Engineering stable prodrug self-assemblies by introducing the bromination effect

Prodrug nano-self-assemblies, composed of the drug, activation, and assembly modules, hold great promise for cancer therapy. However, it remains challenging to formulate stable prodrug nano-self-assemblies to achieve prolonged blood circulation and high tumor accumulation. A critical factor in prodrug self-assembly is the rational design of assembly modules to balance driving and repulsive forces during self-assembly. We have designed and synthesized two paclitaxel prodrugs with a disulfide bond as an activation module and palmitic acid or 2-bromopalmitic acid as assembly modules, respectively. The bromine atom incorporated in the self-assembly module significantly increased the hydrophobicity of the compound. Moreover, the relatively large atomic size of the bromine atom induced steric hindrance. These two factors simultaneously enhanced the driving and the repulsive forces. This chemical structure optimization resulted in highly stable prodrug nano-assemblies (PA(Br)-SS-PTX NPs) with superior blood circulation and tumor accumulation, overall leading to potent anti-cancer efficacy. Our findings demonstrate an important role of the bromination effect in prodrug self-assembly and introducing the bromination effect represents a promising new strategy for developing effective prodrug-based self-assembled nanomedicines for cancer treatment.