Hydrophobic/Amphiphilic Prodrug Coassembly Strategy: Exploring the Effect of Oligoethylene Glycol Chains on the Antitumor Efficacy of Nanoassemblies

The self-assembly prodrugs can be classified into hydrophobic and amphiphilic prodrugs. While hydrophobic prodrugs can form nanoassemblies through strong hydrophobic interactions, these tend to aggregate due to the high surface free energy. Amphiphilic prodrugs reduce surface energy but often lack a sufficient hydrophobic driving force for stable self-assembly. To overcome these limitations, we developed a prodrug coassembly strategy using a hydrophobic paclitaxel-palmitic acid (PA) prodrug (PTX-SS-PA) and three amphiphilic paclitaxel-oligoethylene glycol (OEG) prodrugs (PTX-SS-OEG₁, PTX-SS-OEG₄, and PTX-SS-OEG₈). The results showed that coassembled nanoassemblies exhibit higher stability than self-assembled nanoassemblies. Furthermore, this study indicated that the cellular uptake efficiency, redox-sensitive activation efficiency, and cytotoxicity of coassembled nanoassemblies were affected by the OEG chain length. Notably, the OEG₁@PA NPs exhibited the best tumor selectivity and redox-sensitive activation efficiency, resulting in potent antitumor activity and favorable safety. These findings present promising strategies for the development of advanced prodrug nanoassemblies.