Design of Nanohydrogels for Targeted Intracellular Drug Transport to the Trans-Golgi Network.

Nanohydrogels combine advantages of hydrogels and nanoparticles. In particular, they represent promising drug delivery systems. Nanogel synthesis by oxidative condensation of polyglycidol prepolymers, that are modified with thiol groups, results in crosslinking by disulfide bonds. Hereby, biomolecules like the antidiabetic peptide RS1-reg, derived from the regulatory protein RS1 of the Na + -D-glucose cotransporter SGLT1, can be covalently bound by cysteine residues to the nanogel in a hydrophilic, stabilizing environment. After oral uptake, the acid-stable nanogels protect their loading during gastric passage from proteolytic degradation. Under alkaline conditions in small intestine the nanohydrogels become mucoadhesive, pass the intestinal mucosa and are taken up into small intestinal enterocytes by endocytosis. Using Caco-2 cells as model for small intestinal enterocytes, we demonstrate by confocal laserscanning microscopy and structured illumination microscopy the colocalization of fluorescent labeled RS1-reg with markers of endosomes, lysosomes and trans-Golgi-network after uptake with polyglycidol-based nanogels formed by precipitation polymerization. This indicates that RS1-reg follows the endosomal pathway. In the following, we describe the design of bespoken nanohydrogels for specific targeting of RS1-reg to its site of action at the trans-Golgi network that might also represent a way of targeted transport for other drugs to their targets at the Golgi apparatus. This article is protected by copyright. All rights reserved.