Exosome-directed catalyst prodrug activation in cancer cells

Cancer Research UK Edinburgh Centre scientists hijack cancer-cell secreted exosomes to enable cytotoxic drug activation in tumour cells: September 2019

Currently used anticancer therapeutics, in addition to targeting tumour cells, often have harmful effects on other parts of the body causing undesired side effects such as tiredness, hair loss and nausea. For a long time scientists have strived to develop technologies that could kill cancer cells without also causing damage to healthy cells and organs. Although success so far has been limited, we might be on the brink of a breakthrough and researchers from the Cancer Research UK Edinburgh Centre lead the way.

Over the past few years the Innovative Therapeutics Group led by Professor Asier Unciti-Broceta pioneered synthesis of biologically active drugs from harmless chemical compounds (prodrugs) in direct proximity of a tumour utilising catalytic reactions mediated by transition metals such as palladium and gold (so called bioorthogonal organometallic reactions). This strategy provides high degree of control over activity of cytotoxic drugs within the body therefore increasing their effectiveness and reducing undesired side-effects. Although there is still a long way before this technology can be tested in humans the group makes steady progress continuously providing exciting new developments.

In a recent study titled “Cancer-derived exosomes loaded with ultrathin palladium nanosheets for targeted bioorthogonal catalysis” published in the journal Nature Catalysis the group described development of a thrilling new technique that enables loading of cancer-cell-produced exosomes with palladium-based nanoscale catalytic reactors capable of cancer-cell-specific release of anticancer drug panobinostat. Exosomes are membrane-enclosed vesicles that are released by cells into the extracellular space to mediate intercellular exchange of biomolecules. They display long circulating half-life, small size, low immunogenicity and ability to preferentially target particular cell types and thus may represent ideal vectors to deliver a therapeutic cargo (e.g. drugs, biomolecules or nanoparticles) to specific cells such as cancer cells. Our researchers used lung cancer cells and glioblastoma cells to demonstrate for the first time that it is possible to use exosomes to protect and deliver a catalytic cargo into a specific type of cancer cell. 

This work represents an important step in preclinical development of bioorthogonal organometallic approaches and may provide new avenues for their potential transition into clinical trials. It was performed in collaboration with Professor Jesus Santamaria’s team from the University of Zaragoza in Spain and supported by funds from the Engineering and Physical Sciences Research Council (EPSRC) and the European Research Council (ERC).

Related Links:

• Article in “Nature Catalysis”
• Innovative Therapeutics Group web page
• General information about exosomes
• General information about nanoparticles

Other recent stories from Innovative Therapeutics Group:

• Synthesis of palladium activated analogue of anticancer drug irinotecan
• Palladium mediated catalysis works in preclinical mouse model
• Development of new inhibitors of oncogenic receptor tyrosine kinases
• Killing cancer cells using palladium nanoparticles
• Gold-Triggered Uncaging Chemistry in Living Systems Opens New Frontiers for Cancer Therapy