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Principal Investigator: Ji-Xin Cheng
Organization: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
Fiscal Year: 2021
Award: $398,440
Funding agency: National Cancer Institute
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 cancers.
Terms: <Address><Amino Acids><Amplifiers><Area><Biopsy><Blood Serum><Body Tissues><Brain Cancer><Breast Cancer><CDDP><Caliber><Cancers><Carbohydrates><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Metabolic Process><Chemicals><Cholesterol><Cholesterol Esters><Cholesteryl Esters><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Cysplatyna><D-Glucose><Detection><Development><Dextrose><Diameter><Dichlorodiammineplatinum><Digital Signal Processing><Drug resistance><Electronics><FTIR><FTIR spectroscopy><Fatty Acids><Fingerprint><Frequencies><Glucose><Goals><IR/UV/Raman Spectroscopy><Illumination><Image><Imaging Device><Imaging Instrument><Imaging Tool><Intermediary Metabolism><Intracellular Communication and Signaling><Intracellular Structure><Kidney Cancer><Kidney Carcinoma><Lateral><Lead><Lighting><Lipids><Lipoproteins><Location><Malignant Cell><Malignant Neoplasms><Malignant Oral Cavity Neoplasm><Malignant Oral Cavity Tumor><Malignant Oral Neoplasm><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Brain><Malignant Tumor of the Ovary><Malignant Tumor of the Prostate><Malignant neoplasm of brain><Malignant neoplasm of ovary><Malignant neoplasm of prostate><Malignant prostatic tumor><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Measures><Mediating><Metabolic><Metabolic Processes><Metabolism><Microscope><Microscopy><Molecular><Mouth Cancer><NMR Spectrometer><NMR Spectroscopy><Noise><Nucleic Acids><Oral Cancer><Organism><Ovary Cancer><Pathogenesis><Pattern><Pb element><Performance><Peyrone's Chloride><Peyrone's Salt><Photons><Physiologic pulse><Platinum Diamminodichloride><Play><Prostate CA><Prostate Cancer><Prostatic Cancer><Proteins><Pulse><Pump><Raman Spectroscopy><Raman Spectrum Analysis><Raman spectrometry><Refractive Indices><Renal Cancer><Renal carcinoma><Research><Resistance><Resolution><Role><Sampling><Scanning><Scheme><Semiconductors><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Spectroscopy, Fourier Transform Infrared><Speed><Subcellular structure><System><Technology><Testing><Time><Tissue Extracts><Tissues><Tumor Cell><Universities><absorption><adipogenesis><aminoacid><base><biological signal transduction><cancer cell><cancer cell metabolism><cancer metabolism><cell metabolism><cellular metabaolism><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><developmental><drug development><drug resistant><electronic device><glucose uptake><heavy metal Pb><heavy metal lead><high resolution imaging><imaging><imaging platform><imaging system><improved><indexing><infrared spectroscopy><innovate><innovation><innovative><leukemia><lipid biosynthesis><lipogenesis><living system><malignancy><malignant breast neoplasm><malignant breast tumor><malignant mouth neoplasm><malignant mouth tumor><metabolic imaging><metal oxide><microscope imaging><microscopic imaging><microscopy imaging><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><neoplastic cell><nuclear magnetic resonance spectroscopy><oral cavity cancer><ovarian cancer><oxidation><programs><refractory cancer><resistance to Drug><resistant><resistant cancer><resistant to Drug><social role><sub micron><submicron><success><tool><tumor cell metabolism><tumor metabolism><uptake><vibration>