@article{1d13f6dec9044105a9ac1126d6a7433d,
title = "Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition",
abstract = "Purpose: The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of the inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies. Experimental Design: We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular-weight palladium porphyrin probe to measure perfused vessels, oxygen tension, and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to an anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan). Results: We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen-carrying ability than those of normal skin, most tumors had inefficient vessels. Further, intervessel heterogeneity in tumors is associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persists, even with reductions in mean extravascular hypoxia. Conclusions: High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.",
author = "Martin, {John D.} and Lanning, {Ryan M.} and Chauhan, {Vikash P.} and Martin, {Margaret R.} and Mousa, {Ahmed S.} and Kamoun, {Walid S.} and Han, {Hee Sun} and Hang Lee and Triantafyllos Stylianopoulos and Bawendi, {Moungi G.} and Duda, {Dan G.} and Brown, {Edward B.} and Padera, {Timothy P.} and Dai Fukumura and Jain, {Rakesh K.}",
note = "J.D. Martin reports personal fees from Nanocarrier Co., Ltd. outside the submitted work. R.M. Lanning reports grants from the Department of Defense Breast Cancer Research Program during the conduct of the study. V.P. Chauhan reports a patent for 13/834,094 pending and a patent for 16/063,353 pending. A.S. Mousa reports other support from Pieris Pharmaceuticals, Inc. outside the submitted work. W.S. Kamoun reports personal fees from Servier outside the submitted work. D.G. Duda reports personal fees from Innocoll and grants from BMS, Bayer, Exelixis, and Surface Oncology outside the submitted work. T.P. Padera reports grants from NIH during the conduct of the study, and personal fees from PureTech Health outside the submitted work. R.K. Jain reports grants from Jane{\textquoteright}s Trust Foundation, the Nile Albright Research Foundation, the National Foundation for Cancer Research, The Ludwig Center at Harvard Medical School, and the US NCI during the conduct of the study; personal fees from Elpis, Innocoll, and SPARC, personal fees and other support from SynDevRx, and other support from Accurius, Enlight, Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund outside the submitted work; and states that no regents or funding from any of these companies was used to support this research. No disclosures were reported by the other authors. The authors thank Julia Kahn, Sylvie Roberge, and Elisabeth Niemeyer for their technical assistance. R.K. Jain{\textquoteright}s research is supported by grants from the Jane{\textquoteright}s Trust Foundation, the Nile Albright Research Foundation, the National Foundation for Cancer Research, the Ludwig Center at Harvard Medical School, the US NCI grants R35CA197743, R01CA259253, R01269672, U01CA261842, and U01CA224348. R.K. Jain{\textquoteright}s and D. Fukumura{\textquoteright}s research is supported by NCI grant R01-CA208205. D. Fukumura{\textquoteright}s work is also supported by NIH grant R01NS118929. D.G. Duda{\textquoteright}s work is supported by NIH grants R01CA260872, R01CA260857, R01CA247441, and R03CA256764, and by Department of Defense grants W81XWH-19-1-0284 and W81XWH-21-1-0738. T.P. Padera{\textquoteright}s research is supported by US National Institute of Health grants R01CA214913, R01HL128168, R21AI135092, and R21AG072205 and by the Rullo Family MGH Research Scholar Award.",
year = "2022",
month = jul,
day = "15",
doi = "10.1158/1078-0432.CCR-22-0486",
language = "English (US)",
volume = "28",
pages = "3076--3090",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "14",
}