Design and testing of hydrophobic core/hydrophilic shell nano/micro particles for drug-eluting stent coating

In this study, we designed a novel drug-eluting coating for vascular implants consisting of a core coating of the anti-proliferative drug docetaxel (DTX) and a shell coating of the platelet glycoprotein IIb/IIIa receptor monoclonal antibody SZ-21. The core/shell structure was sprayed onto the surface of 316L stainless steel stents using a coaxial electrospray process with the aim of creating a coating that exhibited a differential release of the two drugs. The prepared stents displayed a uniform coating consisting of nano/micro particles. In vitro drug release experiments were performed, and we demonstrated that a biphasic mathematical model was capable of capturing the data, indicating that the release of the two drugs conformed to a diffusion-controlled release system. We demonstrated that our coating was capable of inhibiting the adhesion and activation of platelets, as well as the proliferation and migration of smooth muscle cells (SMCs), indicating its good biocompatibility and anti-proliferation qualities. In an in vivo porcine coronary artery model, the SZ-21/DTX drug-loaded hydrophobic core/hydrophilic shell particle coating stents were observed to promote re-endothelialization and inhibit neointimal hyperplasia. This core/shell particle-coated stent may serve as part of a new strategy for the differential release of different functional drugs to sequentially target thrombosis and in-stent restenosis during the vascular repair process and ensure rapid re-endothelialization in the field of cardiovascular disease

Allosteric cross-talk in chromatin can mediate drug-drug synergy

Exploitation of drug-drug synergism and allostery could yield superior therapies by capitalizing on the immensely diverse, but highly specific, potential associated with the biological macromolecular landscape. Here we describe a drug-drug synergy mediated by allosteric cross-talk in chromatin, whereby the binding of one drug alters the activity of the second. We found two unrelated drugs, RAPTA-T and auranofin, that yield a synergistic activity in killing cancer cells, which coincides with a substantially greater number of chromatin adducts formed by one of the compounds when adducts from the other agent are also present. We show that this occurs through an allosteric mechanism within the nucleosome, whereby defined histone adducts of one drug promote reaction of the other drug at a distant, specific histone site. This opens up possibilities for epigenetic targeting and suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions