Selective arterial embolisation of a tumour’s feeding artery and subsequent local delivery of chemotherapeutic agents is known as trans-arterial chemoembolisation (TACE). A favourable controlled-release delivery of the chemotherapeutic drug is guaranteed by the DC Bead system, which occludes the blood flow permanently and delivers a local and sustained dose of drug to the tumour cells.(1) DC Bead is precisely calibrated and available in three size ranges: 100µm–300µm; 300µm–500µm; and 500–700µm. In addition, DC Bead with a nominal bead size of 70–150µm is available.(1) The very small diameter of the beads prohibits premature proximal occlusion of tumour-feeding vessels. The narrower size distribution also allows a more concentrated drug delivery within the tumour and greater tumoural devascularisation. However, the loading efficacy of the DC Bead microspheres is limited to positively charged antineoplastic drugs.(1,2) The microspheres are based on a biocompatible polyvinyl alcohol (PVA) hydrogel that is modified with negatively charged sulphonate groups. The increased number of sulphonate moieties permits cationic antineoplastic drugs to be loaded and to be released from the microspheres into dilution media or biological fluids by ion exchange.(1,2) 5-Fluorouracil, cisplatin, and oxaliplatin do not possess the correct characteristics for interaction with DC Beads. Only a small percentage of the loaded drug binds to the beads by ionic interaction and it will be released almost instantaneously after delivery.(3)
Doxorubicin- (DEBDOX) and irinotecan-loaded DC Bead (DEBIRI) are currently used for the local treatment of hepatocellular carcinoma and liver metastases of various tumours, especially metastatic colorectal cancer. Doxorubicin is released over several weeks and irinotecan over several days. Topotecan-loaded beads have been evaluated and could result in a new approach for the treatment of pancreatic cancer.(4) In addition, topotecan-loaded beads may be a new approach for the treatment of ovarian cancer using different local routes (for example, intraperitoneal, intratumoural) of delivery.
Topotecan·HCl is commercially available in a lyophilised form (Hycamtin®) for intravenous use and is approved for use in ovarian cancer. The semi-synthetic topoisomerase I inhibitor binds to the topoisomerase–DNA complex and prevents relegation of single strand breaks. The positively charged topotecan salt is suitable to be loaded by ionic interaction to DC Bead (Figure 1). In aqueous solution, topotecan undergoes a pH-dependent, reversible equilibrium between the closed ring lactone form and the open ring carboxylate form. The cytotoxic activity of the camptothecin derivatives is linked to the lactone form and its binding to the topoisomerase I–DNA complex.(5–7) The drug formulation as well as the ionic interaction with DC Bead favours the active topotecan lactone form, the DC Bead-loading capacity most probably greatly exceeds the favourable dose in humans.(3)
Loading of DC Bead with topotecan hydrochloride
The loading capacity and stability of topotecan-loaded DC Bead was determined in experimental studies.(8) The packing solution of DC Bead (1mmol sodium phosphate solution) was removed as far as possible from the microspheres. Commercially available topotecan hydrochloride powder (Hycamtin®) was reconstituted with water for injection to yield a nominal concentration of 1mg/ml topotecan. The PVA-based microsphere DC Bead 300–500µm 2ml/vial was mixed with 4ml reconstituted topotecan solution and stored light-protected at room temperature under static or agitated conditions for seven days. The loading level of topotecan-loaded beads (TEB) was assessed at different time intervals up to seven days by using a stability-indicating reverse phase high performance liquid chromatography (RP-HPLC) assay.(8) The percentage rate of loading was calculated according to the residual drug concentration in the excess solution compared with the nominal initial drug concentration. After addition of the topotecan solution concentrate to the blue-tinted DC Bead slurry, the excess solution depleted in colour and the blue-tinted microspheres turned yellow–green. Topotecan uptake by the microspheres under agitated conditions was very rapid: 86% of topotecan was loaded in five minutes. Under static conditions, drug uptake required a longer time and after five minutes only 65% of topotecan was loaded. It took approximately one hour to reach a loading capacity of 87%. Topotecan loading increased up to 95% over a seven-day period. Although the drug uptake into DC Bead was faster under agitated loading conditions, after one hour approximately 90% of the topotecan was loaded, independent of the loading conditions. This result matches the loading capacity of a pure topotecan loading solution.(4) The concentration used for all studies was the same, that is, 1mg/ml topotecan. The maximum loading rate of 90% may be caused by the low concentration of the loading solution. Loading of DC Bead (300–500µm) with 2mg/ml doxorubicin loading solution takes 9 or 18 hours depending on the dose loaded (50mg or 75mg). When a 25mg/ml doxorubicin loading solution is used, the loading capacity is 98% after 90 minutes for 75mg. In pharmacy-based cytotoxic preparation units the beads are agitated gently directly after mixing the drug solution with the bead slurry. Afterwards the vials are stored under static conditions in the laminar air flow hood until loading is completed. With regard to this standard procedure, a loading time of one hour for TEB can be used.
Time to achieve maximum loading
The time to achieve maximum loading is also dependent on the size of the beads. Drug uptake is more rapid in smaller beads (100–300µm) than in larger beads, which can be explained by a decreasing surface area with increasing bead sizes.(2) It can be assumed that the smaller bead sizes, which are also used in clinical practice, are loaded at the same rate.
During the period of seven days and light-protected storage at room temperature, topotecan remained loaded in the microspheres and no degradation products could be detected. This observation corresponds with results of stability tests for topotecan infusion solutions.(6) The excipients contained in the commercially available topotecan injection do not affect the loading of topotecan into the beads but favour the stability of the active topotecan lactone form. In the earlier studies, reconstituted topotecan infusion concentrates were already shown to be physico-chemically stable under refrigeration and at room temperature for 28 days.(6) For microbiological reasons, refrigerated storage is recommended. With regard to the loading level and purity of topotecan, the drug–device combination can be categorised as stable over a minimum of one week. The loading and stability of topotecan-loaded DC Bead is suitable and convenient for preparation in a pharmacy-based cytotoxic unit.
Administration of drug-eluting beads
The topotecan-loaded beads are transferred to a 10ml syringe. Administration is usually performed in the radiology department for administration in a minimally invasive (non-surgical) procedure by an interventional radiologist. Before administration the bead slurry is to be mixed with an equal volume of non ionic contrast media via a three-way connector and a second syringe.(9) The suspension should be prepared by gentle mixing and the beads allowed to equilibrate in the mixture, ideally for 5–10 minutes. A static suspension with a minimum number of beads sinking or floating is most appropriate for administration. If the beads are sinking, more contrast media, which raises the fluid density, is added. If the beads are floating, 0.9% sodium chloride solution is to be added, which reduces fluid density and facilitates beads to go into suspension. Poor suspension may lead to catheter-blocking.(9) The admixture of TEB with contrast media in the pharmacy departments is not favourable because rapid elution of topotecan might take place.(7,10) Furthermore, physicians do not take advantages of the ready-to-administer admixtures because the optimum mixing ratios depend on arterial and patient individual delivery conditions. Finally, the syringe with the TEB–contrast media suspension is connected to a microcatheter and delivered by slow, pulsatile injection guided by the contrast media. If the mixture requires re-suspension, the syringe is gently inverted several times.(9)
- DC Bead is successfully used for trans-arterial chemoembolisation resulting in permanent embolisation and sustained release of positively-charged cytotoxic drugs loaded into the beads.
- The loading of DC Bead with commercially available topotecan HCl results in a 90%
- loading efficacy after a loading time of one hour for a dose of 4mg and a loading solution with the concentration of 1mg/ml under agitated and static conditions.
- Over a storage period of seven days, topotecan HCl remains loaded in the DC Bead microspheres at a level of >90%.
- Loading and stability of topotecan-loaded DC Bead is acceptable and convenient for preparation in a pharmacy-based cytotoxic unit.
- Admixture of topotecan-loaded DC Bead and non-ionic contrast media should be carried out by the radiologist directly before delivery in order to avoid unwanted drug release from
- the beads.
- Lewis AL et al. DC bead: in vitro characterization of a drug-delivery device for transarterial chemoembolization. J Vasc Interv Radiol 2006;17(2 Pt 1):335–42.
- Krämer I. Drug-eluting beads: a pharmaceutical assessment. Hosp Pharm Eur 2007;May/June:35–6.
- Biocompatibles UK. DC BeadTM – FAQ. www.biocompatibles.com/products/faq/dcbead (accessed 11 July 2012).
- Forster RE et al. Comparison of DC Bead-irinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer. J Mater Sci Mater Med 2010; 21(9):2683–90.
- Pizzolato JF, Saltz LB. The camptothecins. Lancet 2003; 361(9376):2235-42.
- Krämer I, Thiesen J. Stability of topotecan infusion solutions in polyvinylchloride bags and elastomeric portable infusion devices. J Oncol Pharm Pract 1999;5:75–82.
- Kaiser J, Thiesen J, Krämer I. Stability of irinotecan-loaded drug eluting beads (DC Bead) used for transarterial chemoembolization. J Oncol Pharm Pract 2010;16:53–61.
- Kaiser J, Krämer I. Loading profile of topotecan into polyvinyl alcohol microspheres (DC Bead TM) over a 7-day period. J Oncol Pharm Pract 2012;18:222–8.
- Biocompatibles UK. DC BeadTM – Drug Delivery Embolisation System – Instructions for use. 2005.
- Taylor RR et al. Irinotecan drug eluting beads for use in chemoembolisation: In vitro and in vivo evaluation of drug release properties. Eur J Pharm Sci 2007;30(1):7–14.