MACROIMAGING is a highly interdisciplinary project encompassing the preparation and optimisation of innovative fluorogenic imaging tools with high selectivity for metastasis-associated macrophages.
The metastatic potential of tumours is defined by the tumour microenvironment (TM), where macrophages are the most abundant cells. However, the role of macrophages in the TM remains elusive mainly because of the lack of technologies to target these unique populations of cells in vivo. CD11b+ metastasis-associated macrophages are recruited by metastasing cancer cells. Their depletion reduces the number and size of metastasis, suggesting that their recruitment is essential for persistent growth of cancer cells. However, there is a need for imaging tools that report the localisation and cell fate of these macrophages to understand how they help tumour cells to progress in the TM.
By means of Dynamic Combinatorial Chemistry, libraries of cyclic peptides will be generated from individual tetrapeptides through reversible disulfide bonds. Governed by thermodynamics, DCC will amplify cyclic peptides showing high affinity for CD11b+ macrophage receptors, involved in the development of metastasis. This technique will supply specific cyclic peptides targeting CD11b. Click chemistry (i.e. CuAAC) will allow the conjugation of these peptides to macrophage-specific fluorophores to generate FLUOROMACS. FLUOROMACS will enable selective imaging of CD11b+ macrophages by means of receptor-mediated endocytosis. Selectivity will be confirmed in vitro using macrophages from normal cohorts and knockouts. Finally Fluoromacs will be optimised as in vivo imaging probes for metastasis-associated macrophages.
In a nutshell, MACROIMAGING will provide the first generation of chemical probes for imaging metastasis-associated macrophages in vivo. This methodology will also have enormous impact in other areas of chemical biology, such as protein recognition, drug discovery and theranostics.
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