Regulating the Anticancer Efficacy of Sgc8–Combretastatin A4 Conjugates: A Case of Recognizing the Significance of Linker Chemistry for the Design of Aptamer-Based Targeted Drug Delivery Strategies

The unique merits of aptamers, including specificity, high binding affinity, easy cell internalization, and rapid tissue accumulation abilities, have led aptamer-drug conjugates to evolve into one of the most attractive strategies for targeted drug delivery purposes. Nevertheless, the critical role of linkers in regulating anticancer efficacy of these conjugates, especially those engineered by automated modular synthesis techniques, has been rarely explored. In this work, we utilized Sgc8c aptamer and combretastatin A4 to develop three conjugates with either a phosphodiester bond linker, a disulfide bond linker, or a carbamate linker to study their payload release mechanisms and the influence on anticancer efficacy. These investigations allowed us to identify the unique activation pathway of the phosphodiester bond linker that is activated by both nucleophilic attack of glutathione and degradation caused by phosphodiesterase, which is highly associated with the higher cytotoxicity of the conjugate. Importantly, the understanding of the chemistry of phosphodiester bond linker activation allowed us to further design another XQ-2d-CA4 conjugate that can induce pancreatic cancer cells apoptosis in a more efficient manner.