# Mapping Cancer Metabolism by Mid-infrared Photothermal Microscopy

> **NIH NIH R33** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2021 · $398,440

## Abstract

Program Summary
 While altered cell metabolism is emerging as a hallmark of cancer, there is an unmet need for new tools for
quantitation of metabolites. NMR spectroscopy, mass spectrometry, FTIR, and Raman spectroscopy are widely
used for molecular detection in tissue extracts or intact tissues. Yet, these tools do not indicate the spatial
locations of the analytes inside the cell. We address this unmet need via development of a lock-in free, wide-
field mid-infrared photothermal (MIP) microscope. Our technology will enable quantitative vibrational imaging of
metabolites in live tumor cells and intact biopsies. In MIP microscopy recently developed in the PI lab (Sci Adv
2016), a visible beam probes the thermal effect (e.g. change of refractive index and thermal expansion) induced
by a pulsed infrared beam. The MIP signal is then extracted through a lock-in amplifier. To match the IR/visible
illumination area, the PI lab further developed a wide-field MIP microscope in which a complementary metal–
oxide–semiconductor (CMOS) camera and synchronization electronics are harnessed for whole-field lock-in
detection (Sci Adv 2019). Despite these initial successes, the sensitivity of MIP microscopy is limited by the
detection schemes. First, the golden standard lock-in detection misses all the harmonic frequencies in the MIP
signal. Second, the well-depth of a typical CMOS camera seriously limits the probe power to 0.01 mW at sample.
Thus, many averages are needed to reach a reasonable signal to noise ratio. We overcome these difficulties
through two innovations. The first one is to digitize the probe photons received by a fast photodiode. Then, in
the frequency domain, a match filter is used to extract all MIP signals at fundamental and harmonic frequencies.
The second one is to perform patterned probe illumination and collect photons with a photodiode which has a
saturation threshold of tens of mW. Then, a MIP image is recovered by matrix inversion. In this “single-pixel
camera” approach, the probe power can be increased by 1000 times, which indicates that the speed can be
improved 30 times to reach the same signal to noise ratio of wide field MIP at the shot noise limit. The goal of
this R33 proposal is to develop a digital signal processing, single pixel camera MIP microscope and validate its
potential for high-content cancer metabolic imaging. In particular, we aim to validate a metabolic switch from
glucose-mediated lipogenesis to fatty acids uptake/oxidation in ovarian cancers that become resistant to cisplatin.
By accomplishing the proposed studies, we will generate a high-speed hyperspectral mid-infrared photothermal
chemical imaging platform that is able to map the live cell metabolism at sub-micron spatial resolution. Metabolic
imaging of live drug-resistant cancer cells by this platform opens new opportunities of unveiling hidden signatures
that can potentially lead to adaptive therapies that inhibit the development of drug resistance in canc...

## Key facts

- **NIH application ID:** 10271761
- **Project number:** 1R33CA261726-01
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** Ji-Xin Cheng
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,440
- **Award type:** 1
- **Project period:** 2021-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271761

## Citation

> US National Institutes of Health, RePORTER application 10271761, Mapping Cancer Metabolism by Mid-infrared Photothermal Microscopy (1R33CA261726-01). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10271761. Licensed CC0.

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