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

等孔有机溶剂纳滤膜可实现生命科学的高价值制造 (iOSN)

基本信息

  • 批准号:
    MR/W009382/1
  • 负责人:
  • 金额:
    $ 191.13万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Fellowship
  • 财政年份:
    2022
  • 资助国家:
    英国
  • 起止时间:
    2022 至 无数据
  • 项目状态:
    未结题

项目摘要

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.
聚合物是由称为单体的重复化学单元组成的长分子。一些生物聚合物,如包含核苷酸序列的寡核苷酸(oligos),被用作治疗剂。寡糖药物通过调节蛋白质的表达和基因的功能起作用。目前市场上有10种经批准的低聚药物,还有更多的药物正在开发中,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。寡核苷酸的确切顺序对其功能至关重要。工业上,低聚物是通过向生长的低聚物中依次添加单体来制造的,在下一个循环之前,要注意去除残留的、未反应的单体,这样就不会出现序列错误。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的寡核苷酸附着在固体载体上,在添加下一个核苷酸之前,用干净的溶剂清洗以去除残留物-这被称为固相合成(SPS)。当寡糖生长完成时,它就从固体支撑中分离出来。然后去除所有其他侧链保护基团,然后我们继续测试最终寡核苷酸的纯度-是否添加了所有需要的核苷酸?通常会有“缺失”单体,因为固体载体上的反应没有完成,通常会找到60-80%所需的n-mer低聚物,以及n-1、n-2、n-3短聚物的“阶梯”,这些低聚物缺失1、2、3或更多核苷酸。梯子必须被移除,这需要大量的,昂贵的色谱。Exactmer有限公司,一家英国生命科学公司,正在商业化一种新的技术平台,纳米筛分,用于大规模低聚物合成。关键的创新是使用有机溶剂纳滤(OSN)膜从未反应的单体中分离生长的低聚物。这是在液相中进行的,分析相对简单。通过将三个正在生长的寡核苷酸连接到一个中心枢纽分子上,形成了一个大的纳米星复合物,增强了膜保留并促进了有效的分离。Exactmer使用Nanostar筛分生产寡核苷酸,对纯度的控制前所未有,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,使它们在低聚物合成所需的有机溶剂环境中稳定,并且非常坚固。然而,它们具有广泛的孔径分布,这意味着分离缺乏效率,导致需要多个膜级才能保持高得率,并且需要大量的溶剂才能达到所需的纯度。在水处理中,通过使用嵌段共聚物的微相分离,已经设计出具有等孔(单孔大小)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交联它们。在这个项目中,未来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,这种聚合物可以用来形成可以蚀刻和交联的膜;第二种方法是通过交联在支撑矩阵上制作薄膜分离层,然后蚀刻。一个充满活力的高科技业务、一个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结合,提供了一个独特的团队,他们装备精良,可以在OSN膜方面取得根本性突破,这将为低聚物合成和其他领域提供改变范式的选择。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
2D Covalent Organic Framework Membranes for Liquid-Phase Molecular Separations: State of the Field, Common Pitfalls, and Future Opportunities.
用于液相分子分离的二维共价有机框架膜:该领域的现状、常见陷阱和未来机遇。
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Zhiwei Jiang其他文献

Synthesis, biophysical properties, and stability studies of mixed backbone oligonucleotides containing segments of methylphosphotriester internucleotidic linkages
含有甲基磷酸三酯核苷酸间键合片段的混合主链寡核苷酸的合成、生物物理性质和稳定性研究
  • DOI:
  • 发表时间:
    1996
  • 期刊:
  • 影响因子:
    0
  • 作者:
    R. Iyer;Dong Yu;Zhiwei Jiang;S. Agrawal
  • 通讯作者:
    S. Agrawal
Application of crop model data assimilation with particle filter for estimating regional winter wheat yields
应用粒子滤波作物模型数据同化估算区域冬小麦产量
A nested group sequential framework for regional evaluation in global drug development program
全球药物开发计划区域评价的嵌套组序贯框架
Mixed-Backbone Oligonucleotides Containing Phosphorothioate and Methylphosphonate Linkages as Second Generation Antisense Oligonucleotide
含有硫代磷酸酯和甲基膦酸酯键的混合主链寡核苷酸作为第二代反义寡核苷酸
  • DOI:
    10.1080/07328319708006109
  • 发表时间:
    1997
  • 期刊:
  • 影响因子:
    0
  • 作者:
    S. Agrawal;Zhiwei Jiang;Qiuyan Zhao;D. Shaw;Daisy Sun;C. Saxinger
  • 通讯作者:
    C. Saxinger
Growth of carbon nanofibers/tubes by an in-situ polymerization route without metal-catalyst
  • DOI:
    http://dx.doi.org/10.1016/j.carbon.2016.01.041
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
  • 作者:
    Fangwei Guo;Guowei Wang;Zhiwei Jiang;Yang Liu;XiaofengZhao;Ping Xiao
  • 通讯作者:
    Ping Xiao

Zhiwei Jiang的其他文献

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