2 Modern molecular medicine has increasingly focused on developing novel target-specific molecular probes to 3 improve the prognosis and diagnosis of diseases and provide the best treatment regimens. To this end, in the 4 past two decades, nucleic acid aptamers have been developed and a series of aptamer-based methods and 5 materials have been used for biomarker identification and the development of targeted drugs. Aptamers are 6 single-stranded oligonucleotides composed of DNA or RNA, usually having a length of 15-60 nucleotides. They 7 demonstrate remarkable binding affinity to a variety of targets including intact cells. Compared to antibodies, 8 aptamers are generated through an in vitro selection process, termed SELEX (Systematic Evolution of Ligands by 9 Exponential Enrichment). Thus, it can be easily resynthesized and chemically modified, with promising batch-to- 0 batch consistency, easy modification and satisfying biocompatibility. It is worth noting that antibodies are still 1 among the most intriguing tools for molecular recognition. However, monoclonal antibodies took more than 20 2 years to be humanized since initial production and much longer for real clinical applications. In comparison, over 3 40 clinical trials with aptamers have already been conducted, highlighting their enormous potential in clinical 4 practice. 5 The PI?s lab has been a leading group in aptamer research and development. In the past decade, the Tan lab 6 has developed aptamer-based theranostics and biomarker discovery strategies. Ever since around ten years ago 7 we initiated the cell-SELEX technology to deliver DNA aptamers specifically targeting intact cells, we have now 8 developed more than 300 aptamers against many types of cancerous and other diseased cells. Besides, 9 combined with the cutting-edge nanomaterials, aptamer-based theranostics have been developed. Despite the 0 enormous potential and recent technical advances made with aptamers, their true impact in biomedicine has not 1 been fully realized. The gaps in advancing their utility are mainly in slow selection process, unknown binding 2 mechanism and low efficacy in using aptamers for clinic studies. The goals here are to address these 3 fundamental gaps and challenges, to push aptamers from molecules to medicine and to open new areas of 4 research using aptamers. 5 Out central goal here is dedicated to fulfilling the promise of aptamers as key molecular tools. Two major 6 areas of research will be carried out: 1) understanding the nature of aptamers and aptamer/target structure and 7 developing new strategies for their use as effective molecular probes and 2) using aptamers to discover and 8 pursue new avenues of research and development. Specifically, we will fill the gaps by developing one round 9 SELEX to increase efficiency and obtain robust aptamers. We will also use cryo-EM microscopy to understand 0 the structural information of selected aptamers with their targets for better-predicted biological performances. 1 Both will not be proposed in a regular NIH proposal as they will be viewed either as too ambitious or too 2 preliminary to support. In addition, we will also optimize and create new aptamers in such a way to show their full 3 utilities as molecular probes in molecular medicine: including aptamer based accurate and smart diagnosis and 4 precision therapy strategies.
Despite the enormous potential and recent technical advances made with aptamers, single stranded DNA/RNA for specific biomarkers, their true impact has not been fully realized. In this grant, we will address the gaps in advancing the utility of aptamers as effective molecular probes by improving in vitro selection method, understanding the structural information of selected aptamers and their targets for better-predicted biological performances and developing an array of molecular tools for accurate diagnostics and precision treatment of major diseases such as lung and pancreatic cancers.
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|Wu, Yuan; Li, Dan; Zhou, Fang et al. (2018) Versatile in situ synthesis of MnO2 nanolayers on upconversion nanoparticles and their application in activatable fluorescence and MRI imaging. Chem Sci 9:5427-5434|