Preparation and in vitro functional validation of a novel antibody-siRNA-Exatecan conjugate (AREC)

Antibody–siRNA conjugate (ARC) is a novel therapeutic strategy developed based on the concept of antibody–drug conjugate (ADC). It combines the targeting specificity of antibodies with the gene silencing ability of small interfering RNA (siRNA) and shows broad application prospects. However, the development of traditional ARC in the field of tumor treatment faces many challenges, and the DNA Topoisomerase I Inhibitor-Exatecan is limited in its clinical application due to its strong hydrophobicity and significant toxicity. In this study, we developed a novel antibody–siRNA–Exatecan conjugate (AREC). By introducing siRNA, we plan to increase the hydrophilicity of small molecule drugs and optimize the drug to antibody ratio (DAR) to 1 and 2. This modification not only significantly reduced the toxic side effects associated with high DAR values, but also provided a basis for evaluating the synergistic anti-tumor effect between STAT3 gene silencing and Exatecan. In vitro experimental results showed that AREC can efficiently kill tumor cells, fully demonstrating its great potential as a multifunctional platform for tumor targeted therapy.