Modularly Engineered Solid‐Phase Synthesis of Aptamer‐Functionalized Small Molecule Drugs for Targeted Cancer Therapy

Abstract

Abstract Biomarker‐guided anticancer strategy has evolved into one of the most reliable and efficient cancer treatment techniques. However, most targeted anticancer molecular platforms are constructed in liquid phase with multi‐step synthesis and complex purification. This work describes a general and modular solid‐phase synthesis strategy to engineer novel targeted anticancer therapeutics based on aptamer‐functionalized small molecule drugs (ASMD). Specifically, anticancer agent Combretastatin A4 (CA4) is transformed into a phosphoramidite module, and then is incorporated into aptamer Sgc8c via automated DNA synthesis technique to obtain intracellular phosphatase‐responsive Sgc8c‐CA4 conjugate (SC). In the rational design, SC retains excellent recognition ability and cytotoxicity against its target colorectal cancer cells. SC shows more efficient and safer therapy than CA4 both in vitro and in vivo. Moreover, the cellular events of SC are systematically visualized when they encounter the target cancer cells. The visualizing mechanism gives a clear picture of the anticancer function of targeted therapeutics against cancer cells. These results may pave the way for utilizing molecularly engineered ASMDs to develop more novel targeted cancer therapeutics for the treatment of different cancer types.