug were visible under X-ray imaging (CT) at 90 days. Peak plasma drug levels and area under the curve were greater for LUMI40-90 compared to LUMI70-150 but comparable to 70-150 μm DC BeadM1™ (DC70-150). Local tissue effects showed extensive hepatic necrosis for Dox, whereas Iri displayed lower toxicity with more pronounced lobar fibrosis. LUMI40-90 remains suspended for longer and have greater vessel penetration compared to the other DC Bead LUMI sizes and are similarly highly biocompatible with long-term visibility under X-ray imaging. Drug loading is equivalent or faster with pharmacokinetics similar to DC70-150 for both Dox and Iri.
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http://dx.doi.org/10.1002/jbm.b.34619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496950PMC
October 2020

Vandetanib-eluting Radiopaque Beads: Pharmacokinetics, Safety, and Efficacy in a Rabbit Model of Liver Cancer.

Radiology 2019 12 15;293(3):695-703. Epub 2019 Oct 15.

From the Department of Radiology and Interventional Radiology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland (R.D., A.D.); Archimmed SARL, 12 rue Charles de Gaulle, Jouy-en-Josas 78350, France (J.N., F.P.); and Biocompatibles UK, a BTG International Group company, Camberley, England (P.C., Z.B., H.K., R.W., S.R., A.L.L.).

Background Transarterial chemoembolization with cytotoxic drugs is standard treatment for unresectable intermediate-stage hepatocellular carcinoma but achieves suboptimal outcomes because of hypoxic stress and the production of detrimental proangiogenic factors. An alternative approach using radiopaque embolization beads loaded with the antiangiogenic drug vandetanib may provide improved anticancer efficacy. Purpose To evaluate the pharmacokinetics, safety, and efficacy of vandetanib-eluting radiopaque bead (VERB) chemoembolization of rabbit liver tumors. Materials and Methods Between April 2015 and March 2016, 60 New Zealand white rabbits with VX2 liver tumors were randomly treated with VERBs at different doses, with nonloaded radiopaque beads (ROBs), or with intra-arterial vandetanib suspension (VS) or were not treated. Vandetanib plasma concentration and tumor growth at US were evaluated. Animals were euthanized after 3 days or 3 weeks. Assessment included bead distribution at x-ray imaging and histologic examination, tumor viability at histologic examination, and vandetanib tissue concentration. Group comparison analysis (Mann-Whitney, Kruskal-Wallis, and χ tests) and predictive factor analysis for tumor growth and viability were performed. Results Vandetanib plasma concentration was lower with VERBs than with VS ( < .01), while concentration in tumor was higher for VERBs (than for VS) at 3 days (median, 29.2 vs 2.74 ng/mg; = .48). Tumor growth was lower with VERBs than with ROBs and with VS at both time points, with median values of +114%, +192%, and +466% at 3 weeks, respectively. Tumor viability was lower at 3 days for VERBs than for ROBs and for VS (3%, 18%, and 38%, respectively) but was not significantly different at 3 weeks. The volume of bead in tumor was a significant predictive factor for lower tumor growth in multivariable analysis at 3 days ( = .03). Drug tumor concentration was a significant predictive factor for lower tumor growth at 3 weeks ( = .04). Conclusion Vandetanib-eluting radiopaque bead chemoembolization showed a pharmacokinetic advantage over intra-arterial drug administration in a preclinical model of liver cancer. High deposition of beads and high vandetanib concentration in tumor led to stronger antitumor effects. © RSNA, 2019 See also the editorial by Kim and Van den Abbeele in this issue.
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http://dx.doi.org/10.1148/radiol.2019190305DOI Listing
December 2019

VEROnA Protocol: A Pilot, Open-Label, Single-Arm, Phase 0, Window-of-Opportunity Study of Vandetanib-Eluting Radiopaque Embolic Beads (BTG-002814) in Patients With Resectable Liver Malignancies.

JMIR Res Protoc 2019 Oct 2;8(10):e13696. Epub 2019 Oct 2.

National Institute for Health Research University College London Hospitals Biomedical Centre, University College London Cancer Institute, London, United Kingdom.

Background: Transarterial chemoembolization (TACE) is the current standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC) and is also a treatment option for patients with liver metastases from colorectal cancer. However, TACE is not a curative treatment, and tumor progression occurs in more than half of the patients treated. Despite advances and technical refinements of TACE, including the introduction of drug-eluting beads-TACE, the clinical efficacy of TACE has not been optimized, and improved arterial therapies are required.

Objective: The primary objectives of the VEROnA study are to evaluate the safety and tolerability of vandetanib-eluting radiopaque embolic beads (BTG-002814) in patients with resectable liver malignancies and to determine concentrations of vandetanib and the N-desmethyl metabolite in plasma and resected liver following treatment with BTG-002814.

Methods: The VEROnA study is a first-in-human, open-label, single-arm, phase 0, window-of-opportunity study of BTG-002814 (containing 100 mg vandetanib) delivered transarterially, 7 to 21 days before surgery in patients with resectable liver malignancies. Eligible patients have a diagnosis of colorectal liver metastases, or HCC (Childs Pugh A), diagnosed histologically or radiologically, and are candidates for liver surgery. All patients are followed up for 28 days following surgery. Secondary objectives of this study are to evaluate the anatomical distribution of BTG-002814 on noncontrast-enhanced imaging, to evaluate histopathological features in the surgical specimen, and to assess changes in blood flow on dynamic contrast-enhanced magnetic resonance imaging following treatment with BTG-002814. Exploratory objectives of this study are to study blood biomarkers with the potential to identify patients likely to respond to treatment and to correlate the distribution of BTG-002814 on imaging with pathology by 3-dimensional modeling.

Results: Enrollment for the study was completed in February 2019. Results of a planned interim analysis were reviewed by a safety committee after the first 3 patients completed follow-up. The recommendation of the committee was to continue the study without any changes to the dose or trial design, as there were no significant unexpected toxicities related to BTG-002814.

Conclusions: The VEROnA study is studying the feasibility of administering BTG-002814 to optimize the use of this novel technology as liver-directed therapy for patients with primary and secondary liver cancer.

Trial Registration: ClinicalTrial.gov NCT03291379; https://clinicaltrials.gov/ct2/show/NCT03291379.

International Registered Report Identifier (irrid): DERR1-10.2196/13696.
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http://dx.doi.org/10.2196/13696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777276PMC
October 2019

Evaluation of novel formulations for transarterial chemoembolization: combining elements of Lipiodol emulsions with Drug-eluting Beads.

Theranostics 2019 28;9(19):5626-5641. Epub 2019 Jul 28.

Biocompatibles UK Ltd (a BTG International group company), Lakeview, Riverside Way, Watchmoor Park, Camberley, Surrey, GU15 3YL, UK.

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 and in a swine model. Dox release from selected formulations was measured using a vascular flow model and 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 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.
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http://dx.doi.org/10.7150/thno.34778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735388PMC
September 2020

Predicting pharmacokinetic behaviour of drug release from drug-eluting embolization beads using in vitro elution methods.

Eur J Pharm Sci 2019 Aug 29;136:104943. Epub 2019 May 29.

Biocompatibles UK Ltd, a BTG International Group Company, Lakeview, Riverside Way, Watchmoor Park, Camberley, GU15 3YL, UK. Electronic address:

Drug-eluting Embolic Bead - Transarterial Chemoembolisation (DEB-TACE) is a minimally invasive embolising treatment for liver tumours that allows local release of chemotherapeutic drugs via ion exchange, following delivery into hepatic arterial vasculature. Thus far, no single in vitro model has been able to accurately predict the complete kinetics of drug release from DEB, due to heterogeneity of rate-controlling mechanisms throughout the process of DEB delivery. In this study, we describe two in vitro models capable of distinguishing between early phase and late phase drug release by mimicking in vivo features of each phase. First, a vascular flow system (VFS) was used to simulate the early phase by delivering DEB into a silicon vascular cast under high pulsatile flow. This yielded a burst release profile of drugs from DEB which related to the dose adjusted C observed in pharmacokinetic plasma profiles from a preclinical swine model. Second, an open loop flow-through cell system was used to model late phase drug release by packing beads in a column with an ultra-low flow rate. DEB loaded with doxorubicin, irinotecan and vandetanib showed differential drug release rates due to their varying chemical properties and unique drug-bead interactions. Using more representative in vitro models to map discrete phases of DEB drug release will provide a better capability to predict the pharmacokinetics of developmental formulations, which has implications for treatment safety and efficacy.
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http://dx.doi.org/10.1016/j.ejps.2019.05.021DOI Listing
August 2019

Comparison of microsphere penetration with LC Bead LUMI™ versus other commercial microspheres.

J Mech Behav Biomed Mater 2018 02 31;78:46-55. Epub 2017 Oct 31.

Biocompatibles UK Ltd, a BTG Group Company, Lakeview, Riverside Way, Watchmoor Park, Camberley GU15 3YL, UK. Electronic address:

The purpose of this study was to evaluate LC Bead LUMI™ (40-90µm and 70-150µm) in order to determine if their increased resistance to compression influences microsphere penetration and distribution compared to more compressible commercial microspheres. LC Bead LUMI™ 40-90µm and 70-150µm, LC BeadM1 70-150µm, Embozene™ 40µm and Embozene™ 100µm size and distributions were measured using optical microscopy. Penetration in vitro was evaluated using an established 'plate model', consisting of a calibrated tapered gap between a glass plate and plastic housing to allow visual observation of microsphere penetration depth. Behaviour in vivo was assessed using a rabbit renal embolization model with histopathologic confirmation of vessel penetration depth. Penetration behaviour in vitro was reproducible and commensurate with the measured microsphere size, the smaller the microsphere the deeper the penetration. Comparison of the microsphere diameter measured on the 2D plate model versus the corresponding average microsphere size measured by histopathology in the kidney showed no significant differences (p = > 0.05 Mann-Whitney, demonstrating good in vitro - in vivo predictive capabilities of the plate model) confirming predictable performance for LC Bead LUMI™ (40-90µm and 70-150µm) based on microsphere size, their increased rigidity having no bearing on their depth of penetration and distribution. An assessment of a LC Bead LUMI™ (40-90µm and 70-150µm) has shown that despite having greater resistance to compression, these microspheres behave in a predictable manner within in vitro and in vivo models comparable with more compressible microspheres of similar sizes.
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http://dx.doi.org/10.1016/j.jmbbm.2017.10.034DOI Listing
February 2018

Vandetanib-eluting Radiopaque Beads: Pharmacokinetics, Safety and Toxicity Evaluation following Swine Liver Embolization.

Theranostics 2017 1;7(8):2164-2176. Epub 2017 Jun 1.

Biocompatibles UK Ltd, a BTG International group company, Lakeview, Riverside Way, Watchmoor Park, Camberley, GU15 3YL, UK.

Purpose: To evaluate the plasma and tissue pharmacokinetics, safety and toxicity following intra-arterial hepatic artery administration of Vandetanib (VTB)-eluting Radiopaque Beads (VERB) in healthy swine.

Materials And Methods: In a first phase, healthy swine were treated with hepatic intra-arterial administration of VERB at target dose loading strengths of 36 mg/mL (VERB36), 72 mg/mL (VERB72) and 120 mg/mL (VERB120). Blood and tissue samples were taken and analysed for VTB and metabolites to determine pharmacokinetic parameters for the different dose forms over 30 days. In a second phase, animals were treated with unloaded radiopaque beads or high dose VTB loaded beads (VERB100, 100 mg/mL). Tissue samples from embolized and non-embolized areas of the liver were evaluated at necropsy (30 and 90 days) for determination of VTB and metabolite levels and tissue pathology. Imaging was performed prior to sacrifice using multi-detector computed tomography (MDCT) and imaging findings correlated with pathological changes in the tissue and location of the radiopaque beads.

Results: The peak plasma levels of VTB (C) released from the various doses of VERB ranged between 6.19-17.3 ng/mL indicating a low systemic burst release. The plasma profile of VTB was consistent with a distribution phase up to 6 h after administration followed by elimination with a half-life of 20-23 h. The AUC of VTB and its major metabolite N-desmethyl vandetanib (NDM VTB) was approximately linear with the dose strength of VERB. VTB plasma levels were at or below limits of detection two weeks after administration. In liver samples, VTB and NDM VTB were present in treated sections at 30 days after administration at levels above the IC for biological effectiveness. At 90 days both analytes were still present in treated liver but were near or below the limit of quantification in untreated liver sections, demonstrating sustained release from the VERB. Comparison of the reduction of the liver lobe size and associated tissue changes suggested a more effective embolization with VERB compared to the beads without drug.

Conclusions: Hepatic intra-arterial administration of VERB results in a low systemic exposure and enables sustained delivery of VTB to target tissues following embolization. Changes in the liver tissue are consistent with an effective embolization and this study has demonstrated that VERB100 is well tolerated with no obvious systemic toxicity.
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http://dx.doi.org/10.7150/thno.19652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505051PMC
March 2018

Long-term biocompatibility, imaging appearance and tissue effects associated with delivery of a novel radiopaque embolization bead for image-guided therapy.

Biomaterials 2016 10 5;103:293-304. Epub 2016 Jul 5.

Biocompatibles UK Ltd, A BTG International group company, Lakeview, Riverside Way, Watchmoor Park, Camberley, Surrey GU15 3YL, UK. Electronic address:

The objective of this study was to undertake a comprehensive long-term biocompatibility and imaging assessment of a new intrinsically radiopaque bead (LC Bead LUMI™) for use in transarterial embolization. The sterilized device and its extracts were subjected to the raft of ISO10993 biocompatibility tests that demonstrated safety with respect to cytotoxicity, mutagenicity, blood contact, irritation, sensitization, systemic toxicity and tissue reaction. Intra-arterial administration was performed in a swine model of hepatic arterial embolization in which 0.22-1 mL of sedimented bead volume was administered to the targeted lobe(s) of the liver. The beads could be visualized during the embolization procedure with fluoroscopy, DSA and single X-ray snapshot imaging modalities. CT imaging was performed before and 1 h after embolization and then again at 7, 14, 30 and 90 days. LC Bead LUMI™ could be clearly visualized in the hepatic arteries with or without administration of IV contrast and appeared more dense than soluble contrast agent. The CT density of the beads did not deteriorate during the 90 day evaluation period. The beads embolized predictably and effectively, resulting in areas devoid of contrast enhancement on CT imaging suggesting ischaemia-induced necrosis nearby the sites of occlusion. Instances of off target embolization were easily detected on imaging and confirmed pathologically. Histopathology revealed a classic foreign body response at 14 days, which resolved over time leading to fibrosis and eventual integration of the beads into the tissue, demonstrating excellent long-term tissue compatibility.
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http://dx.doi.org/10.1016/j.biomaterials.2016.06.064DOI Listing
October 2016

Pregnane X receptor activators inhibit human hepatic stellate cell transdifferentiation in vitro.

Gastroenterology 2006 Jul;131(1):194-209

School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland.

Background & Aims: The activated pregnane X receptor is antifibrogenic in rodent chronic liver injury in vivo models. The aim of this study was to determine the effects of human pregnane X receptor activators on human hepatic stellate cell transdifferentiation to a profibrogenic phenotype in vitro.

Methods: Hepatic stellate cells were isolated from resected human liver and cultured under conditions in which they trans-differentiate into profibrogenic myofibroblasts.

Results: The pregnane X receptor was expressed in primary cultures at the level of messenger RNA and protein and was activated by the ligand rifampicin as judged by increases in binding of proteins to the pregnane X receptor ER6 DNA response element and by increases in ER6-dependent reporter gene expression. Short-term treatment of hepatic stellate cells with rifampicin inhibited the expression of selected fibrosis-related genes (transforming growth factor beta1, alpha-smooth muscle actin), proliferation-related genes, and WNT signaling-associated genes. There was also an increase in interleukin-6 secretion and an inhibition in DNA synthesis. Long-term treatment with rifampicin over several weeks reduced the proliferation and transdifferentiation of hepatic stellate cells. Small interfering RNA knockdown of the pregnane X receptor in a hepatic stellate cell line reduced the binding of proteins to the ER6 DNA response element and abrogated pregnane X receptor activator-dependent changes in transforming growth factor beta1 expression, interleukin-6 secretion, and proliferation.

Conclusions: The pregnane X receptor is transcriptionally functional in human hepatic stellate cells and activators inhibit transdifferentiation and proliferation. The pregnane X receptor may therefore be an effective target for antifibrotic therapy.
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http://dx.doi.org/10.1053/j.gastro.2006.04.012DOI Listing
July 2006