Functionalization of Cellulose Nanocrystals with PEG-Metal-Chelating Block Copolymers via Controlled Conjugation in Aqueous Media

[Image: see text] Elongated nanoparticles have recently been shown to have distinct advantages over their spherical counterparts in drug delivery applications. Cellulose nanocrystals (CNCs) have rodlike shapes in nature and have demonstrated biocompatibility in a variety of mammalian cell lines. In this report, CNCs are put forward as a modular platform for the production of multifunctional rod-shaped nanoparticles for cancer imaging and therapy. For the first time, PEGylated metal-chelating polymers containing diethylenetriaminepentaacetic acid (DTPA) (i.e., mPEG-PGlu(DPTA)(18)-HyNic and PEG-PGlu(DPTA)(25)-HyNic) are conjugated to CNCs to enable the chelation of radionuclides for diagnostic and therapeutic applications. The entire conjugation is based on UV/vis-quantifiable bis-aryl hydrazone-bond formation, which allows direct quantification of the polymers grafted onto the CNCs. Moreover, it has been shown that the mean number of polymers grafted per CNC could be controlled. The CNCs are also fluorescently labeled with rhodamine and Alexa Fluor 488 by embedding the probes in the polymer corona. Preliminary evaluation in a human ovarian cancer cell line (HEYA8) demonstrated that these CNCs are nontoxic and their penetration properties can be readily assessed in multicellular tumor spheroids (MCTSs) by optical imaging. These findings provide support for biomedical applications of CNCs, and further in vitro and in vivo studies are warranted to evaluate their potential as imaging and therapeutic agents for cancer treatment.