Minor change in the length of carbon chain has a great influence on the antitumor effect of paclitaxel-fatty alcohol prodrug nanoassemblies: Small roles, big impacts

Prodrug-based nanoassembly emerges as a hopeful way for the efficient delivery of antitumor drugs, with carrier-free structure and ultra-high drug loading. Carbon chains are widely used to design self-assembling prodrugs. The impacts of the length of carbon chains on the self-assembly stability, drug delivery efficiency and antitumor effect of prodrugs have not been fully elucidated. Here, three paclitaxel prodrugs were synthesized by conjugating paclitaxel with octanol (C₈), decanol (C₁₀) or dodecanol (C₁₂) through disulfide bond. The three prodrugs could form homogeneous nanoparticles, with over 50% drug loading and redox dual-responsivity. Interestingly, the length extension of carbon chains ameliorates the self-assembly and the colloidal stability of prodrugs, thus improving the drug delivery efficiency. The optimal paclitaxel-dodecanol prodrug nanoassemblies exhibit better antitumor efficacy than Taxol and Abraxane. These findings are meaningful for the rational design of advanced nanomedicines in cancer therapy.