Hydrophilic Ethylene\nGlycol Fragments: A Determinant\nAffecting the Therapeutic Index of Paclitaxel Prodrug Nanoassemblies

Prodrug-based nanoassemblies are promising platforms\nfor cancer\ntherapy. Prodrugs typically consist of three main components: drug\nmodules, intelligent response modules, and modification modules. However,\nthe available modification modules are usually hydrophobic aliphatic\nside chains, which affect the activation efficiency of the prodrugs.\nHerein, hydrophilic ethylene glycol fragments were inserted between\nthe modification modules and the response modules, and the important\neffects of hydrophilic fragments on the assembly, drug release, and\ntherapeutic index of the prodrugs were investigated. Notably, the\nintroduction of hydrophilic fragments affected the intermolecular\nforces of the prodrugs and increased the interaction of hydrogen bonding.\nIn addition, hydrophilic fragments significantly improved the redox\ndrug release profiles, which affected the therapeutic index of the\nprodrug nanoassemblies. PTX-SS-OA NPs with hydrophilic fragments exhibited\nincreased redox sensitivity, enhanced cytotoxicity, and superior antitumor\nefficacy. In comparison, PTX-SS-OAL NPs without hydrophilic fragments\nshowed limited redox sensitivity and cytotoxicity but displayed better\nsafety. Overall, the hydrophilic fragment is a critical determinant\nin modulating the therapeutic index of the prodrug nanoassemblies,\nwhich contributes to the development of advanced prodrug nanodelivery\nsystems.