Abstract
Engineering controllable cellular interactions into nanoscale drug delivery systems is key to enable their full potential. Here, using folic acid (FA) as a model targeting ligand and dendron micelles (DM) as a nanoparticle (NP) platform, we present a comprehensive experimental and modeling investigation of the structural properties of DMs that govern the formation of controllable, FA-mediated cellular interactions. Our experimental results demonstrate that a high level of control over the specific cell interactions of FA-targeted DMs can be achieved through modulation of the PEG corona length and the FA content. Using various molecular weight PEGs (0.6K, 1K, and 2K g/mol) and contents of dendron-FA conjugate incorporated into DMs (0, 5, 10, 25 wt %), the cell interactions of the targeted DMs could be controlled to exhibit minimal to >25-fold enhancement over nontargeted DMs. Molecular dynamics simulations indicated that structural characteristics, such as solvent accessible surface area of FA, local PEG density near FA, and FA mobility, account in part for the experimental differences in cellular interactions. The molecular structure that allows FA to depart from the surface of DMs to facilitate the initial cell surface binding was revealed to be the most important contributor for determining FA-mediated cellular interactions of DMs. The modular properties of DMs in controlling their specific cell interactions support the potential of DMs as a delivery platform and offer design cues for future development of targeted NPs.