title: Glycosaminoglycans in the cellular uptake of drug delivery vectors - bystanders or active players?
abstract: The implementation of efficient strategies for cellular delivery is the most significant hurdle in the development of oligonucleotide and protein-based nanomedicines. Unlike small molecule drugs that enter cells by virtue of hydrophobicity or by being substrates of transporters, these macromolecules lack the capacity to cross the plasma membrane in a non-disruptive way, therefore requiring the combination with carriers that mediate entry. Remarkably, for the major part, these carriers lack distinct structural features except for a high density of positive charge. Uptake has been attributed to the ability to engage in electrostatic interactions with the lipid bilayer and negatively charged glycosaminoglycans (GAGs) of the cellular glycocalyx. However, conflicting evidence has been obtained to which degree the interaction with GAGs contributes to uptake and the molecular mechanisms involved in uptake. Also, it is not clear to which extent the same molecular mechanisms apply for the different types of cationic delivery vectors. Here, we review the available data for cationic delivery vectors, including lipoplexes, polyplexes and cell-penetrating peptides (CPPs). We show that in spite of their different molecular size and degree of positive charge, all types of vectors share major characteristics with respect to the suggested role of GAGs in uptake. Moreover, by a comparison with the role of heparan sulfates in viral uptake we propose new avenues in the search for molecular mechanisms that trigger uptake of drug delivery vehicles and discuss how these insights may translate into new design principles for nanomedicines.
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Marco E
authors.initials: ME
authors.lastname: Favretto
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Rike
authors.initials: R
authors.lastname: Wallbrecher
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Samuel
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands.
authors.forename: Romy
authors.initials: R
authors.lastname: van de Putte
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands. Electronic address: r.brock@ncmls.ru.nl.
authors.forename: Roland
authors.initials: R
authors.lastname: Brock
mesh_terms: D000818:Animals; D002240:Carbohydrate Sequence; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D016503:Drug Delivery Systems; D004705:Endocytosis; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism*
chemical_list: D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D006025:Glycosaminoglycans; D011509:Proteoglycans
keywords: Cell-penetrating peptides; Drug delivery; Endocytosis; Glycocalyx; Syndecan; Virus