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Particle shape has been described as a key factor in improving cell internalization and biodistribution among the different properties investigated for drug-delivery systems. In particular, tubular structures have been identified as promising candidates for improving drug delivery. Here, we investigate the influence of different design elements of cyclic peptide-polymer nanotubes (CPNTs) on cellular uptake including the nature and length of the polymer and the cyclic peptide building block. By varying the composition of these cyclic peptide-polymer conjugates, a library of CPNTs of lengths varying from a few to over a 150 nm were synthesized and characterized using scattering techniques (small-angle neutron scattering and static light scattering). In vitro studies with fluorescently labeled CPNTs have shown that nanotubes comprised of a single polymer arm with a size between 8 and 16 nm were the most efficiently taken up by three different mammalian cell lines. A mechanistic study on multicellular tumor spheroids has confirmed the ability of these compounds to penetrate to their core. Variations in the proportion of paracellular and transcellular uptake with the self-assembling potential of the CPNT were also observed, giving key insights about the behavior of CPNTs in cellular systems.

biomacromolecules

Comparative Study of the Cellular Uptake and Intracellular Behavior of a Library of Cyclic Peptide–Polymer Nanotubes with Different Self-Assembling Properties