Surface Density of Mono- and Trivalent High-Mannan-Derived Targeting Structures with Different Affinities Impacts Cellular Uptake of Human Serum Albumin-Derived Nanocarriers.

Abstract

Actively targeted delivery of nanocarriers (NC) modified with targeting structures (TS) binding to cell surface receptors, specific to target cells, enables enhanced selectivity and efficacy of cellular uptake. This is influenced by the ligand density on the NC surface. Herein, the impact of type, valency, and surface density of high-mannan derived TS on the C-type lectin receptor (CLR)-mediated uptake of human serum albumin (HSA)-based NCs in immune cell populations was investigated. Monovalent and trivalent TSs were prepared via efficient synthesis protocols and investigated regarding their affinity versus isolated carbohydrate recognition domains (CRD) of CD206 and CD209 within a NanoDSF study. Conjugation to HSA resulted in low valency and saturated NCs with a well-defined mannose epitope count. An in vitro study with bone-marrow-derived dendritic cells and splenic immune cells revealed the impact of the NC surface modification on cellular uptake and cell selectivity, allowing insights into the design of TSs and NCs.