Drug-Poly(Lysine) Conjugates: Their Potential for Chemotherapy and for the Study of Endocytosis

Abstract

Poly(L-Lysine) (poly(Lys)), a strongly cationic macromolecule, is efficiently transported into cells by endocytosis (Ryser et al., 1982). This uptake is preceeded by a strong adsorption to the cell surface, which is due to a non-specific interaction of the polymer’s positive charges with the negative charges present at the surface of most mammalian cells. The membrane transport of poly(Lys), therefore, can be defined as non-specific adsorptive endocytosis, as opposed to fluid-phase endocytosis or to receptor-mediated endocytosis (Fig. 1). In fluid-phase endocytosis macromolecules do not bind to any sites at the cell surface, and their transport occurs only through the internalization of a small quantum of medium engulfed by the constitutive process of membrane vesiculation. In receptor-mediated endocytosis a macromolecule binds to a specific site usually located in clathrin coated area of the membrane. Such specialized area gives rise to clathrin coated pits and baskets, which pinch off to form clathrin coated vesicles. The number of binding sites for a specific ligand is usually limited (1 × 1 × 104 to 1 × 106/cell) which accounts for the saturable nature of the transport process (Fig. 1). Specificity is established by demonstrating competition with unlabeled ligand and lack of competition with chemically related molecules. The specific sites are commonly called membrane receptors, even when they are not yet associated with specific cellular functions.