Isoporous Organic Solvent Nanofitration Membranes to Enable High Value Manufacturing for Life Sciences (iOSN)

聚合物是由重复的化学单元组成的长分子，称为单体。一些生物聚合物，例如包含一系列核苷酸的寡聚核苷酸(寡聚核苷酸)被用作治疗剂。寡聚药物通过调节蛋白质的表达和基因的功能发挥作用。现在市场上有10种已批准的寡聚药物，还有更多正在开发中，人们越来越需要一种高效的制造技术来制造这些高价值的分子。寡核苷酸的准确顺序对其功能是绝对关键的。在工业上，通过将单体顺序添加到生长中的低聚物中来制造低聚物，在下一个周期之前小心地去除残留的未反应的单体，以便在序列中没有错误。这需要在每个耦合周期结束时进行良好的分离。一种非常有效的方法是将生长中的寡聚连接到固体载体上，在添加下一个核苷酸之前，用清洁的溶剂洗涤固体载体以去除残留物-这被称为固相合成(SPS)。当寡聚生长完成时，它从固体支撑物中分离出来。然后移除所有其他侧链保护基团，然后我们继续测试最终寡聚的纯度--是否添加了所有必需的核苷酸？由于固体载体上的反应没有完成，通常会发现60-80%的所需n-聚寡聚，以及缺失1、2、3或更多核苷酸的n-1、n-2、n-3聚体较短的寡聚“阶梯”，因此常常会出现“缺失”单体。这一阶梯必须被移除，这需要广泛而昂贵的层析。英国生命科学公司Exactmer Limited正在将一种新的技术平台--NanSTAR筛分--商业化，用于大规模的寡聚合成。关键的创新是使用有机溶剂纳滤膜(OSN)将生长中的低聚物从未反应的单体中分离出来。这是在液相中进行的，分析相对简单。通过将三个不断增长的低聚物连接到中心枢纽分子，创建了一个大型的纳米STAR复合体，增强了膜保留率，促进了高效分离。Exactmer使用NanSTAR筛分来生产具有前所未有的纯度控制的寡聚，最近与包括诺华和阿斯利康在内的几家大型制药公司签订了许可和开发协议。Exactmer的OSN膜工作令人满意。它们是交联的，使它们在寡聚合成所需的有机溶剂环境中稳定，并且非常健壮。然而，它们的孔径分布很广，这意味着分离效率低下，因此需要多个膜阶段来保持高产率，并需要大量的溶剂来获得所需的纯度。在水处理中，通过嵌段共聚物的微相分离，设计了具有等孔(单孔)结构的分子分离膜。这些膜还不能用于有机溶剂系统，因为目前还没有办法将它们交联。在这个项目中，未来的领导研究员蒋志伟博士打算开发用于有机溶剂的等孔膜，并将其应用于低聚物合成。为了实现这一目标，他将采用两种方法，一种是基于创造新的聚合物，可以用来形成可以进行蚀刻和交联的膜；另一种是通过交联法在载体基质上制造薄膜分离层，然后进行蚀刻。不断增长的高科技业务、才华横溢的研究工程师/科学家、独特的膜制造设施和关键的制造需求的强大组合，为OSN膜提供了一支装备精良的独特团队，能够在OSN膜领域取得根本性突破，为寡聚合成和其他领域提供改变范式的选择。

Polymers are long molecules comprising repeated chemical units known as monomers. Some biopolymers, such as oligonucleotides (oligos) comprising a sequence of nucleotides, are used as therapeutic agents. Oligo medicines work by modulating the expression of proteins and the functioning of genes. There are now 10 approved oligo drugs on the market and many more in development, and there is a growing need for an efficient manufacturing technology to make these high value molecules. The exact order of the nucleotides in an oligo is absolutely crucial its function. Oligos are made industrially by sequential addition of monomers to growing oligos, taking care to remove residual, unreacted monomer before the next cycle, so that there are no errors in the sequence. This requires excellent separation at the end of each coupling cycle. A very effective way of doing this is to attach the growing oligo to a solid support, which is washed with clean solvents to remove residuals, before the next nucleotide is added - this is known as Solid Phase Synthesis (SPS). When oligo growth is complete, it is cleaved from the solid support. All other side chain protecting groups are then removed, and we proceed to test the purity of the final oligo - have all the required nucleotides been added? Often there are "missing" monomers because the reactions on the solid support did not go to completion, and it is typical to find 60-80% of the desired n-mer oligo, together with a "ladder" of n-1, n-2, n-3 mer shorter oligos which are missing 1, 2, 3 or more nucleotides. The ladder must be removed, and this requires extensive, and expensive, chromatography.Exactmer Limited, a UK Life Sciences business is commercialising a new technology platform, Nanostar Sieving, for large scale oligo synthesis. The key innovation is to use organic solvent nanofiltration (OSN) membranes to separate a growing oligo from unreacted monomers. This is carried out in the liquid phase and analysis is relatively straightforward. By connecting three growing oligos to a central hub molecule, a large nanostar complex is created, enhancing membrane retention and promoting efficient separation. Exactmer use Nanostar Sieving to produce oligos with unprecedented control over purity, and have recently entered into licensing and development agreements with several large pharma companies including Novartis and AstraZeneca.Exactmer has OSN membranes that work satisfactorily. They are crosslinked to make them stable in the organic solvent environment required for oligo synthesis, and are very robust. However, they have a wide distribution of pore sizes, and this means that the separation lacks efficiency, resulting in the need for multiple membrane stages to maintain a high yield, and a high volume of solvent to achieve the desired purity. In water treatment, molecular separation membranes have been designed that have an isoporous (single pore size) structure, through using micro-phase separations of block co-polymers. These membranes cannot yet be used in organic solvent systems, as there is no way currently to crosslink them. In this project the Future Leadership Fellow, Dr Zhiwei Jiang, intends to develop isoporous membranes for organic solvent use, and to apply these in oligo synthesis. To achieve this, he will work with two approaches, one based on creating new polymers which can be used to form membranes that can undergo etching and crosslinking; and a second approach in which a thin film separating layer is made on a support matrix by crosslinking, and then etched. This powerful combination of a dynamic growing high-tech business, a highly talented research engineer/scientist, unique membrane making facilities, and a crucial manufacturing need, offers a unique team well equipped to make a fundamental breakthrough in OSN membranes that will offer paradigm changing options to oligo synthesis and beyond.