TY - JOUR
T1 - Development of NIR-II Photoacoustic Probes Tailored for Deep-Tissue Sensing of Nitric Oxide
AU - Lucero, Melissa Y.
AU - East, Amanda K.
AU - Reinhardt, Christopher J.
AU - Sedgwick, Adam C.
AU - Su, Shengzhang
AU - Lee, Michael C.
AU - Chan, Jefferson
N1 - Funding Information:
M.Y.L. thanks the Alfred P. Sloan Foundation for financial support. A.K.E. acknowledges the Beckman Institute Graduate Fellowship for financial support. C.J.R. thanks the Chemistry–Biology Interface Training Grant (T32 GM070421) and the Seemon Pines Graduate Fellowship for support. M.C.L. thanks the National Science Foundation for a Graduate Fellowship (Grant No. 1746047). Major funding for the 500 MHz Bruker CryoProbe was provided by the Roy J. Carver Charitable Trust (Muscatine, Iowa; Grant No. 15-4521) to the School of Chemical Sciences NMR Lab. The Q-Tof Ultima mass spectrometer was purchased in part with a grant from the National Science Foundation, Division of Biological Infrastructure (DBI-0100085). We also acknowledge Dr. Iwona Dobrucka and the Molecular Imaging Laboratory at the Beckman Institute for use of the IVIS imaging system, Drs. Nicole Herndon and Jessica Xu for help generating the liver metastasis model, and Prof. Hee-Sun Han for access to the Cary 5000 UV–vis–NIR spectrophotometer.
Funding Information:
This work was supported the National Institutes of Health (R35GM133581).
Publisher Copyright:
© 2021 American Chemical Society. All rights reserved.
PY - 2021/5/12
Y1 - 2021/5/12
N2 - Photoacoustic (PA) imaging has emerged as a reliable in vivo technique for diverse biomedical applications ranging from disease screening to analyte sensing. Most contemporary PA imaging agents employ NIR-I light (650-900 nm) to generate an ultrasound signal; however, there is significant interference from endogenous biomolecules such as hemoglobin that are PA active in this window. Transitioning to longer excitation wavelengths (i.e., NIR-II) reduces the background and facilitates the detection of low abundance targets (e.g., nitric oxide, NO). In this study, we employed a two-phase tuning approach to develop APNO-1080, a NIR-II NO-responsive probe for deep-tissue PA imaging. First, we performed Hammett and Brønsted analyses to identify a highly reactive and selective aniline-based trigger that reacts with NO via N-nitrosation chemistry. Next, we screened a panel of NIR-II platforms to identify chemical structures that have a low propensity to aggregate since this can diminish the PA signal. In a head-to-head comparison with a NIR-I analogue, APNO-1080 was 17.7-fold more sensitive in an in vitro tissue phantom assay. To evaluate the deep-tissue imaging capabilities of APNO-1080 in vivo, we performed PA imaging in an orthotopic breast cancer model and a heterotopic lung cancer model. Relative to control mice not bearing tumors, the normalized turn-on response was 1.3 ± 0.12 and 1.65 ± 0.07, respectively.
AB - Photoacoustic (PA) imaging has emerged as a reliable in vivo technique for diverse biomedical applications ranging from disease screening to analyte sensing. Most contemporary PA imaging agents employ NIR-I light (650-900 nm) to generate an ultrasound signal; however, there is significant interference from endogenous biomolecules such as hemoglobin that are PA active in this window. Transitioning to longer excitation wavelengths (i.e., NIR-II) reduces the background and facilitates the detection of low abundance targets (e.g., nitric oxide, NO). In this study, we employed a two-phase tuning approach to develop APNO-1080, a NIR-II NO-responsive probe for deep-tissue PA imaging. First, we performed Hammett and Brønsted analyses to identify a highly reactive and selective aniline-based trigger that reacts with NO via N-nitrosation chemistry. Next, we screened a panel of NIR-II platforms to identify chemical structures that have a low propensity to aggregate since this can diminish the PA signal. In a head-to-head comparison with a NIR-I analogue, APNO-1080 was 17.7-fold more sensitive in an in vitro tissue phantom assay. To evaluate the deep-tissue imaging capabilities of APNO-1080 in vivo, we performed PA imaging in an orthotopic breast cancer model and a heterotopic lung cancer model. Relative to control mice not bearing tumors, the normalized turn-on response was 1.3 ± 0.12 and 1.65 ± 0.07, respectively.
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U2 - 10.1021/jacs.1c03004
DO - 10.1021/jacs.1c03004
M3 - Article
C2 - 33905646
AN - SCOPUS:85106466158
SN - 0002-7863
VL - 143
SP - 7196
EP - 7202
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 18
ER -