Esterase-Responsive\nFloxuridine-Tethered Multifunctional\nNanoparticles for Targeted Cancer Therapy

Floxuridine is a potential clinical\nanticancer drug for the treatment\nof various cancers. However, floxuridine typically causes unfavorable\nside effects due to its very poor tumor selectivity, and, hence, there\nis a high demand for the development of novel approaches that permit\nthe targeted delivery of floxuridine into cancerous cells. Herein,\nthe design and synthesis of an esterase-responsive multifunctional\nnanoformulation for the targeted delivery of floxuridine in esterase-overexpressed\ncancer cells is reported. Photopolymerization of floxuridine-tethered\nlipoic acid results in the formation of amphiphilic floxuridine-tethered\npoly(disulfide). Self-assembly of the amphiphilic polymer results\nin the formation of nanoparticles with floxuridine decorated on the\nsurfaces of the particles. Integration of aptamer DNA for nucleolin\nonto the surface of the nanoparticle is demonstrated by exploring\nthe base-pairing interaction of floxuridine with adenine. Targeted\ninternalization of the aptamer-decorated nanoparticle into nucleolin-expressed\ncancer cells is demonstrated. Esterase triggered cleavage of the ester\nbond connecting floxuridine with the polymer backbone, and the subsequent\ntargeted delivery of floxuridine into cancer cells is also shown.\nExcellent therapeutic efficacy is observed both in vitro and also\nin the 3D tumor spheroid model. This noncovalent strategy provides\na simple yet effective strategy for the targeted delivery of floxuridine\ninto cancer cells in a less laborious fashion.