Polylysine as a vehicle for extracellular matrix-targeted local drug delivery, providing high accumulation and long-term retention within the vascular wall

We present the first steps in the elaboration of an approach of extracellul ar matrix-targeted local drug delivery (ECM-LDD), designed to provide a hig h concentration, ubiquitous distribution, and long-term retention of a drug within the vessel wall after local intravascular delivery. The approach is based on the concept of a bifunctional drug comprising a "therapeutic effe ctor" and an "affinity vehicle," which should bind to an abundant component of the vessel wall. The aim of the present study was to select molecules s uitable for the role of affinity vehicles for ECM-LDD and to study their in travascular delivery and retention ex vivo and in an animal model. By use o f fluorescence microscopy, the following molecules were selected on the bas is of strong binding to cross sections of human vessels: protamine, polylys ine, polyarginine, a glycosaminoglycan-binding peptide from vitronectin, an d a synthetic dendrimer. With polylysine as a prototypic affinity vehicle, we showed that after intravascular delivery, polylysine was concentrated th roughout a luminal layer of the vascular wall to an extremely high concentr ation of 20 g/L and was retained therein for at least 72 hours of perfusion without noticeable losses. Low molecular weight (fluorescein) and high mol ecular weight (hirudin) compounds could be chemically conjugated to polylys ine and were retained in the vessel wall after intravascular delivery of th e conjugates. Tn conclusion, by use of the ECM-LDD method, an extremely hig h concentration and long-term retention of locally delivered drug can be re ached. Polycationic molecules can be considered as potential affinity vehic les for ECM-LDD.