Water-Soluble Blue Fluorescent Nonconjugated Polymer Dots from Hyaluronic Acid and Hydrophobic Amino Acids

[Image: see text] Fluorescent polymers have been increasingly investigated to improve their water solubility and biocompatibility to enhance their performance in drug delivery and theranostic applications. However, the environmentally friendly synthesis and dual functionality of such systems remain a challenge due to the complicated synthesis of conventional fluorescent materials. Herein, we generated a novel blue fluorescent polymer dot through chemical conjugation of hydrophobic amino acids to hyaluronic acid (HA) under one-pot green chemistry conditions. These nonconjugated fluorescent polymer dots (NCPDs) are water soluble, nontoxic to cells, have high fluorescence quantum yield, and can be used for in vitro bioimaging. HA-derived NCPDs exhibit excitation wavelength-dependent fluorescent properties. In addition, the NCPDs also show enhanced doxorubicin loading and delivery in naive and drug-resistant breast cancer cells in 2D and 3D tumor cellular systems. These results demonstrate the potential for successful synthetic scale-up and applications for HA-derived NCPDs.