Drug detection with high-sensitivity using ToF SIMS

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The high attrition rate of pharmaceutical drug compounds adds enormously to the cost of those that make it to market, so there is an urgent and growing need to identify failure at earlier stages of drug development.

In order to do so, researchers require as much information as possible. Specifically, there is a need to measure the concentration of a drug at the target in order to accurately predict its pharmacological effect. This then requires a means of generating label-free sub-cellular imaging, as fluorescent labels may affect drug chemistry, altering results.

Time of flight secondary ion mass spectrometry (ToF SIMS) is a powerful tool for label-free chemical imaging, having typically very high lateral resolution capable of resolving sub-cellular features with 3D analysis capabilities.

ToF SIMS is thus a potentially powerful analysis tool for the screening of new drug compounds. However, the use of high energy projectiles for ToF SIMS analysis can cause molecules to fragment, preventing the molecular ion from being detected. This can lead to a lot of ambiguity, for example distinguishing between a drug compound and its metabolites.

Another possible stumbling block is the issue of sensitivity, particularly for those compounds of most interest. In a recent study by the National Physical Laboratory (NPL), Vorng et al. demonstrate that the sensitivity in ToF SIMS is proportional to the Log P of that compound, such that compounds with low or negative Log P values are extremely difficult to detect.  

Log P, or partition coefficient, is a measure of hydrophobicity, and is a major factor used in pre-clinical assessment of a compound’s druglikeness.  It is advisable that a drug candidate be as hydrophilic as possible while still retaining adequate binding affinity to the therapeutic protein target, i.e. that the Log P be as low (or negative) as practicable. This presents an obvious problem for the use of ToF SIMS as an analytical tool in this context.

Cluster beam colliding with a surface.

We have recently led the development of a new type of ion source for ToF SIMS that provides unparalleled sensitivity particularly for organic species. Available exclusively on the J105 SIMS, the Water Cluster Source simultaneously reduces fragmentation while increasing ionization, for truly unparalleled sensitivity of drugs, metabolites, biomarkers, lipids, peptides and more.

Combining this new ion source with the already impressive sensitivity of the J105 SIMS, even low Log P compounds can be detected in tissue and cells, with direct, label-free imaging of the molecular compounds at sub-cellular resolutions.

To demonstrate this, we doped tissue homogenate with 4 different pharmaceutical compounds that span the range of Log P from -0.8 to 7.6. The relationship between sensitivity and Log P reported by NPL is observed in this data, however the slope of the line is greatly reduced, with only a factor of 40 between the highest and lowest values.

ToF SIMS sensitivity to drugs as a function of Log P
ToF SIMS sensitivity of four different drugs using the Water Source. Sensitivity shows a linear relationship to the partition coefficient, Log P, though the slope is not steep.

As a comparison, we performed the same experiments with a state-of-the-art Ar gas cluster ion beam and plotted the yield against that of the new Water Source. The Water Source increased sensitivity by an order of magnitude in most cases, with the largest increase being for those compounds with the lowest Log P values. This indicates that the improvement in sensitivity is greatest for those compounds that need it the most.

Comparing sensitivity of argon and water cluster beams for four different drugs
Comparing sensitivity of a state-of-the-art Ar cluster source with the Water Source. Sensitivity improves by roughly an order of magnitude when using water, with the largest increase for those compounds with lower Log P values.

As a final demonstration of the capabilities of the J105 with the Water Source, we performed tandem MS analysis on the homogenate samples. Tandem MS is an important step for confirming any assignment in mass spectrometry, however the inefficiency of the process often means it can only be performed on high intensity peaks. With the boost in sensitivity provided by the Water Source, tandem MS analysis is possible even on compounds with relatively low Log P values, such as ciprofloxacin.

Tandem MS analysis of the drug ciprofloxacin
Tandem MS performed on the J105 SIMS with a Water Source. Greater sensitivity allows definitive confirmation of many more peaks.

ToF SIMS is a potentially powerful analysis tool for the screening of new drug compounds, however research is hampered by the inherently low sensitivity to many drug candidates. The J105 SIMS in combination with the Water Cluster Source provides unparalleled sensitivity to drug compounds, particularly in complex matrices such as tissue and cells, even for low Log P compounds. This unprecedented sensitivity combined with sub-cellular imaging and high-resolution 3D imaging mean the J105 SIMS is a powerful tool for drug analysis.

To learn more about how the J105 SIMS can benefit your research or to set up a demonstration, get in touch via our Contact Page.

Employee Spotlight: Dr Naoko Sano

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As a small company, Ionoptika is very proud of its skilled and dedicated staff, who together with our loyal users make up our global community. So each month we will be putting the spotlight on one of our talented colleagues to introduce you to some of the people behind Ionoptika.

The first to be in the spotlight is one of most recent hires, Dr Naoko Sano, our new Applications Scientist. We asked Naoko about her career and what she enjoys about working at Ionoptika.

Employee spotlight - quote

Where were you before you started at Ionoptika?

I joined Ionoptika from Nara Women’s University in Japan where I was Associate Professor in textile science.

What does a typical day look like for you?

Most days I spend my time working on new applications and processing SIMS data. At lunch time I sometimes like to go for a walk with friends from the office, which really helps me refresh. The rest of the time I can be found running samples on the J105 ToF SIMS instrument for existing and potential customers. I’m also involved in testing new software and providing feedback back to the software team.

What do you love most about your job?

One of the most exciting parts of my job is the great variety of applications that I’m involved in, from investigating neurotransmitters in brain tissue, to analysing the frictional properties of lubricants. This makes the job of Application Scientist immensely challenging but hugely rewarding!

Why did you decide to study science when you were at school or university?

A working experience with the Surface Analysis group at NPL in 2006-7 gave a great impact to me in a good way and I really enjoyed UK/London life whilst I was there. Fortunately, around the end of the working experience, Prof. John F. Watts offered a PhD studentship, so I decided to study surface science in University of Surrey, which was my big turning point in my life.

What’s it like working at Ionoptika?

All colleagues here in Ionoptika are friendly, so I enjoy chatting with them at the office. So I miss it very much because of the current WFH situation…

What has been your best memory or achievement in your career?

It would be my first poster award in SIMS-XVII. On the day for the award ceremony, I was late to get to the venue, because I didn’t care for the ceremony at all (a naughty student!). When I got into the venue and tried to find a space to sit, the chairman (coincidentally it was John, my supervisor) on the stage, said ‘Naoko, you are there!’. Everybody turned back and looked at me. I was so proud of my work on the stage, but I felt so embarrassed as well…

What do you enjoy doing in your spare time?

Aromatherapy and reading books.

Have you been doing anything interesting/different/new to cope with the lockdown?

I’ve started online yoga lessons. I still prefer to do it in an actual studio with people, but online yoga class works at least. 

What are you looking forward to most once the lockdown is over?

Travel to see my family and friends all over the world. Miss you all very much!

You can catch up with Naoko and the rest of the Ionoptika team at various conferences throughout the year. Interested in becoming part of our team? Visit our Careers page.