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.

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

“…Biliary dilatation is likely indicative of hepatic artery ischemia caused by the embolization, because the biliary ducts are supplied by hepatic arteries rather than portal vein blood supply. There was no obvious difference in the radiopacity between VERB with different drug doses used in the phase one study, despite the drug potentially contributing slightly to the overall radiopacity due to the presence of radiodense bromine atoms on the drug structure 34. The radiopacity of the beads did not change over the 90 day period confirming the stability of the device as demonstrated previously with this radiopaque platform 37.…”

“…This slow in vivo release of VTB is attributed to both the radiopaque bead platform, which has a more hydrophobic matrix that retards drug elution, and to the physicochemical properties of the drug, as its solubility is reduced at neutral pH 34. These properties lead to minimal systemic exposure of drug when delivered from VERB, which is highly desirable when the drug is associated with potential severe adverse cardiac effects when delivered orally at higher doses.…”

“…There were however, significant adverse events including diarrhoea, rash, GI haemorrhage and QT prolongation associated with the systemic exposure, which might be overcome by DEB delivery. We have recently reported on the preparation and characterization of a Vandetanib-eluting Radiopaque Bead (VERB) 34, which has also demonstrated efficacy in the VX2 tumor model (unpublished data). Here we report on the pharmacokinetics and safety of a preloaded version of VERB in a healthy swine liver embolization model, in preparation for first in human clinical evaluation.…”

Locoregional Therapy Approaches for Hepatocellular Carcinoma: Recent Advances and Management Strategies

“…New developments in drug-eluting bead technology have allowed the loading of tyrosine kinase inhibitors (e.g., sunitinib, vandetanib) and anti-VEGF antibodies (e.g., bevacizumab) in preclinical stages with promising results in halting tumor growth [152][153][154][155]. Experiments in immunotherapy such as oncolytic viruses, dendritic cells, and immune checkpoint inhibitors (against CTLA-4, PD-1, PD-L1) are also underway [156,157].…”

Radiopaque and uniform alginate microspheres loaded with tantalum nanoparticles for real-time imaging during transcatheter arterial embolization

“…Several groups have investigated such radiopaque DEBs. For example, 2,3,5-triiodobenzaldehyde has been coupled to the backbone of polyvinyl alcohol to produce DC Bead LUMI 17 - 20 , whereas radiopaque composites of poly lactic-co-glycolic acid and a radiopaque glass have also been produced 21 . However, the synthesis of such copolymers or radiopaque glass is rather complicated, and so there is need for a universal method to economically and easily produce radiopaque DEBs from readily available materials.…”