Indented Polymer Microparticles with Shape Variety Reminiscent of Poikilocytosis for Intratumoral Drug Delivery after Transarterial Chemo-Embolization

Abstract

Transarterial chemo-embolization with drug-eluting embolic beads (DEB-TACE) is rapidly gaining acceptance and importance in interventional oncology, particularly in the treatment of patients with intermediate-stage hepatocellular carcinoma. The technique is still evolving, recent technical developments include the launching of imageable radiopaque drug-eluting particles which consist of crosslinked poly(vinylalcohol) with covalent bonds to sulfonate groups and single-aromatic rings to which 3 (X-absorbing) iodine atoms are attached. Here, we report on conceptually different radiopaque polymeric drug-eluting embolic particles, which are (i), crosslinked poly(methacrylates); (ii), radiopaque since 4-iodobenzoylethyl methacrylate was built-in; (iii), microporous; (iv), having one large indentation to accommodate crystalline drug; (v), able to carry/release lipophilic drugs into/inside the tumor's microvasculature; many effective cytostatics in clinical use fall into this category. We were stunned to find indented microparticles after running a suspension polymerization in the presence of Cu(0). The particles have the same shape-variety that is well-known to exist for erythrocytes (red blood cells), although they are roughly 3000 times larger. This is -to the best of our knowledge- a novum in macromolecular/organic chemistry. Quite old theoretical studies explaining the peculiar shapes of healthy and diseased red blood cells, and recent studies on the catalytic effect of Cu(0) on free-radical polymerizations, provided clues to understand our findings. More importantly, the indented particles were found to be chargeable with lipophilic drugs which cannot be used with normal DEB-TACE formulations, and which are nonetheless crucially important in oncology. This concerns the taxanes (diterpenes) in particular. Hence, we believe that our new indented non-spherical particles hold the promise of becoming scope-widening for DEB-TACE, which is likely to become a cornerstone technique of interventional oncology in the years ahead.