Sulfation of Heparan and Chondroitin Sulfate Ligands Enables Cell Specific Homing of Nanoprobes

Abstract

Demystifying the sulfation code of glycosaminoglycans (GAGs) to induce precise homing of nanoparticles in tumor or neuron cells influences the development of a potential drug or gene delivery system. However, GAGs, particularly heparan sulfate (HS) and chondroitin sulfate (CS), are structurally highly heterogeneous, and synthesizing well-defined HS/CS composed nanoparticles is challenging. Here, we decipher how specific sulfation patterns on HS and CS regulate receptor-mediated homing of nanoprobes in primary and secondary cells. We discovered that aggressive cancer cells such as MDA-MB-231 displayed a strong uptake of GAG-nanoprobes compared to mild or moderate aggressive cancer cells. However, there was no selectivity towards the GAG sequences, indicating the presence of more than one receptor mediated uptake. Whereas U87 cells, olfactory bulb and hippocampal primary neurons showed selective or preferential uptake of CS-E coated nanoprobes compared to other GAG-nanoprobes. Further, mechanistic studies revealed that 4,6-O-disulfated-CS nanoprobe utilized CD44 and caveolin-dependent endocytosis pathway for the uptake. These results imply new opportunities to use GAG nanoprobes in nanomedicine.