Abstract
CD123 is the clinical molecular therapy target for several hematological malignancies. However, CD123 is also expressed on normal cells, which may lead to severe side effects during targeted therapy. Our pre-experiment has developed a conformationally tunable aptamer ZW25, with “targeting molecule” and “drug” dual-function. We further found that ZW25 could generate selective cytotoxicity to CD123+ hematological malignancies, such as blastic plasmacytoid dendritic cell neoplasm (BPDCN). ZW25 firstly targets CD123-positive cells, and only changes its conformation due to intracellular alkalescent pH value of BPDCN cells after internalization. Then, ZW25 acts on LXR receptor α (LXRα) and induces tumor cytotoxicity subsequently. This project is further to analyze the pH-dependent tunable conformation mechanism of ZW25 by multi-dimensional computation and experiments, to clarify the regulating mechanism of ZW25 to LXRα transcription factor activity, and to elucidate the “CD123 targeting→internalization and conformation→LXRα” pathway of ZW25 in BPDCN selective killing at the cellular and animal levels. This project aims to establish a new interaction mode for controlled multimodal aptamer, and by means of aptamer as a tool to provide an avenue for tumor targeted therapy.
Biography
