Aliphatic alcohols-based modification strategy to balance efficacy and safety of cabazitaxel prodrug nanoassemblies

Prodrug-based nanoassemblies have emerged as advanced carrier-free nanomedicines. These prodrugs typically consist of drug modules, response modules, and modification modules. The general role of modification modules is to modulate the self-assembly ability of the prodrugs. How to optimize the structure of modification modules for balanced efficacy and safety of high-toxicity chemotherapeutic drugs deserves to be further investigated. In this study, a modification strategy of aliphatic alcohols with various chain lengths (SC₄, SC₈, SC₁₂, SC₁₆ and SC₂₀) was carried out to design five cabazitaxel (CBZ) prodrugs. Among them, CBZ-SC NPs with shorter chain length (SC₄ and SC₈) showed poor self-assembly stability. CBZ-SC₁₂ NPs also failed to remain stable while the other two CBZ-SC NPs exhibited good stability. In turn, the drug release rate was hindered by the increasing chain length. CBZ-SC₁₂ NPs caused kidney damage due to their high redox-sensitivity and rapid release rate during circulation. By contrast, CBZ-SC NPs with longer chain length (SC₁₆ and SC₂₀) not only demonstrated superior stability with improved pharmacokinetic behavior, but also might solve the dilemma of dose-related toxicity caused by CBZ. Overall, these findings emphasized the importance of chain length in modification module to modulate the efficacy and safety of CBZ prodrug nanoassemblies.