Aptamers are promising agents in both diagnostic and therapeutic applications. We are a collaborating team (Guangdong-Hong Kong-Macao Greater Bay Area Research Platform for Aptamer-based Translational Medicine and Drug Discovery (HKAP)) with top scientists in this field. We have established state-of-the-art technologies with research outcomes being published in high-impact journals (Cell, Science, Nature, Nature Medicine, Nature Communications, ACS Nano, PNAS). One of our aptamers for osteogenesis imperfecta therapy has been granted by US-FDA for Orphan Drug Designation (DRU-2019-6966).
Task 1: Aptamer selection optimization: Standard selection method SELEX is time-consuming with high failure rates. With rich experiences in SELEX and well-established automatic microfluidic system, we will develop a fully integrated SMART and high-throughput microfluidic platform for rapid, efficient and reliable selection of aptamers against circulating proteins. Selected aptamers against purified transmembrane proteins often fail to recognize targets in live cells. We will develop an innovative LOSS-GAIN cell-SELEX methodology incorporating into the microfluidics for selecting aptamers against transmembrane proteins on live cells. Task 2: Aptamer molecular insight: The 3D structure of aptamer-target could not only help to understand the interaction mechanism, but also guide chemical modifications to improve affinity and activity of aptamers to facilitate applications. We have developed the aptamer LC07 against osteosarcoma cells and the aptamer XQ-2d against pancreatic cancer cells. PARP1 and CD71 were then identified as the target of LC07 and XQ-2d, respectively. We will determine the binding mode of LC07-PARP1 and XQ-2d-CD71, respectively, using our developed methodologies. Phosphorodithioate substitution will be performed on LC07 and XQ-2d with the guidance of the determined 3D structures, respectively, to enhance the induced-fit arrangement and binding affinity. Task 3: Diagnostic aptamers: Cancer diagnosis at early stage is a major challenge in the clinic. We have established highly sensitive aptamer-based diagnostic devices for various diseases. We will develop an aptamer-mediated multiplexing diagnostic methodology by novel nucleic acid chemistries ideally for low-abundance biomarkers in latent pancreatic cancer. Task 4: Therapeutic aptamer-drug conjugates: The highly specific aptamers is a promising strategy for targeted delivery of cytotoxic natural products. However, the low conjugating efficiency of aptamer to drug and the chemical instability of conjugating linker in liquid-phase reactions restrained their drugability. We will develop solid-phase aptamer-drug conjugating methodology to synthesize conjugates of pancreatic cancer-specific aptamer XQ-2d with cytotoxic anti-tumor natural products and examine their antitumor activities and toxicities, respectively. This project will promote molecular insight and translational theranostics of aptamers, allowing Hong Kong to become the world-leading centre for aptamer research.
Project Investigator
Professor Lyu Aiping (SCM)
Co-principal Investigators
Dr Ren Kangning (CHEM)
Professor Zhang Ge (SCM)
Funding
Research Grants Council - Theme-based Research Scheme