By Dr Paco López-Cuevas
A study led by the labs of Prof Steve Mann (Chemistry) and Prof Paul Martin (Biochemistry) at the University of Bristol has demonstrated a new potential anti-cancer therapy that boosts the body’s inflammatory response using miniature artificial particles called protocells. This discovery is documented in an article published in Advanced Science, which specialises in interdisciplinary studies.
Our inflammatory cells, macrophages and neutrophils in particular, have remarkable cancer surveillance capacities, and therefore they act as “vigilants” to detect any cancer cell arising in the body. However, when these immune cells encounter the malignant cells, rather than killing them, they generally feed them with nutrients, which favours cancer growth. In this study, we developed a novel therapeutic system to reprogram immune cells away from cancer nurturing and towards cancer killing.
To achieve this, we injected miniature artificial protocells into the bloodstream of zebrafish, which are translucent and thus allow us to live image protocell dynamics and cell-cell interactions in real time. We observed that protocells were selectively taken up by inflammatory cells which were then reprogrammed, by specific cargoes loaded in the protocells, to make them more effective at killing cancer. The “reprogramming” cargo packaged in protocells was a miR223 inhibitor, anti-miR223, which maintains a pro-inflammatory/anti-cancer state in inflammatory cells, otherwise repressed by the presence of endogenous miR223. We showed that protocell-mediated reprogramming of the immune response led to reduced cancer cell proliferation and melanoma shrinkage in zebrafish.
In collaboration with Prof Ash Toye’s lab (Biochemistry), we established an in vitro assay with human macrophages supplemented with protocells. Our results showed that the protocells were able to promote anti-cancer reprogramming in human macrophages, too, which suggests that this novel protocell system may be a promising cancer immunotherapy strategy against human melanomas, and possibly also for other cancers with a pro-inflammatory vulnerability.
The research is explained in this scribble video:
Having demonstrated the ability of protocells to deliver cargoes to tumour-associated leukocytes and enhance their anti-cancer capacities, the Mann and Martin groups now plan to expand the therapeutic application of the protocell system beyond cancer and test the feasibility of using protocells to modulate the inflammatory response to unresolved/chronic wounds in order to improve wound healing in these clinically relevant inflammatory conditions. This research is currently ongoing and is supported by funding from BrisEngBio.
This work was funded by grants from the Spanish Rafael del Pino Foundation, Marie Curie, Biotechnology and Biological Sciences Research Council (BBSRC), Bristol Centre for Engineering Biology (BrisEngBio), National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Red Blood Cell Products, National Health Service Blood and Transplant (NHSBT), Wellcome Trust, Elizabeth Blackwell Institute, European Research Council (ERC), Cancer Research UK (CRUK), and by a generous Bristol Cancer Bequest.
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Macrophage Reprogramming with Anti-miR223-Loaded Artificial Protocells Enhances In Vivo Cancer Therapeutic Potential
Paco López-Cuevas, Can Xu, Charlotte E. Severn, Tiah C. L. Oates, Stephen J. Cross, Ashley M. Toye, Stephen Mann, Paul Martin
Adv. Sci. 2022, 2202717, https://doi.org/10.1002/advs.202202717