Synthetic heparin sulfate-like oligosaccharide fragments for a targeted multi-delivery nanoparticle platform
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
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.
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.
