Synthetic heparin sulfate-like oligosaccharide fragments for a targeted multi-delivery nanoparticle platform

低聚糖是细胞表面和细胞内基质上普遍存在的生物分子，是许多关键生物调控过程的核心，包括细胞分化、癌症、细菌和病毒感染和炎症。特别是，硫酸肝素寡糖（hso）在许多这样的过程中是必不可少的，所以有很大的兴趣来提高我们对HS化学生物学和生物分子相互作用的理解。更好地了解这一领域将导致利用碳水化合物结构开发相关下一代糖疗法的新技术。脂质体药物开发之所以引起人们的兴趣，是因为它允许以持续的方式向肿瘤输送潜在毒性药物，同时减少对非靶器官的毒性。该项目涉及合成碳水化合物和低聚糖化学以及脂质体技术的多学科结合，以开发一个具有跨越许多生物医学靶标潜力的平台。这项技术将使曼彻斯特癌症研究中心能够评估它们的细胞生物学潜力和功效。该项目将扩大合成能力，以产生接合的关键中间体。纯合成hso片段和修饰衍生物的合成将与生物分子修饰脂质体的前沿工作相结合，以创建和分析新的hso脂质体。具有适当末端偶联物的合成肝素模拟物将被连接到囊泡上。hso -脂质偶联物将首先插入空脂质体中，并通过DLS， TEM， SEM进行表征，然后再使用临床可用的脂质体配方。HSO脂质负载密度和可变HSO长度将在许多生物测定靶标上测试其亲和力（细胞毒性）。将发展合成碳水化合物和低聚糖技术，以提供适合偶联的新结构以及脂质体的制造，偶联和结构研究方法。这项工作将由曼彻斯特生物技术研究所/化学学院的两个小组进行。生物学工作将在曼彻斯特癌症研究中心进行。

Oligosaccharides are ubiquitous biomolecules on cell surfaces and the intra-cellular matrix, and are central to many critical biological regulatory processes, including cell-differentiation, cancer, bacterial and viral infections and inflammation. In particular, heparan sulphate oligosaccharides (HSOs) are essential to many such processes, so there is major interest in advancing our understanding of HS chemical biology and biomolecular interactions. A better understanding of the area will lead to new technologies that exploit carbohydrate structures for the development of related next-generation glycotherapeutics. Liposomal drug development is of interest because it allows delivery of potentially toxic drugs in a sustained manner to tumours, while reducing toxicity to non-target organs.This project involves a multidisciplinary combination of synthetic carbohydrate and oligosaccharide chemistry and liposome technology to develop a platform with potential across a number of biomedical targets. This technology will enable assessing their cell biological potential and efficacy at the Manchester Cancer Research Centre.The project will extend synthetic capability to generate key intermediates for conjugation. The synthesis of pure synthetic HSO-fragments and modified derivatives will be combined with forefront work on biomolecule-modified liposomes to create and analyze new HSO-liposomes. Synthetic heparin mimics with appropriate terminal conjugates will be ligated to vesicles. HSO-lipid conjugates will first be inserted into empty liposomes and characterised by DLS, TEM, SEM, before clinically available liposomal formulations are used. HSO-lipid loading densities and variable HSO lengths will be tested for their affinity (cytotoxicity) across a number of bioassay targets. Synthetic carbohydrate and oligosaccharide skills will be developed to provide novel structures suitable for conjugations alongside methods for manufacture, conjugation and structural studies of liposomes. This work will be conducted in two groups both based in the Manchester Institute of Biotechnology / School of Chemistry. Biological work will be undertaken in the Manchester Cancer Research Centre.