Digital one-disc-one-compound array for high-throughput discovery of cancer-targe

项目描述（由申请人提供）：拟发展一种以微流体为导向的数字编码组合方法，即数字一盘一化合物（ODOC）阵列，将最先进的组合化学与新兴的微流体、微加工、编码和矩阵理论相结合，以低成本发现高通量、高效率、高精度的癌症靶向分子。组合化学是生物学和医学研究中不可缺少的工具，它使生物分子的高效模块化合成和特异性生物靶点先导化合物的高通量探索成为可能。然而，现有的组合策略只允许大规模合成或化学寻址，而不是两者兼而有之。此外，高设备成本和复杂的化学处理限制了它们的应用仅限于实验室。在可重构微流控网络中，我们通过引入带数字条形码的批量制备微盘载体和矩阵定向组合合成，将大规模组合合成、数字分子鉴定、合成通量、平行筛选和组合化学的定量分析作为一个整体。具体而言，将在数字ODOC阵列上设计和合成癌症整合素靶向肽文库，然后对阵列上的细胞-配体相互作用进行微流控定量筛选。通过对每个单个化合物盘进行定量细胞结合获得的综合结构-活性关系（SAR）数据，有助于设计靶向文库，快速优化癌症靶向配体，具有比先前发现的更高的特异性和亲和力。简而言之，所提出的数字ODOC阵列一旦开发出来，将为针对各种类型癌细胞受体的生物分子的高通量、高效率筛选、优化和表征提供一个变革性的范例。

DESCRIPTION (provided by applicant): The objective of the proposed research is to develop a microfluidics-guided digitally encoded combinatorial method, referred to as digital one-disc-one-compound (ODOC) array, integrating state-of-the-art combinatorial chemistry with emerging microfluidics, microfabrication, encoding and matrix theories, for discovery of cancer-targeting molecules with high throughput, high efficiency and high accuracy at low cost. As an indispensable tool for biology and medicine, combinatorial chemistry has enabled high-efficiency modular synthesis of biomolecules and high-throughput exploration of the lead compounds for specific biological targets. However, existing combinatorial strategies only allow either large-scale synthesis or chemical addressability, but not both. Moreover, high equipment cost and complex chemical processing limit their utility to laboratories only. Under the proposed research, we aim at addressing large- scale combinatorial synthesis, digital molecular identification, synthetic throughput, parallel screening, and quantitative analysis of combinatoria chemistry as a whole, by introducing batch-fabricated microdisc carriers with digital barcodes and matrix-directed combinatorial synthesis in reconfigurable microfluidic networks. Specifically, cancer integrin-targeting peptide libraries will be designed and synthesized on the digital ODOC array, followed by microfluidic quantitative screening of the cell-ligand interactions on the array Comprehensive structure-activity relationship (SAR) data obtained by quantitative cell binding of every single compound-disc facilitates design of focused libraries for rapid optimization of cancer-targeting ligands with higher specificity and affinity than those previously discovered. In brief, the proposed digital ODOC array, once developed, will provide a transformative paradigm for high-throughput high-efficiency screening, optimization, and characterization of biomolecules targeting at various types of cancer cell receptors.