Pathways of protein and lipid receptor-mediated transcytosis in drug delivery.

INTRODUCTION: A critical factor for the efficacy of drugs is their availability at the site of interest. However, crossing endothelial and epithelial cell layers like the blood-brain barrier and the blood-intestinal barrier represents a major bottleneck for drug targeting. Coupling drugs to carriers that recognize endogenous receptors, which are then transported through cell layers by transcytosis, is a promising approach to overcome this bottleneck. Areas covered: This review focuses on the intracellular pathways of receptor-mediated transcytosis and their applicability for transcellular drug delivery. It gives an overview about transcytotic trafficking routes in epithelia and highlights the well-studied examples of immungobulin transcytosis and transferrin transcytosis. The current knowledge about the less understood transcytosis pathways in endothelia is also summarized and low-density lipoprotein transcytosis is described. In addition, transcytosis pathways that are based on glycosphingolipids and lectins as their receptors are presented. Expert opinion: Multiple transcellular drug delivery approaches based on proteinaceous receptors have been developed in recent years, whereas lectins that bind to glycosphingolipids emerge as promising alternative. Closer investigation of endogenous transcytosis mechanisms, especially in endothelia, will be a fruitful endeavor to devise more optimized carriers for transcytotic drug delivery.

Gb3-binding lectins as potential carriers for transcellular drug delivery.

OBJECTIVES: Epithelial cell layers as well as endothelia forming the blood-brain barrier can drastically reduce the efficiency of drug targeting. Our goal was to investigate lectins recognizing the glycosphingolipid globotriaosylceramide (Gb3) for their potential as carriers for transcytotic drug delivery. METHODS: We utilized an in vitro model based on Madin-Darby canine kidney cells transfected with Gb3 synthase to characterize transcytosis of the Gb3-binding lectins LecA from Pseudomonas aeruginosa and the B-subunit of Shiga toxin (StxB). RESULTS: Both lectins were rapidly transcytosed from the apical to the basolateral plasma membrane and vice versa. Whereas StxB proceeded on retrograde and transcytotic routes, LecA avoided retrograde transport. This differential trafficking could be explained by our observation that LecA and StxB segregated into different domains during endocytosis. Furthermore, inhibiting the small GTPase Rab11a, which organizes trafficking through apical recycling endosomes, blocked basolateral to apical transcytosis of both lectins. CONCLUSIONS: Gb3-binding lectins are promising candidates for transcytotic drug delivery. Our findings highlight that LecA and StxB, which both bind Gb3 but exhibit dissimilar valence and molecular structures of their carbohydrate binding sites and can take divergent intracellular trafficking routes. This opens up the possibility of developing tailor-made glycosphingolipid-binding carrier lectins, which take optimized trafficking pathways.