Comparison of DC Bead-irinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer.

DC Bead is a drug delivery embolisation system that can be loaded with doxorubicin or irinotecan for the treatment of a variety of liver cancers. In this study we demonstrate that the topoisomerase I inhibitor topotecan hydrochloride can be successfully loaded into the DC Bead sulfonate-modified polyvinyl alcohol hydrogel matrix, resulting in a sustained-release drug eluting bead (DEBTOP) useful for therapeutic purposes. The in vitro drug loading capacity, elution characteristics and the effects on mechanical properties of the beads are described with reference to our previous work with irinotecan hydrochloride (DEBIRI). Results showed that drug loading was faster when the solution was agitated compared to static loading and a maximum loading of ca. 40-45 mg topotecan in 1 ml hydrated beads was achievable. Loading the drug into the beads altered the size, compressibility moduli and colour of the bead. Elution was shown to be reliant on the presence of ions to perform the necessary exchange with the electrostatically bound topotecan molecules. Topotecan was shown by MTS assay to have an IC(50) for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 microM compared to 28.1 and 19.2 microM for irinotecan at 48 and 72 h, respectively. The cytotoxic efficacy of DEBTOP on PSN-1 was compared to DEBIRI. DEPTOP loaded at 6 & 30 mg ml(-1), like its free drug form, was shown to be more potent than DEBIRI of comparable doses at 24, 48 & 72 h using a slightly modified MTS assay. Using a PSN-1 mouse xenograft model, DEBIRI doses of 3.3-6.6 mg were shown to be well-tolerated (even with repeat administration) and effective in reducing the tumour size. DEBTOP however, was lethal after 6 days at doses of 0.83-1.2 mg but demonstrated reasonable efficacy and tolerability (again with repeat injection possible) at 0.2-0.4 mg doses. Care must therefore be taken when selecting the dose of topotecan to be loaded into DC Bead given its greater potency and potential toxicity.

Drug loading and elution from a phosphorylcholine polymer-coated coronary stent does not affect long-term stability of the coating in vivo.

A drug eluting coronary stent was developed for use in preclinical and clinical trial evaluation. The stent was coated with a phosphorylcholine (PC)-based polymer coating containing the cell migration inhibitor batimastat. A pharmacokinetic study was conducted in a rabbit iliac model using (14)C-radiolabeled version of the drug; this showed the drug release to be first order with 94% of it being released within 28 days. Unloaded and drug-loaded stents were implanted in a porcine coronary artery model; a number were explanted at 5 days and scanning electron microscopy was used to show that the presence of the drug did not affect the rate of stent endothelialization. The remainder of the stents were removed after 6 months and the stents carefully removed from the arterial tissue. Fourier-transform infrared (FT-IR) spectroscopy (both attenuated total reflectance and microscopic imaging) was used to show the presence of the PC coating on control unloaded, drug-loaded and explanted stents, providing evidence that the coating was still present. This was further confirmed by use of atomic force microscopy (AFM) amplitude-phase, distance (a-p,d) curves which generated the characteristic traces of the PC coating. Further AFM depth-profiling techniques found that the thicknesses of the PC coatings on an control unloaded stent was 252+/-19 nm, on an control batimastat-loaded stent 906+/-224 nm and on an explanted stent 405+/-224 nm. The increase in thickness after the drug-loading process was a consequence of drug incorporation in the film, and the return to the unloaded dimensions for the explanted sample indicative of elution of the drug from the coating. The drug delivery PC coating was therefore found to be stable following elution of the drug and after 6 months implantation in vivo.