Exploring the optimal chain length of modification module in disulfide bond bridged paclitaxel prodrug nanoassemblies for breast tumor treatment.

In the prodrug-based self-assembled nanoassemblies, prodrugs usually consist of drug modules, response modules, and modification modules. Modification modules play a critical role in regulating the nano-assembly ability of the prodrugs. Herein, we carried out a "fatty alcoholization" strategy and chose various lengths of aliphatic alcohol chains (AC) as modification modules to construct disulfide bond bridged paclitaxel (PTX) prodrug nanoassemblies. The PTX-AC prodrugs would self-assemble into nanoassemblies (PTX-AC PNs) with higher drug loading, stability, and tumor selectivity than commercial preparations. After comprehensive exploration, we found the chain length (AC, AC, AC, AC) of modification modules affected the assembly of PTX-AC PNs, further leading to disparate in vivo fate and antitumor efficacy. With the increase of the chain length of the modification modules (from AC to AC), the assembly ability of the nanoassemblies was improved, attributed to the appropriate enhancement of hydrophobic force. When the chain length was further increased to AC, the excessive hydrophobic force will lead to the aggregation of prodrugs and weaken the assembly ability. Therefore, PTX-AC PNs with proper chain length may solve the paradox of efficacy and tolerance in 4 T1 breast tumor owing to their optimal nano-assembly stability and modest redox-sensitivity. In short, this work highlighted the importance of screening optimal modification modules in developing prodrug nanoassemblies.