Drug Delivery Systems Based On Highly Hydrophilic PEG-Dendron Hybrids

Developing suitable materials for drug delivery systems requires precise design of synthetic polymers, which can be functionalized with drug molecules. Such polymeric systems can potentially target hydrophobic drugs to the site of disease. This goal is challenging due to the hydrophobic nature of the loaded drugs and the need to travel through hydrophilic polar environments in the body. To overcome this obstacle, many delivery systems of various forms, such as micelles, dendrimers and liposomes, were designed by different research groups over the years. Dendrimers offer great advantages due to their globular size, monodispersity and highly tunable properties. However, due to the hydrophobicity of the drug molecules not all the dendritic end-groups can be functionalized. Importantly, it was recently reported that labeling the periphery of PAMAM dendrimer gives mixture of labeled products with different numbers of fluorescent dyes on the surface.¹ Moreover, each of the formed species showed different cell internalization capability, demonstrating the need for the development of more controlled methodologies for the functionalization of dendrimers with hydrophobic drug molecules. To address this challenge and gain control over the size of the dendrimer and the number of conjugated drugs without impairing the monodispersity of the system, we designed highly hydrophilic PEG-dendron hybrids with internal functionalities. We examined the covalent connection between the loaded molecules and the hybrid by introduction of an enzymatically cleavable bond between the dendron and a fluorescent dye. These delivery platforms are envisioned to release their payload through disease-associated enzymatic degradation of the drugs, aiming to release the drug only at the site of disease.

Reference:

1. Dougherty, C. A., Vaidyanathan, S., Orr, B. G. & Banaszak Holl, M. M. Fluorophore:Dendrimer Ratio Impacts Cellular Uptake and Intracellular Fluorescence Lifetime. Bioconjug. Chem. 26, 304–315 (2015).