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

Abstract

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 (AC₁₂, AC₁₆, AC₂₀, AC₂₄) 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 AC₁₂ to AC₂₀), the assembly ability of the nanoassemblies was improved, attributed to the appropriate enhancement of hydrophobic force. When the chain length was further increased to AC₂₄, the excessive hydrophobic force will lead to the aggregation of prodrugs and weaken the assembly ability. Therefore, PTX-AC₂₀ 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.