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Trehalose glycolipids as immunomodulators and their incorporation into liposomes for drug delivery

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posted on 15.11.2021, 00:17 by Chee, Stephanie Houping

The development of novel therapies for cancer and other diseases is an area of enormous research effort due to the growing need for better patient outcomes. As such, not only is the chemical synthesis of new drugs and adjuvants required, but ways to improve drug delivery also need to be explored. Accordingly, there has been much recent effort towards the synthesis and the biological evaluation of bacterial cell wall components as immunomodulatory compounds. To this end, trehalose glycolipids (TGs), which have been isolated from bacteria of the Mycobacteria family, are of significant interest, due to their anti-tumour and adjuvant activities.  In this thesis, the efficient synthesis of trehalose monoesters (TMEs) was investigated and the ability of these monoesters to activate macrophages via Mincle was studied and compared to the activities of their trehalose diester (TDE) counterparts. In this way, a better understanding of how TG structure influences biological activity was explored. Liposomes containing a representative TG (the C26 TDE) were also synthesised, with the objective being to explore whether TGliposomes could be used as improved drug delivery vehicles. To meet these overall objectives, TGs in solution, as well as TG incorporated into liposomes, were tested for their ability to activate macrophages derived from both C57BL/6 and Mincle-/- mice, whereby the Mincle receptor is a known receptor for TDEs.  In the TME studies, an optimised synthesis of the monoesters was developed. The ability of the TMEs to active macrophages was explored and, for the first time, it was observed that TMEs have similar biological activities to TDEs. In the TGliposome studies, a variety of liposomes containing different concentrations of phosphatidylcholine (PC) as well as the C26 TDE was prepared, so as to explore how differences in these two constituent parts influence the activation of macrophages. From this work, it was observed that increasing concentrations of TG in the liposome and increasing concentrations of liposomes gave increased macrophage activation. A concentration of PC above 200 !M also led to macrophage activation, and non-specific cell death was observed at time points > 48 h (for the wild type macrophages) and at time points ≥ 48 h for the Mincle-/- macrophages. Thus, in the case of the TG liposomes, macrophage activation is independent of Mincle, which was unusual as macrophage activation in the case of the individual TGs was dependent on this receptor.  Taken as a whole, these results pave the way for further investigations into utilising TGs in the treatment of diseases. In particular, this work provided insight into the requirement of TG/Mincle binding for improved TGs as potential adjuvants. Moreover, these studies demonstrated that the incorporation of TGs into liposomes leads to enhanced macrophage activation and therefore, potentially enhanced phagocytosis by these immune cells. Accordingly, TG-liposomes may find future application as drug delivery vehicles, in diseases where macrophages play a prominent role.

History

Copyright Date

01/01/2015

Date of Award

01/01/2015

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Chemistry

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Masters

Degree Name

Master of Science

ANZSRC Type Of Activity code

970103 Expanding Knowledge in the Chemical Sciences

Victoria University of Wellington Item Type

Awarded Research Masters Thesis

Language

en_NZ

Victoria University of Wellington School

School of Chemical and Physical Sciences

Advisors

Stocker, Bridget; Timmer, Mattie