A calorimetric investigation of doxorubicin–polymer bead interactions

Abstract

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.

Review of the Development of Methods for Characterization of Microspheres for Use in Embolotherapy: Translating Bench to Cathlab

“…Drug and water distribution and their transport phenomena within the microsphere structure have provided some mechanistic insight into drug–microsphere interactions. [80a] Isothermal titration calorimetry has been investigated for its suitability in determining stoichiometry and thermodynamics of drug–bead interactions . Drug elution investigations at the single microsphere level have also been performed using a microfluidic device consisting of a network of microchannels.…”

In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System

“…To determine the sulfur concentrationdwhich reflects the amount of negatively charged gel network sites (SO 3 À ) in the beadsdthe gel structure was degraded. 29 Vials containing 2 ml each of the 3 bead sizes were shaken to distribute the beads homogeneously in the packing solution (approximately 6 ml of 1-mM PBS 6,30,31 ). From each vial, 0.5 mL was transferred to a 50-mL Kjeldahl flask to which 4.0-mL HNO 3 (65%) and 2.0 mL H 2 O 2 (30%) were added.…”

Characterizing Drug-Polymer Bead Interactions Using Isothermal Titration Calorimetry

“…Bead size experiments were also undertaken using a single injection method (SIM) whereby 100 mL of 10 mM doxorubicin was injected into 25 mg of beads to facilitate a kinetic comparative profile. Determination of drug to sulfonate group ratio was undertaken based on our previously published calculation method, 16 using a weight percentage of 2-acrylamido-2-methyl-1-propane sulfonic acid (AMPS) in PVA-AMPS of 45.45% and weight percentage of 3-sulfo propylacrylate (SPA) in PEG (polyethylene glycol hydrogel)-SPA beads of 35.74%. All experiments were undertaken in triplicate and overall binding ratio errors reported as standard deviation values.…”

“…15 More recently, polymer beads have been studied using one drug, namely doxorubicin, with one bead type, namely DC BeadM1™ (a sulfonate-modified polyvinylalcohol hydrogel bead termed PVA-AMPS), and found the drug to binding sites on the bead ratio to be far lower than anticipated when compared with previously established binding data. 16 However, it has since been determined that conditions encountered within the work had created a system in which sodium counter ions present on the sulfonate groups created a charge-shielding effect that prevented their complete displacement by the drug when titrated under the experimental conditions applied. 17 This study presents an alternative approach through a series of experimental considerations to ensure that the binding phenomenon observed using ITC is a more appropriate reflection of the binding known to occur in the clinical pharmacy.…”