Serum Biomolecules Unable to Compete with Drug Refilling into Cyclodextrin Polymers Regardless of Form

Polymers that are refillable and sustain local release will have a great impact in both preventing and treating local cancer recurrence as well as addressing non-resectable disease. Polymerized cyclodextrin (pCD) disks, which reload drug into molecular 'pockets' in vivo using affinity interactions, have previously shown to localize doxorubicin (Dox) to treat glioblastoma multiforme. However, one concern is whether drug refilling is influenced by competition from local biomolecules. In addition the impact of polymer form on drug refilling is unknown. Herein, different pCD formulations are synthesized from γ-cyclodextrin (γ-CD) and are compared in vitro using competitive drug filling/refilling assays. Data reveals that affinity-based drug refilling occurs as a function of both polymer form and sustained release polymeric liquid (SRPL) dilution factor, pointing to surface/volume ratio, as well as CD pocket density, and distance between pocket effects. In vitro refilling experiments with cholesterol demonstrated no interference with Dox filling of the CD polymer, while albumin presence only slightly reduced Dox filling of pCD-γ-MP (microparticle) and pCD-γ-SRPL forms, but not pCD-γ-disks. Moreover, whole serum competition did not inhibit filling or refilling of pCD-γ-MP with Dox at multiple concentrations and filling times, which indicates that this polymer (re)filling is primarily driven by affinity-based interactions that can overcome physiological conditions that may limit other drug delivery approaches. This was supplemented by isolating variables through docking simulations and affinity measurements. These results attest to the efficiency of in vivo or in situ polymer filling/refilling in the presence of competitive biological molecules achieved partially through high affinity drug to polymer interactions.