An improved method for evaluating drug release behaviour of drug-eluting embolization beads (DEBs) was developed utilizing an open-loop flow-through system, in which the beads were packed into an occlusive mass within the system and extracted with a flowing elution medium over time. Glass beads were introduced into the beads mass in order to ensure laminar flow, reduce dead volume and improve reproducibility by compensating for swelling phenomena. The effects of glass bead ratio, elution medium flow rate and ion concentration, DEB size and drug concentration and drug type (doxorubicin and irinotecan) were evaluated using DEB composed of a sulfonate-modified polyvinyl alcohol hydrogel (DC Bead™) as the test article. The rate and amount of drug elution from the packed beads was affected by flow rate, the bead size and initial loading dose. The raw data from the concentration profile analysis provided valuable information to reveal the drug elution behaviour akin to the pharmacokinetic data observed for embolized beads (yielding in vitro Cmax and tmax data) which was complementary to the normal cumulative data obtained. A good correlation with historical reported in vivo data validated the usefulness of the method for predicting in vivo drug elution behaviour.
11Isothermal titration calorimetry (ITC) was utilised to investigate suitability of the technique to determine 12 the stoichiometry and thermodynamics of the interactions that occur between a commonly used chemotherapeutic 13 drug, namely doxorubicin, and a polymer bead-based drug delivery embolisation system (DC Bead™). Six 14 temperatures were selected for drug-polymer titrations (293 to 313 K) and in all cases an initially exothermic signal 15 reverted to an endothermic response upon the saturation of the beads with drug. From these experiments, and 16 subsequent calculations, the molar ratio of drug to SO 3 -(polymer) was found to be 0.4:1 at all temperatures studied. 17Enthalpic data was calculated from the raw ITC data with an average enthalpy of drug-polymer binding of -14.8 20in a small increase in the negativity in change in enthalpy recorded. The application of ITC in this study (with its 21 unique ability to monitor real-time interactions and facilitate stoichiometric calculations) resolves the lack of 22 knowledge regarding the thermodynamics of this specific drug-polymer interaction. This study confirms that ITC is 23 not only useful for this specific system, but also highlights the potential use of ITC for more general studies in this 24 area.
Isothermal titration calorimetry was used to investigate thermodynamic and kinetic binding interactions between 4 clinically relevant drugs: doxorubicin (Dox), irinotecan (Iri), mitoxantrone (Mitox), and topotecan (Topo) and a range of commercially available embolization microspheres. Five drug-eluting beads were chosen to consider the effect of bead size (ranging from 70-150 mm to 500-700 mm) and bead type (sulfonate-modified polyvinylalcohol hydrogel, known commercially as DC BeadM1™, and a sulfonatemodified polyethylene glycol hydrogel bead, known commercially as LifePearl™). The molar ratio of drug to SO 3 À was found to be 0.9:1, 0.8:1, 0.4:1, and 0.9:1 for Dox, Iri, Mitox, and Topo, respectively. These findings indicate the steric effects of drug shape, charge, and size on binding ability. Four distinct bead sizes all produced drug:bead binding ratios of >0.9:1 doxorubicin:SO 3 À , thus indicating that bead size does not affect binding stoichiometry. Interestingly, bead size did affect the rate of binding as bead size was found to be indirectly proportional to binding rate. Finally, it was found for the sulfonate-modified polyethylene glycol hydrogel beads that doxorubicin binding was faster (at certain ratios of drug to bead) than that for the sulfonate-modified polyvinylalcohol hydrogel yet was maximal at a drug to bead ratio of only 0.7:1.
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