Fructose-Based Single-Chain Polymer Nanoparticles for GLUT1-Mediated Delivery: Impact of Polymer Design on Uptake and...

We introduce the preparation and biological evaluation of head-tail, tadpole-like, single-chain nanoparticle (SCNP). These libraries are designed to study the influence of block arrangement on cellular uptake and biodistribution. In the first library, PEG-NPs consisted of a PEG-based crosslinked head with a fructose-containing glycopolymer tail (PEG-head), while the design was reversed in the second library (Fru-head). Cellular uptake studies revealed significantly higher uptake of NPs with Fru-head compared to NPs with PEG head, which is attributed to the surface accessibility of the fructose units to glucose transporters (GLUT). In contrast, the fructose moieties in PEG-NPs are more likely to be embedded within the core of the PEG head, thereby limiting receptor interaction. Additionally, uptake selectivity followed the order MDA-MB-231 > MCF-7 > RAW 264.7, correlating with GLUT expression levels. Mechanistic studies showed that uptake is strongly suppressed by GLUT1 inhibition but surprisingly unaffected by GLUT5 inhibition, a finding attributed to the pyranose structure of fructose. Fru-head tadpoles showed prolonged blood circulation and reduced clearance in vivo, with a mean residence time (MRD) of around 21 h, depending on the length of the PEG tail.