Using SERS to Study How Cells Respond to Pharmaceuticals

Surface-enhanced Raman spectroscopy (SERS) has made significant progress in recent years (1), and its application to biomedical studies is of particular interest. Colin Campbell of the University of Edinburgh is taking the biomedical application of SERS to a new level by using the technique to make spatially resolved measurements in live three-dimensional (3D) cell cultures to determine the response to drugs during drug discovery operations. For this work, Campbell received a FACSS Innovation Award at the SciX 2015 conference last October. This interview is part of the Spectroscopy­–SciX interview series.

An important aspect of your work using SERS in drug discovery is that you are measuring cell response within 3D cell structures. Can you explain how that is different from methods commonly used today? How representative are the metabolic processes in those 3D structures-which are grown in the lab-compared to metabolic processes that occur in living tissue, such as in the human body?

Three-dimensional cell culture is important because the microenvironment of the cells is more like real tissue than two-dimensional (2D) cell culture. The microenvironment plays an important role in defining the phenotype (for example, metabolism) of the cells and as a result 3D culture is becoming more widely used in research. While 3D culture is not exactly the same as in vivo, it could provide a useful model intermediate between 2D and in vivo. For us, it’s exciting to be studying a challenging biological system where our chemistry could make a difference.

Your method involves the use of SERS nanosensors, which are incorporated into the 3D structures. Can you briefly describe the nanosensors?

Our nanosensors are gold nanoparticles coated in reporter molecules that change their structure in response to changes in their environment (pH and redox potential). The gold nanoparticles allow us to measure surface-enhanced Raman spectra of the reporters and thus the spectra that we measure give useful information on the pH and redox potential of the cells. The pH and redox potential can give us information about the type of metabolic pathway that the cells are using and thus we can get metabolic information in real-time.

After the nanostructures are taken up by the cells, how do you know where a nanosensor is at any given moment?

We can make a Raman map of a cell and find the exact location of the nanosensor. This involves measuring multiple Raman spectra across the cell and making an image based on the Raman spectra.

What are you currently using this technique to investigate?

We’re looking at the response of cells in 3D culture to perturbations such as treatment with drugs. We are seeing some of the interesting metabolic properties that we expect from 3D cultures and hope to see differences between different types of treatment.

How do those results compare to what one sees using current techniques?

Currently there is no other way to make these particular measurements in 3D culture so it’s difficult to compare. I think it’s a great strength of our technique that it gives us information that isn’t accessible otherwise. It also makes for a lot of exciting challenges for my students and me.

What other metabolic processes would be amenable to measurement using this technique?

We’re using our nanosensors to investigate a range of interesting phenomena, such as how oxygen availability controls the metabolic pathway used. Ultimately, we’d really like to get a better understanding of how oxygen availability and its impact on metabolism are important in the pathology and treatment of diseases like cancer.

Do the nanosensors affect the viability of the cells, or otherwise affect the metabolic activities they are measuring?

That’s an important question and we have spent a lot of time ensuring that the nanosensors don’t have an impact on viability, cell death, or cell metabolism.

What are your next steps in this work?

In the near future we hope to work with a major pharmaceutical company to investigate the use of our technology in their drug discovery process.

Reference:

(1)          F. Adar, Spectroscopy30 (11), 14–19 (2015).  http://www.spectroscopyonline.com/sers-update-progress-made