ApoE - Functionalization of Nanoparticles for Targeted Brain Delivery - A Feasible Method for Polyplexes?

Abstract

Abstract The blood- brain barrier (BBB) poses a major obstacle in the treatment of all types of central nervous system (CNS) diseases. Small interfering RNA (siRNA) offers in principle a promising therapeutic approach by downregulating disease-related genes via RNA interference. However, the BBB is a formidable barrier for macromolecules such as nucleic acids. In an effort to develop a brain-targeted strategy for siRNA delivery systems formed by electrostatic interactions with cationic polymers (polyplexes, PXs), we investigated the suitability of the well-known surfactant-based approach for Apolipoprotein E (ApoE)-functionalization of nanoparticles (NPs). In the present work, we used cationic branched 25kDa poly(ethyleneimine) (b-PEI) and nylon-3 polymers to form PXs with siRNA and subsequently, we coated them with ApoE without or after precoating with polysorbate 80 (PS 80). We utilized highly hydrophobic NM0.2/CP0.8 nylon-3 polymers to evaluate the effects of hydrophobic cyclopentyl (CP) subunits on ApoE binding efficacy. In conclusion, this study demonstrated that ApoE functionalization particularly of hydrophobically modified PXs is in principle possible and very promising for siRNA delivery based on in vitro results, but further optimization and more sophisticated in vitro models are required to achieve an appropriate in vitro-in vivo translation in future approaches.