title: Preparation and characterisation of vandetanib-eluting radiopaque beads for locoregional treatment of hepatic malignancies.
abstract: Since their introduction around a decade ago, embolic drug-eluting beads (DEBs) have become a well-established treatment option for the locoregional transarterial treatment of hepatic malignancies. Despite this success, the therapy is seen to be limited by the choice of drug and more effective options are therefore being sought. These include the small molecule multi-tyrosine kinase inhibitors (MTKi), which exert an anti-angiogenic and anti-proliferative effect that could be highly beneficial in combating some of the unwanted downstream consequences of embolization. Vandetanib is an MTKi which acts against such targets as vascular endothelial growth factor receptor (VEGFR) and epithelial growth factor receptor (EGFR) and has demonstrated modest activity against hepatocellular carcinoma (HCC), albeit with some dose-limiting cardiac toxicity. This makes this compound an interesting candidate for DEB-based locoregional delivery. In this study we describe the preparation and characterisation of vandetanib DEBs made from DC Bead™ and its radiopaque counterpart, DC Bead LUMI™. Drug loading was shown to be dependent upon the pH of the drug loading solution, as vandetanib has multiple sites for protonation, with the bead platform also having a fundamental influence due to differences in binding capacities and bead shrinkage effects. Fourier transform infrared (FTIR) spectroscopy and energy dispersive X-ray (EDX) Spectroscopy confirmed drug interaction is by ionic interaction, and in the case of the radiopaque DEB, the drug is distributed uniformly inside the bead and contributes slightly to the overall radiopacity by virtue of a bromine atom on the vandetanib structure. Drug release from both bead platforms is controlled and sustained, with a slightly slower rate of release from the radiopaque bead due to its more hydrophobic nature. Vandetanib DEBs therefore have suitable characteristics for intra-arterial delivery and site-specific sustained release of drug into liver tumours.
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Moulsecoomb, Brighton BN2 4GJ, UK; Biocompatibles UK Ltd., BTG International Group Company, Lakeview, Riverside Way, Watchmoor Park, Camberley GU15 3YL, UK. Electronic address: alice.hagan@btgplc.com.
authors.forename: Alice
authors.initials: A
authors.lastname: Hagan
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Moulsecoomb, Brighton BN2 4GJ, UK.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Phillips
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Moulsecoomb, Brighton BN2 4GJ, UK.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Macfarlane
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Moulsecoomb, Brighton BN2 4GJ, UK.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Lloyd
authors.affiliation: Biocompatibles UK Ltd., BTG International Group Company, Lakeview, Riverside Way, Watchmoor Park, Camberley GU15 3YL, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Czuczman
authors.affiliation: Biocompatibles UK Ltd., BTG International Group Company, Lakeview, Riverside Way, Watchmoor Park, Camberley GU15 3YL, UK.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Lewis
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D003287:Contrast Media / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008863:Microspheres; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D003287:Contrast Media; D004337:Drug Carriers; D010880:Piperidines; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; C452423:vandetanib
keywords: Drug-eluting beads; Transarterial chemoembolization; Tyrosine kinase inhibitors; Vandetanib