Iterative Synthesis with Organic Solvent Nanofiltration for Precision Manufacture of High Value Sequence-Controlled Polymers (ItSyN)

该项目将开发一种新的制造工艺，以精确的方式制造高价值的序列控制聚合物。序列控制的聚合物包括（生物）聚合物，例如DNA、RNA（一起称为“寡聚物”）和肽。它们还包括合成聚合物，对于这些聚合物，精确控制聚合物长度或单体顺序是必要的。这些聚合物是制药工业所需要的，在制药工业中，它们被用作生物活性材料（“药物”），以及用作用于递送和保护药物的分子组装体的一部分;并且具有新兴的非生物用途。添加这些单体的确切顺序对最终聚合物的功能绝对至关重要。这些聚合物是由工业化学方法通过一系列单体加成以模仿自然的方式制成的（我们称之为迭代合成），并且在下一个循环之前要非常小心地去除未反应单体的残基，以避免序列中的错误。一种非常有效的方法是将生长的聚合物附着到固体载体相，在加入下一个单体之前，用干净的溶剂洗涤以除去残留物。当聚合物生长完成时，其从固体支持物裂解。然而，该方法是昂贵的，因为必须使用更多的单体以确保反应在固体载体上完成，并且因为载体本身是昂贵的。对于我们想要精确控制分子量的合成聚合物，例如聚乙二醇（PEG），它被广泛用于稳定药物并使它们在体内持续更长时间，我们可以一次又一次地添加相同的单体，直到我们达到所需的链长，然后从载体上切割最终的聚合物。目前还没有这样做，因为固相支持的迭代合成的成本太高和/或化学方法不可用。固体载体是可变的，并且难以以精确可重复的方式制造;事实上，载体中的微小差异可以导致用于将单体连接到生长的聚合物上的反应中的相当大的变化。此外，由于反应物的分子位于载体材料的孔隙内，因此很难对反应混合物进行分析，判断反应是否正常进行。帝国理工学院最近的研究开发了有机溶剂纳滤（OSN），使用在溶剂中稳定的膜，能够将小分子从大分子中分离出来。我们的关键创新是在序列控制聚合物合成的每个阶段使用这些膜，将生长的聚合物与未反应的单体分离。这个过程将在液相中进行，分析将更加简单;聚合物生长的反应将更快，更有效，使用更少的单体。此外，如果两个或更多个生长的聚合物连接到中心分子以产生homostar复合物，这将使膜保留的溶质更大，并促进更有效的分离。我们提出了OSN迭代合成（Iterative Synthesis with OSN，简称ItSyN）作为一种精确制备序列控制聚合物的新方法。将致力于ItSyN项目的化学工程师和化学家的多学科团队将开发工艺化学，使纯化更好;建造实验室工厂合成器，使该过程可以自动化，选择溶剂和探索溶剂回收，并通过设计使用质量，使流程更高效。如果我们成功，该项目将产生一种新的序列控制聚合物制造技术，并将导致更精确的聚合物可用于医疗保健等领域。

This project will develop a new manufacturing process for making high value sequence-controlled polymers in a precise way. Sequence-controlled polymers include (bio)polymers such as DNA, RNA (together, "oligos") and peptides. They also include synthetic polymers for which precise control of polymer length or monomer order is necessary. These polymers are in demand by the pharmaceutical industry, where they are used as biologically active materials ("drugs"), and as parts of molecular assemblies that are used to deliver and protect drugs; and have emerging non-biological uses.Nature makes sequence-controlled polymers such as oligos or peptides by sequentially adding different monomers in a prescribed sequence. The exact order of that these monomers are added is absolutely crucial to the function of the final polymer. These same polymers are made by industrial chemistry in a way that apes Nature, through a sequence of monomer additions (we call this iterative synthesis), and a great deal of care is taken to remove the residues of unreacted monomer before the next cycle, to avoid errors in the sequence.A very effective way of doing this is to attach the growing polymer to a solid support phase, which is washed with clean solvents to remove the residues, before the next monomer is added. When polymer growth is complete, it is cleaved from the solid support. However this process is expensive, because more monomer must be used to ensure the reaction reaches completion on the solid support, and because the supports themselves are expensive. For synthetic polymers where we want to control the molecular weight exactly, for example poly(ethylene glycols) (PEGs), which are widely used to stabilise drugs and make them last longer in the body, we could add the same monomer over and over until we reach a desired chain length, and then cleave the final polymer from the support. This is not done at present, because the cost of solid supported iterative synthesis is too high and/or the chemistry is not available.There are other problems with solid supported synthesis. The solid supports are variable, and hard to make in a precisely repeatable way; in fact small differences in the supports can lead to quite big changes in the reactions used to link the monomers onto the growing polymer. Also, it is very hard to carry out analyses on the reaction mixture to tell whether the reactions are proceeding correctly, because the molecules of interest are inside the pores of a support material.Recent research at Imperial College has developed Organic Solvent Nanofiltration (OSN), using membranes that are stable in solvents, and able to separate small molecules from large molecules. Our key innovation is to use these membranes at each stage of sequence-controlled polymer synthesis to separate the growing polymer from the unreacted monomers. This process will be carried out in the liquid phase and analysis would be far more straightforward; and the reactions to grow the polymer will be faster and more efficient, and use less monomer. Further, if two or more of the growing polymers are connected to a hub molecule to create a homostar complex, this will make the solute to be retained by the membrane larger and promotes a more efficient separation. We propose this Iterative Synthesis with OSN, or ItSyN for short, as a new approach to precisely manufacture sequence-controlled polymers.The multidisciplinary team of chemical engineers and chemists who will work on the ItSyN project will develop the process chemistry to make the purification better; construct Lab Plant synthesisers so that the process can be automated, select solvents and explore solvent recovery, and use quality by design to make the process more efficient. If we are successful, the project will result in a new technology for sequence-controlled polymer manufacture, and will lead to more precise polymers being available for applications in healthcare and beyond.