Imaging the Tumor Microenvironment

  • Marie-Caline Z. Abadjian
  • W. Barry Edwards
  • Carolyn J. Anderson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1036)


The tumor microenvironment consists of tumor, stromal, and immune cells, as well as extracellular milieu. Changes in numbers of these cell types and their environments have an impact on cancer growth and metastasis. Non-invasive imaging of aspects of the tumor microenvironment can provide important information on the aggressiveness of the cancer, whether or not it is metastatic, and can also help to determine early response to treatment. This chapter provides an overview on non-invasive in vivo imaging in humans and mouse models of various cell types and physiological parameters that are unique to the tumor microenvironment. Current clinical imaging and research investigation are in the areas of nuclear imaging (positron emission tomography (PET) and single photon emission computed tomography (SPECT)), magnetic resonance imaging (MRI) and optical (near infrared (NIR) fluorescence) imaging. Aspects of the tumor microenvironment that have been imaged by PET, MRI and/or optical imaging are tumor associated inflammation (primarily macrophages and T cells), hypoxia, pH changes, as well as enzymes and integrins that are highly prevalent in tumors, stroma and immune cells. Many imaging agents and strategies are currently available for cancer patients; however, the investigation of novel avenues for targeting aspects of the tumor microenvironment in pre-clinical models of cancer provides the cancer researcher with a means to monitor changes and evaluate novel treatments that can be translated into the clinic.


Microenvironment PET SPECT Optical Fluorescence MR Imaging 



The authors would like to acknowledge funding from the National Cancer Institute (R01 CA214018 (CJA) and R21 EB023364 (WBE)), University of Pittsburgh Physicians (UPP) Academic Foundation Award (WBE) and Department of Energy and National Institute of Biomedical Imaging and Bioengineering (DE-SC0008833; for MCZA).


  1. 1.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.PubMedCrossRefGoogle Scholar
  2. 2.
    Huang T, Civelek AC, Li J, Jiang H, Ng CK, Postel GC, Shen B, Li XF. Tumor microenvironment-dependent 18F-FDG, 18F-fluorothymidine, and 18F-misonidazole uptake: a pilot study in mouse models of human non-small cell lung cancer. J Nucl Med. 2012;53(8):1262.PubMedCrossRefGoogle Scholar
  3. 3.
    Yanar M, Abel F, Haalck T, Klutmann S, Schumacher U. The microenvironment in the human lung partly determines the site of the first metastasis. Anticancer Res. 2014;34:3845–9.PubMedGoogle Scholar
  4. 4.
    Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13:759–71.PubMedCrossRefGoogle Scholar
  5. 5.
    Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315:1650–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene. 2010;29:1093–102.PubMedCrossRefGoogle Scholar
  7. 7.
    Rashidian M, Keliher EJ, Bilate AM, Duarte JN, Wojtkiewicz GR, Jacobsen JT, Cragnolini J, Swee LK, Victora GD, Weissleder R, Ploegh HL. Noninvasive imaging of immune responses. Proc Natl Acad Sci U S A. 2015;112:6146–51.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res. 2007;13:1472–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Denardo DG, Andreu P, Coussens LM. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 2010;29:309–16.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007;117:1155–66.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Wang Y-C, He F, Feng F, Liu X-W, Dong G-Y, Qin H-Y, Hu X-B, Zheng M-H, Liang L, Feng L, Liang Y-M, Han H. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 2010;70:4840–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A. Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol. 2013;228:1404–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, Liu B, Deng H, Wang F, Lin L. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19:541–55.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Pérez-Medina C, Tang J, Abdel-Atti D, Hogstad B, Merad M, Fisher EA, Fayad ZA, Lewis JS, Mulder WJM, Reiner T. PET imaging of tumor-associated macrophages with 89Zr-Labeled high-density lipoprotein nanoparticles. J Nucl Med. 2015;56:1272–7.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Locke LW, Mayo MW, Yoo AD, Williams MB, Berr SS. PET imaging of tumor associated macrophages using mannose coated 64Cu liposomes. Biomaterials. 2012;33:7785–93.PubMedCrossRefGoogle Scholar
  19. 19.
    Movahedi K, Schoonooghe S, Laoui D, Houbracken I, Waelput W, Breckpot K, Bouwens L, Lahoutte T, de Baetselier P, Raes G. Nanobody-based targeting of the macrophage mannose receptor for effective in vivo imaging of tumor-associated macrophages. Cancer Res. 2012;72:4165–77.PubMedCrossRefGoogle Scholar
  20. 20.
    Tavare R, McCracken MN, Zettlitz KA, Knowles SM, Salazar FB, Olafsen T, Witte ON, Wu AM. Engineered antibody fragments for immuno-PET imaging of endogenous CD8+ T cells in vivo. Proc Natl Acad Sci U S A. 2014;111:1108–13.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47.PubMedCrossRefGoogle Scholar
  22. 22.
    Murdoch C, Muthana M, Lewis CE. Hypoxia regulates macrophage functions in inflammation. J Immunol. 2005;175:6257–63.PubMedCrossRefGoogle Scholar
  23. 23.
    Semenza GL. Angiogenesis ischemic and neoplastic disorders. Annu Rev Med. 2003;54:17–28.PubMedCrossRefGoogle Scholar
  24. 24.
    Lee C-T, Boss M-K, Dewhirst MW. Imaging tumor hypoxia to advance radiation oncology. Antioxid Redox Signal. 2014;21:313–37.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Vaupel P, Mayer A. Hypoxia in tumors: pathogenesis-related classification, characterization of hypoxia subtypes, and associated biological and clinical implications. Adv Exp Med Biol. 2014;812:19–24.PubMedCrossRefGoogle Scholar
  26. 26.
    Hsieh CH, Chang HT, Shen WC, Shyu WC, Liu RS. Imaging the impact of Nox4 in cycling hypoxia-mediated U87 glioblastoma invasion and infiltration. Mol Imaging Biol. 2012;14:489–99.PubMedCrossRefGoogle Scholar
  27. 27.
    Avni R, Cohen B, Neeman M. Hypoxic stress and cancer: imaging the axis of evil in tumor metastasis. NMR Biomed. 2011;24:569–81.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Horsman MR, Mortensen LS, Petersen JB, Busk M, Overgaard J. Imaging hypoxia to improve radiotherapy outcome. Nat Rev Clin Oncol. 2012;9:674–87.PubMedCrossRefGoogle Scholar
  29. 29.
    Mendichovszky I, Jackson A. Imaging hypoxia in gliomas. Br J Radiol. 2014;84(2):S145–58.Google Scholar
  30. 30.
    Sun X, Niu G, Chan N, Shen B, Chen X. Tumor hypoxia imaging. Mol Imaging Biol. 2011;13:399–410.PubMedCrossRefGoogle Scholar
  31. 31.
    Wang L, Li C. Fluorescence nanoprobe imaging tumor by sensing the acidic microenvironment. Boca Raton: Science Publishers; 2012.Google Scholar
  32. 32.
    Carlin S, Humm JL. PET of hypoxia: current and future perspectives. J Nucl Med. 2012;53:1171–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Carlin S, Zhang H, Reese M, Ramos NN, Chen Q, Ricketts S-A. A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracers. J Nucl Med. 2014;55:515–21.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Hoigebazar L, Jeong JM. Hypoxia imaging agents labeled with positron emitters. Recent Results Cancer Res. 2013;194:285–99.PubMedGoogle Scholar
  35. 35.
    Kelada OJ, Carlson DJ. Molecular imaging of tumor hypoxia with positron emission tomography. Radiat Res. 2014;181:335–49.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Kersemans V, Cornelissen B, Hueting R, Tredwell M, Hussien K, Allen PD, Falzone N, Hill SA, Dilworth JR, Gouverneur V. Hypoxia imaging using PET and SPECT: the effects of anesthetic and carrier gas on [64 Cu]-ATSM,[99m Tc]-HL91 and [18 F]-FMISO tumor hypoxia accumulation. PLoS One. 2011;6:e25911.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Kurihara H, Honda N, Kono Y, Arai Y. Radiolabelled agents for PET imaging of tumor hypoxia. Curr Med Chem. 2012;19:3282–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Yip C, Blower PJ, Goh V, Landau DB, Cook GJ. Molecular imaging of hypoxia in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging. 2015;42:956–76.PubMedCrossRefGoogle Scholar
  39. 39.
    Bell C, Dowson N, Fay M, Thomas P, Puttick S, Gal Y, Rose S. Hypoxia imaging in gliomas with 18F-fluoromisonidazole PET: toward clinical translation. Semin Nucl Med. 2015;45:136–50.PubMedCrossRefGoogle Scholar
  40. 40.
    Rajendran JG, Krohn KA. F-18 fluoromisonidazole for imaging tumor hypoxia: imaging the microenvironment for personalized cancer therapy. Semin Nucl Med. 2015;45:151–62.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Kobayashi K, Hirata K, Yamaguchi S, Kobayashi H, Terasaka S, Manabe O, Shiga T, Magota K, Kuge Y, Tamaki N. FMISO PET at 4 hours showed a better lesion-to-background ratio uptake than 2 hours in brain tumors. J Nucl Med. 2015;56:373.Google Scholar
  42. 42.
    Kawai N, Lin W, Cao W-D, Ogawa D, Miyake K, Haba R, Maeda Y, Yamamoto Y, Nishiyama Y, Tamiya T. Correlation between 18F-fluoromisonidazole PET and expression of HIF-1α and VEGF in newly diagnosed and recurrent malignant gliomas. Eur J Nucl Med Mol Imaging. 2014;41:1870–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Huang T, Civelek AC, Zheng H, Ng CK, Duan X, Li J, Postel GC, Shen B, Li X-F. 18F-misonidazole PET imaging of hypoxia in micrometastases and macroscopic xenografts of human non-small cell lung cancer: a correlation with autoradiography and histological findings. Am J Nucl Med Mol Imaging. 2013;3:142.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Trinkaus ME, Blum R, Rischin D, Callahan J, Bressel M, Segard T, Roselt P, Eu P, Binns D, Macmanus MP. Imaging of hypoxia with 18F-FAZA PET in patients with locally advanced non-small cell lung cancer treated with definitive chemoradiotherapy. J Med Imaging Radiat Oncol. 2013;57:475–81.PubMedCrossRefGoogle Scholar
  45. 45.
    Zegers CM, van Elmpt W, Wierts R, Reymen B, Sharifi H, Öllers MC, Hoebers F, Troost EG, Wanders R, van Baardwijk A. Hypoxia imaging with [18 F] HX4 PET in NSCLC patients: defining optimal imaging parameters. Radiother Oncol. 2013;109:58–64.PubMedCrossRefGoogle Scholar
  46. 46.
    Busk M, Mortensen LS, Nordsmark M, Overgaard J, Jakobsen S, Hansen K, Theil J, Kallehauge J, D’Andrea F, Steiniche T. PET hypoxia imaging with FAZA: reproducibility at baseline and during fractionated radiotherapy in tumour-bearing mice. Eur J Nucl Med Mol Imaging. 2013;40:186–97.PubMedCrossRefGoogle Scholar
  47. 47.
    Peeters SG, Zegers CM, Lieuwes NG, van Elmpt W, Eriksson J, van Dongen GA, Dubois L, Lambin P. A comparative study of the hypoxia PET tracers [18 F] HX4,[18 F] FAZA, and [18 F] FMISO in a preclinical tumor model. Int J Radiat Oncol Biol Phys. 2015;91:351–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Segard T, Robins PD, Yusoff IF, Ee H, Morandeau L, Campbell EM, Francis RJ. Detection of hypoxia with 18F-fluoromisonidazole (18F-FMISO) PET/CT in suspected or proven pancreatic cancer. Clin Nucl Med. 2013;38:1–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Chen L, Zhang Z, Kolb HC, Walsh JC, Zhang J, Guan Y. 18F-HX4 hypoxia imaging with PET/CT in head and neck cancer: a comparison with 18F-FMISO. Nucl Med Commun. 2012;33:1096–102.PubMedCrossRefGoogle Scholar
  50. 50.
    Hu M, Xing L, Mu D, Yang W, Yang G, Kong L, Yu J. Hypoxia imaging with 18F-Fluoroerythronitroimidazole integrated PET/CT and immunohistochemical studies in non–small cell lung cancer. Clin Nucl Med. 2013;38:591–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Yue J, Yang Y, Cabrera A, Sun X, Zhao S, Xie P, Zheng J, Ma L, Fu Z, Yu J. Measuring tumor hypoxia with 18F-FETNIM PET in esophageal squamous cell carcinoma: a pilot clinical study. Dis Esophagus. 2012;25:54–61.PubMedCrossRefGoogle Scholar
  52. 52.
    Laurens E, Yeoh SD, Rigopoulos A, Cao D, Cartwright GA, O’Keefe GJ, Tochon-Danguy HJ, White JM, Scott AM, Ackermann U. Radiolabelling and evaluation of novel haloethylsulfoxides as PET imaging agents for tumor hypoxia. Nucl Med Biol. 2012;39:871–82.PubMedCrossRefGoogle Scholar
  53. 53.
    Servagi-Vernat S, Differding S, Hanin F-X, Labar D, Bol A, Lee JA, Grégoire V. A prospective clinical study of 18 F-FAZA PET-CT hypoxia imaging in head and neck squamous cell carcinoma before and during radiation therapy. Eur J Nucl Med Mol Imaging. 2014;41:1544–52.PubMedCrossRefGoogle Scholar
  54. 54.
    Murakami M, Zhao S, Zhao Y, Chowdhury NF, Yu W, Nishijima K-I, Takiguchi M, Tamaki N, Kuge Y. Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma. Int J Oncol. 2012;41:1593–600.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Tachibana I, Nishimura Y, Shibata T, Kanamori S, Nakamatsu K, Koike R, Nishikawa T, Ishikawa K, Tamura M, Hosono M. A prospective clinical trial of tumor hypoxia imaging with 18F-fluoromisonidazole positron emission tomography and computed tomography (F-MISO PET/CT) before and during radiation therapy. J Radiat Res. 2013;54:1078–84.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Zips D, Zöphel K, Abolmaali N, Perrin R, Abramyuk A, Haase R, Appold S, Steinbach J, Kotzerke J, Baumann M. Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer. Radiother Oncol. 2012;105:21–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Sakr T, Essa B, El-Essawy F, El-Mohty A. Synthesis and biodistribution of 99m Tc-PyDA as a potential marker for tumor hypoxia imaging. Radiochemistry. 2014;56:76–80.CrossRefGoogle Scholar
  58. 58.
    Giglio J, Fernández S, Pietzsch H-J, Dematteis S, Moreno M, Pacheco JP, Cerecetto H, Rey A. Synthesis, in vitro and in vivo characterization of novel 99m Tc-‘4+ 1’-labeled 5-nitroimidazole derivatives as potential agents for imaging hypoxia. Nucl Med Biol. 2012;39:679–86.PubMedCrossRefGoogle Scholar
  59. 59.
    Sakr T, Motaleb M, Ibrahim I. 99mTc–meropenem as a potential SPECT imaging probe for tumor hypoxia. J Radioanal Nucl Chem. 2012;292:705–10.CrossRefGoogle Scholar
  60. 60.
    Kimura S, Umeda IO, Moriyama N, Fujii H. Synthesis and evaluation of a novel 99m Tc-labeled bioreductive probe for tumor hypoxia imaging. Bioorg Med Chem Lett. 2011;21:7359–62.PubMedCrossRefGoogle Scholar
  61. 61.
    Tateishi K, Tateishi U, Sato M, Yamanaka S, Kanno H, Murata H, Inoue T, Kawahara N. Application of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET imaging to predict highly malignant tumor grades and hypoxia-inducible factor-1α expression in patients with glioma. Am J Neuroradiol. 2013;34:92–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Hansen AE, Kristensen AT, Jørgensen JT, McEvoy FJ, Busk M, Van der Kogel AJ, Bussink J, Engelholm SA, Kjær A. 64Cu-ATSM and 18FDG PET uptake and 64Cu-ATSM autoradiography in spontaneous canine tumors: comparison with pimonidazole hypoxia immunohistochemistry. Radiat Oncol. 2012;7:89.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Hansen AE, Kristensen AT, Law I, McEvoy FJ, Kjær A, Engelholm SA. Multimodality functional imaging of spontaneous canine tumors using 64 Cu-ATSM and 18 FDG PET/CT and dynamic contrast enhanced perfusion CT. Radiother Oncol. 2012;102:424–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Bourgeois M, Rajerison H, Guerard F, Mougin-Degraef M, Barbet J, Michel N, Cherel M, Faivre-Chauvet A. Contribution of [64Cu]-ATSM PET in molecular imaging of tumour hypoxia compared to classical [18F]-MISO—a selected review. Nucl Med Rev Cent East Eur. 2011;14:90–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Bonnitcha PD, Bayly SR, Theobald MB, Betts HM, Lewis JS, Dilworth JR. Nitroimidazole conjugates of bis (thiosemicarbazonato) 64 Cu (II)–potential combination agents for the PET imaging of hypoxia. J Inorg Biochem. 2010;104:126–35.PubMedCrossRefGoogle Scholar
  66. 66.
    Grigsby PW, Malyapa RS, Higashikubo R, Schwarz JK, Welch MJ, Huettner PC, Dehdashti F. Comparison of molecular markers of hypoxia and imaging with (60)Cu-ATSM in cancer of the uterine cervix. Mol Imaging Biol. 2007;9:278–83.PubMedCrossRefGoogle Scholar
  67. 67.
    Wu Y, Hao G, Ramezani S, Saha D, Zhao D, Sun X, Sherry AD. [68 Ga]-HP-DO3A-nitroimidazole: a promising agent for PET detection of tumor hypoxia. Contrast Media Mol Imaging. 2015;10(6):465–72.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Sano K, Okada M, Hisada H, Shimokawa K, Saji H, Maeda M, Mukai T. In vivo evaluation of a radiogallium-labeled bifunctional radiopharmaceutical, Ga-DOTA-MN2, for hypoxic tumor imaging. Biol Pharm Bull. 2013;36:602–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Hoigebazar L, Jeong JM, Hong MK, Kim YJ, Lee JY, Shetty D, Lee Y-S, Lee DS, Chung J-K, Lee MC. Synthesis of 68 Ga-labeled DOTA-nitroimidazole derivatives and their feasibilities as hypoxia imaging PET tracers. Bioorg Med Chem. 2011;19:2176–81.PubMedCrossRefGoogle Scholar
  70. 70.
    Gulaka PK, Rojas-Quijano F, Kovacs Z, Mason RP, Sherry AD, Kodibagkar VD. GdDO3NI, a nitroimidazole-based T 1 MRI contrast agent for imaging tumor hypoxia in vivo. J Biol Inorg Chem. 2014;19:271–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Pacheco-Torres J, López-Larrubia P, Ballesteros P, Cerdán S. Imaging tumor hypoxia by magnetic resonance methods. NMR Biomed. 2011;24:1–16.PubMedCrossRefGoogle Scholar
  72. 72.
    Egeland TA, Gulliksrud K, Gaustad JV, Mathiesen B, Rofstad EK. Dynamic contrast-enhanced-MRI of tumor hypoxia. Magn Reson Med. 2012;67:519–30.PubMedCrossRefGoogle Scholar
  73. 73.
    Gulliksrud K, Øvrebø KM, Mathiesen B, Rofstad EK. Differentiation between hypoxic and non-hypoxic experimental tumors by dynamic contrast-enhanced magnetic resonance imaging. Radiother Oncol. 2011;98:360–4.PubMedCrossRefGoogle Scholar
  74. 74.
    Stoyanova R, Huang K, Sandler K, Cho H, Carlin S, Zanzonico PB, Koutcher JA, Ackerstaff E. Mapping tumor hypoxia in vivo using pattern recognition of dynamic contrast-enhanced MRI data. Transl Oncol. 2012;5:437–IN2.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Wu Y, Zhang W, Li J, Zhang Y. Optical imaging of tumor microenvironment. Am. J. Nucl Med Mol Imaging. 2013;3:1–15.Google Scholar
  76. 76.
    Zheng X, Wang X, Mao H, Wu W, Liu B, Jiang X. Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo. Nat Commun. 2015;6:5834.PubMedCrossRefGoogle Scholar
  77. 77.
    Napp J, Behnke T, Fischer L, WÜRth C, Wottawa M, Katschinski DRM, Alves F, Resch-Genger U, Schäferling M. Targeted luminescent near-infrared polymer-nanoprobes for in vivo imaging of tumor hypoxia. Anal Chem. 2011;83:9039–46.PubMedCrossRefGoogle Scholar
  78. 78.
    Palmer GM, Fontanella AN, Zhang G, Hanna G, Fraser CL, Dewhirst MW. Optical imaging of tumor hypoxia dynamics. J Biomed Opt. 2010;15:7–066021.CrossRefGoogle Scholar
  79. 79.
    Okuda K, Okabe Y, Kadonosono T, Ueno T, Youssif BG, Kizaka-Kondoh S, Nagasawa H. 2-Nitroimidazole-tricarbocyanine conjugate as a near-infrared fluorescent probe for in vivo imaging of tumor hypoxia. Bioconjug Chem. 2012;23:324–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Takahashi S, Piao W, Matsumura Y, Komatsu T, Ueno T, Terai T, Kamachi T, Kohno M, Nagano T, Hanaoka K. Reversible off–on fluorescence probe for hypoxia and imaging of hypoxia–normoxia cycles in live cells. J Am Chem Soc. 2012;134:19588–91.PubMedCrossRefGoogle Scholar
  81. 81.
    Son A, Kawasaki A, Hara D, Ito T, Tanabe K. Phosphorescent ruthenium complexes with a nitroimidazole unit that image oxygen fluctuation in tumor tissue. Chemistry. 2015;21:2527–36.PubMedCrossRefGoogle Scholar
  82. 82.
    Liu J, Liu Y, Bu W, Bu J, Sun Y, Du J, Shi J. Ultrasensitive nanosensors based on upconversion nanoparticles for selective hypoxia imaging in vivo upon near-infrared excitation. J Am Chem Soc. 2014;136:9701–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Komatsu H, Yoshihara K, Yamada H, Kimura Y, Son A, Nishimoto SI, Tanabe K. Ruthenium complexes with hydrophobic ligands that are key factors for the optical imaging of physiological hypoxia. Chemistry. 2013;19:1971–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Zhang S, Hosaka M, Yoshihara T, Negishi K, Iida Y, Tobita S, Takeuchi T. Phosphorescent light–emitting iridium complexes serve as a hypoxia-sensing probe for tumor imaging in living animals. Cancer Res. 2010;70:4490–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Gillies RJ. In vivo molecular imaging. J Cell Biochem Suppl. 2002;39:231–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Gallagher FA, Kettunen MI, Day SE, Hu D-E, Ardenkjær-Larsen JH, Jensen PR, Karlsson M, Golman K, Lerche MH, Brindle KM. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature. 2008;453:940–3.PubMedCrossRefGoogle Scholar
  87. 87.
    Engin K, Leeper DB, Cater JR, Thistlethwaite AJ, Tupchong L, McFarlane JD. Extracellular pH distribution in human tumours. Int J Hyperth. 1995;11:211–6.CrossRefGoogle Scholar
  88. 88.
    Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989;49:6449–65.PubMedGoogle Scholar
  89. 89.
    Damaghi M, Wojtkowiak JW, Gillies RJ. pH sensing and regulation in cancer. Front Physiol. 2013;4:370.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    van den Berg AP, Wike-Hooley JL, van den Berg-Blok AE, van der Zee J, Reinhold HS. Tumour pH in human mammary carcinoma. Eur J Cancer Clin Oncol. 1982;18:457–62.PubMedCrossRefGoogle Scholar
  91. 91.
    Bicher HI, Hetzel FW, Sandhu TS, Frinak S, Vaupel P, O’Hara MD, O’Brien T. Effects of hyperthermia on normal and tumor microenvironment. Radiology. 1980;137:523–30.PubMedCrossRefGoogle Scholar
  92. 92.
    Calderwood SK, Dickson JA. pH and tumor response to hyperthermia. Adv. Radiat. Biol. 1983;10:135–90.Google Scholar
  93. 93.
    Gallagher FA, Kettunen MI, Brindle KM. Imaging pH with hyperpolarized 13C. NMR Biomed. 2011;24:1006–15.PubMedCrossRefGoogle Scholar
  94. 94.
    Jindal AK, Merritt ME, Suh EH, Malloy CR, Sherry AD, Kovács Z. Hyperpolarized 89Y complexes as pH sensitive NMR probes. J Am Chem Soc. 2010;132:1784–5.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Scholz DJ, Janich MA, Köllisch U, Schulte RF, Ardenkjaer-Larsen JH, Frank A, Haase A, Schwaiger M, Menzel MI. Quantified pH imaging with hyperpolarized 13C-bicarbonate. Magn Reson Med. 2015;73:2274–82.PubMedCrossRefGoogle Scholar
  96. 96.
    Ward KM, Balaban RS. Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn Reson Med. 2000;44:799.PubMedCrossRefGoogle Scholar
  97. 97.
    Huang Y, Coman D, Ali MM, Hyder F. Lanthanide ion (III) complexes of 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraaminophosphonate for dual biosensing of pH with chemical exchange saturation transfer (CEST) and biosensor imaging of redundant deviation in shifts (BIRDS). Contrast Media Mol Imaging. 2015;10:51–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Moon BF, Jones KM, Chen LQ, Liu P, Randtke EA, Howison CM, Pagel MD. A comparison of iopromide and iopamidol, two acidoCEST MRI contrast media that measure tumor extracellular pH. Contrast Media Mol Imaging. 2015;10:446–55.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Chen LQ, Randtke EA, Jones KM, Moon BF, Howison CM, Pagel MD. Evaluations of tumor acidosis within in vivo tumor models using parametric maps generated with AcidoCEST MRI. Mol Imaging Biol. 2015;17:488–96.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Chen LQ, Howison CM, Jeffery JJ, Robey IF, Kuo PH, Pagel MD. Evaluations of extracellular pH within in vivo tumors using acidoCEST MRI. Magn Reson Med. 2014;72:1408–17.PubMedCrossRefGoogle Scholar
  101. 101.
    Longo DL, Busato A, Lanzardo S, Antico F, Aime S. Imaging the pH evolution of an acute kidney injury model by means of iopamidol, a MRI-CEST pH-responsive contrast agent. Magn Reson Med. 2013;70:859–64.PubMedCrossRefGoogle Scholar
  102. 102.
    Longo DL, Sun PZ, Consolino L, Michelotti FC, Uggeri F, Aime S. A general MRI-CEST ratiometric approach for pH imaging: demonstration of in vivo pH mapping with iobitridol. J Am Chem Soc. 2014;136:14333–6.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Aime S, Delli Castelli D, Terreno E. Novel pH-reporter MRI contrast agents. Angew Chem Int Ed Engl. 2002;114:4510–2.CrossRefGoogle Scholar
  104. 104.
    Chen Y, Yin Q, Ji X, Zhang S, Chen H, Zheng Y, Sun Y, Qu H, Wang Z, Li Y, Wang X, Zhang K, Zhang L, Shi J. Manganese oxide-based multifunctionalized mesoporous silica nanoparticles for pH-responsive MRI, ultrasonography and circumvention of MDR in cancer cells. Biomaterials. 2012;33:7126–37.PubMedCrossRefGoogle Scholar
  105. 105.
    Sheth VR, Li Y, Chen LQ, Howison CM, Flask CA, Pagel MD. Measuring in vivo tumor pHe with CEST-FISP MRI. Magn Reson Med. 2012;67:760–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Nwe K, Huang C-H, Tsourkas A. Gd-labeled glycol chitosan as a pH-responsive magnetic resonance imaging agent for detecting acidic tumor microenvironments. J Med Chem. 2013;56:7862–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Lee YJ, Kang HC, Hu J, Nichols JW, Jeon YS, Bae YH. pH-sensitive polymeric micelle-based pH probe for detecting and imaging acidic biological environments. Biomacromolecules. 2012;13:2945–51.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Crayton SH, Tsourkas A. pH-Titratable superparamagnetic iron oxide for improved nanoparticle accumulation in acidic tumor microenvironments. ACS Nano. 2011;5:9592–601.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Rivas C, Stasiuk GJ, Gallo J, Minuzzi F, Rutter GA, Long NJ. Lanthanide(III) complexes of Rhodamine-DO3A conjugates as agents for dual-modal imaging. Inorg Chem. 2013;52:14284–93.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Li Y, Wang Y, Yang S, Zhao Y, Yuan L, Zheng J, Yang R. Hemicyanine-based high resolution ratiometric near-infrared fluorescent probe for monitoring pH changes in vivo. Anal Chem. 2015;87:2495–503.PubMedCrossRefGoogle Scholar
  111. 111.
    Doria F, Folini M, Grande V, Cimino-Reale G, Zaffaroni N, Freccero M. Naphthalene diimides as red fluorescent pH sensors for functional cell imaging. Org Biomol Chem. 2015;13:570–6.PubMedCrossRefGoogle Scholar
  112. 112.
    Wang L, Fan Z, Zhang J, Changyi Y, Huang C, Gu Y, Xu Z, Tang Z, Lu W, Wei X. Evaluating tumor metastatic potential by imaging intratumoral acidosis via pH-activatable near-infrared fluorescent probe. Int J Cancer. 2015;136:E107–16.PubMedCrossRefGoogle Scholar
  113. 113.
    Liu X-D, Xu Y, Sun R, Xu Y-J, Lu J-M, Ge J-F. A coumarin–indole-based near-infrared ratiometric pH probe for intracellular fluorescence imaging. Analyst. 2013;138:6542–50.PubMedCrossRefGoogle Scholar
  114. 114.
    Ding C, Tian Y. Gold nanocluster-based fluorescence biosensor for targeted imaging in cancer cells and ratiometric determination of intracellular pH. Biosens Bioelectron. 2015;65:183–90.PubMedCrossRefGoogle Scholar
  115. 115.
    Liu X, Chen Q, Yang G, Zhang L, Liu Z, Cheng Z, Zhu X. Magnetic nanomaterials with near-infrared pH-activatable fluorescence via iron-catalyzed AGET ATRP for tumor acidic microenvironment imaging. J Mater Chem B. 2015;3:2786–800.CrossRefGoogle Scholar
  116. 116.
    Wang Y, Zhou K, Huang G, Hensley C, Huang X, Ma X, Zhao T, Sumer BD, Deberardinis RJ, Gao J. A nanoparticle-based strategy for the imaging of a broad range of tumors by nonlinear amplification of microenvironment signals. Nat Mater. 2014;13:204–12.PubMedCrossRefGoogle Scholar
  117. 117.
    Ko JY, Park S, Lee H, Koo H, Kim MS, Choi K, Kwon IC, Jeong SY, Kim K, Lee DS. pH-sensitive nanoflash for tumoral acidic pH imaging in live animals. Small. 2010;6:2539–44.PubMedCrossRefGoogle Scholar
  118. 118.
    Li C, Xia J, Wei X, Yan H, Si Z, Ju S. pH-activated near-infrared fluorescence nanoprobe imaging tumors by sensing the acidic microenvironment. Adv Funct Mater. 2010;20:2222–30.CrossRefGoogle Scholar
  119. 119.
    Dong C, Liu Z, Zhang L, Guo W, Li X, Liu J, Wang H, Chang J. pHe-induced charge-reversible NIR fluorescence nanoprobe for tumor-specific imaging. ACS Appl Mater Interfaces. 2015;7:7566–75.PubMedCrossRefGoogle Scholar
  120. 120.
    Lemon CM, Curtin PN, Somers RC, Greytak AB, Lanning RM, Jain RK, Bawendi MG, Nocera DG. Metabolic tumor profiling with pH, oxygen, and glucose chemosensors on a quantum dot scaffold. Inorg Chem. 2014;53:1900–15.PubMedCrossRefGoogle Scholar
  121. 121.
    Dennis AM, Rhee WJ, Sotto D, Dublin SN, Bao G. Quantum dot–fluorescent protein FRET probes for sensing intracellular pH. ACS Nano. 2012;6:2917–24.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Wu W, Aiello M, Zhou T, Berliner A, Banerjee P, Zhou S. In-situ immobilization of quantum dots in polysaccharide-based nanogels for integration of optical pH-sensing, tumor cell imaging, and drug delivery. Biomaterials. 2010;31:3023–31.PubMedCrossRefGoogle Scholar
  123. 123.
    Shirmanova MV, Druzhkova IN, Lukina MM, Matlashov ME, Belousov VV, Snopova LB, Prodanetz NN, Dudenkova VV, Lukyanov SA, Zagaynova EV. Intracellular pH imaging in cancer cells in vitro and tumors in vivo using the new genetically encoded sensor SypHer2. Biochim Biophys Acta. 2015;1850:1905–11.PubMedCrossRefGoogle Scholar
  124. 124.
    Tantama M, Hung YP, Yellen G. Imaging intracellular pH in live cells with a genetically encoded red fluorescent protein sensor. J Am Chem Soc. 2011;133:10034–7.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Huang G, Si Z, et al. Dextran based pH-sensitive near-infrared nanoprobe for in vivo differential-absorption dual-wavelength photoacoustic imaging of tumors. J Mater Chem. 2012;22:22575–81.CrossRefGoogle Scholar
  126. 126.
    Flavell RR, Truillet C, Regan MK, Ganguly T, Blecha JE, Kurhanewicz J, Vanbrocklin HF, Keshari KR, Chang CJ, Evans MJ, Wilson DM. Caged [(18)F]FDG glycosylamines for imaging acidic tumor microenvironments using positron emission tomography. Bioconjug Chem. 2016;27:170–8.PubMedCrossRefGoogle Scholar
  127. 127.
    Andreev OA, Engelman DM, Reshetnyak YK. pH-sensitive membrane peptides (pHLIPs) as a novel class of delivery agents. Membr Biol. 2010;27:341–52.CrossRefGoogle Scholar
  128. 128.
    Andreev OA, Engelman DM, Reshetnyak YK. Targeting diseased tissues by pHLIP insertion at low cell surface pH. Front Physiol. 2014;5:97.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Adochite R-C, Moshnikova A, Carlin SD, Guerrieri RA, Andreev OA, Lewis JS, Reshetnyak YK. Targeting breast tumors with pH (low) insertion peptides. Mol Pharm. 2014;11:2896–905.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Cruz-Monserrate Z, Roland CL, Deng D, Arumugam T, Moshnikova A, Andreev OA, Reshetnyak YK, Logsdon CD. Targeting pancreatic ductal adenocarcinoma acidic microenvironment. Sci. Rep. 2014;4:4410/1–8.Google Scholar
  131. 131.
    Loja MN, Luo Z, Greg Farwell D, Luu QC, Donald PJ, Amott D, Truong AQ, Gandour-Edwards RF, Nitin N. Optical molecular imaging detects changes in extracellular pH with the development of head and neck cancer. Int J Cancer. 2013;132:1613–23.PubMedCrossRefGoogle Scholar
  132. 132.
    Macholl S, Morrison MS, Iveson P, Arbo BE, Andreev OA, Reshetnyak YK, Engelman DM, Johannesen E. In vivo pH imaging with 99mTc-pHLIP. Mol Imaging Biol. 2012;14:725–34.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Rothberg JM, Sameni M, Moin K Live-cell imaging of tumor proteolysis: impact of cellular and non-cellular microenvironment. Biochim Biophys Acta. 2012;1824:123–32.Google Scholar
  134. 134.
    Mason SD, Joyce JA. Proteolytic networks in cancer. Trends Cell Biol. 2011;21:228–37.PubMedCrossRefGoogle Scholar
  135. 135.
    Matusiak N, van Waarde A, Bischoff R, Oltenfreiter R, van de Wiele C, Dierckx RA, Elsinga PH. Probes for non-invasive matrix metalloproteinase-targeted imaging with PET and SPECT. Curr Pharm Des. 2013;19:4647–72.PubMedCrossRefGoogle Scholar
  136. 136.
    Narunsky L, Oren R, Bochner F, Neeman M. Imaging aspects of the tumor stroma with therapeutic implications. Pharmacol Ther. 2014;141:192–208.PubMedCrossRefGoogle Scholar
  137. 137.
    Chen H, Zhang X, Dai S, Ma Y, Cui S, Achilefu S, Gu Y. Multifunctional gold nanostar conjugates for tumor imaging and combined photothermal and chemo-therapy. Theranostics. 2013;3:633–49. 17 ppPubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    D’Alessio S, Ferrari G, Cinnante K, et al. Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism. J Biol Chem. 2008;283:87–99.PubMedCrossRefGoogle Scholar
  139. 139.
    Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature. 1994;370:61–5.PubMedCrossRefGoogle Scholar
  140. 140.
    Uekita T, Itoh Y, Yana I, Ohno H, Seiki M. Cytoplasmic tail-dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity. J Cell Biol. 2001;155:1345–56.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Matusiak N, Castelli R, Tuin AW, Overkleeft HS, Wisastra R, Dekker FJ, Prély LM, Bischoff RPH, van Waarde A, Dierckx RAJO. A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging. Bioorganic. Med Chem. 2015;23:192–202.CrossRefGoogle Scholar
  142. 142.
    Altiparmak BL, Yurt F, Citak A. Design of radiolabeled gelatinase inhibitor peptide (99mTc-CLP) and evaluation in rats. Appl Radiat Isot. 2014;89:130–3.PubMedCrossRefGoogle Scholar
  143. 143.
    Efrem Mebrahtu AZ, Hur MA, Laforest R, Lapi SE. Initial characterization of a dually radiolabeled peptide for simultaneous monitoring of protein targets and enzymatic activity. Nucl Med Biol. 2013;40:190.PubMedCrossRefGoogle Scholar
  144. 144.
    Da Rocha Gomes S, Miguel J, Azéma L, Eimer S, Ries C, Dausse E, Loiseau H, Allard M, Toulmé JJ. 99mTc-MAG3-Aptamer for imaging human tumors associated with high level of matrix Metalloprotease-9. Bioconjug Chem. 2012;23:2192–200.PubMedCrossRefGoogle Scholar
  145. 145.
    Kondo N, Temma T, Shimizu Y, Watanabe H, Higano K, Takagi Y, Ono M, Saji H. Miniaturized antibodies for imaging membrane type-1 matrix metalloproteinase in cancers. Cancer Sci. 2013;104:495–501.PubMedCrossRefGoogle Scholar
  146. 146.
    van Duijnhoven SMJR, Marc S, Nicolay K, Gruell H. In vivo biodistribution of radiolabeled MMP-2/9 activatable cell-penetrating peptide probes in tumor-bearing mice. Contrast Media Mol Imaging. 2015;10:59–66.PubMedCrossRefGoogle Scholar
  147. 147.
    van Duijnhoven SMJR, Marc S, Nicolay K, Gruell H. Tumor targeting of MMP-2/9 activatable cell-penetrating imaging probes is caused by tumor-independent activation. J Nucl Med. 2011;52:279–86.PubMedCrossRefGoogle Scholar
  148. 148.
    Zhao T, Harada H, Teramura Y, Tanaka S, Itasaka S, Morinibu A, Shinomiya K, Zhu Y, Hanaoka H, Iwata H, Saji H, Hiraoka M. A novel strategy to tag matrix metalloproteinases-positive cells for in vivo imaging of invasive and metastatic activity of tumor cells. J Control Release. 2010;144:109–14.PubMedCrossRefGoogle Scholar
  149. 149.
    Al Rawashdeh W, Arns S, Gremse F, Ehling J, Knüchel-Clarke R, Kray S, Spöler F, Kiessling F, Lederle W. Optical tomography of MMP activity allows a sensitive noninvasive characterization of the invasiveness and angiogenesis of SCC xenografts. Neoplasia. 2015;16:235–46.CrossRefGoogle Scholar
  150. 150.
    Wang Y, Lin T, Zhang W, Jiang Y, Jin H, He H, Yang VC, Chen Y, Huang Y. A prodrug-type, MMP-2-targeting nanoprobe for tumor detection and imaging. Theranostics. 2015;5:787–95.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Kawano T, Murata M, Piao JS, Narahara S, Hamano N, Kang JH, Hashizume M. Systemic delivery of protein nanocages bearing CTT peptides for enhanced imaging of MMP-2 expression in metastatic tumor models. Int J Mol Sci. 2015;16:148–58.CrossRefGoogle Scholar
  152. 152.
    Chen WH, Xu XD, Jia HZ, Lei Q, Luo GF, Cheng SX, Zhuo RX, Zhang XZ. Therapeutic nanomedicine based on dual-intelligent functionalized gold nanoparticles for cancer imaging and therapy in vivo. Biomaterials. 2013;34:8798–807.PubMedCrossRefGoogle Scholar
  153. 153.
    Zhang X, Bresee J, Fields GB, Barry Edwards W. Near-infrared triple-helical peptide with quenched fluorophores for optical imaging of MMP-2 and MMP-9 proteolytic activity in vivo. Bioorg Med Chem Lett. 2014;24:3786–90.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Shimizu Y, Temma T, Hara I, Makino A, Kondo N, Ozeki E, Ono M, Saji H. In vivo imaging of membrane type-1 matrix metalloproteinase with a novel activatable near-infrared fluorescence probe. Cancer Sci. 2014;105:1056–62.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Myochin T, Hanaoka K, Iwaki S, Ueno T, Komatsu T, Terai T, Nagano T, Urano Y. Development of a series of near-infrared dark quenchers based on Si-rhodamines and their application to fluorescent probes. J Am Chem Soc. 2015;137:4759–65.PubMedCrossRefGoogle Scholar
  156. 156.
    Rood MT, Raspe M, ten Hove JB, Jalink K, Velders AH, van Leeuwen FW. MMP-2/9-specific activatable lifetime imaging agent. Sensors (Basel). 2015;15:11076–91.CrossRefGoogle Scholar
  157. 157.
    Levi J, Kothapalli SR, Bohndiek S, Yoon JK, Dragulescu-Andrasi A, Nielsen C, Tisma A, Bodapati S, Gowrishankar G, Yan X, Chan C, Starcevic D, Gambhir SS. Molecular photoacoustic imaging of follicular thyroid carcinoma. Clin Cancer Res. 2013;19:1494–502.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Waschkau B, Faust A, Schäfers M, Bremer C. Performance of a new fluorescence-labeled MMP inhibitor to image tumor MMP activity in vivo in comparison to an MMP-activatable probe. Contrast Media Mol Imaging. 2013;8:1–11.PubMedCrossRefGoogle Scholar
  159. 159.
    Gallo J, Kamaly N, Lavdas I, Stevens E, Nguyen QD, Wylezinska-Arridge M, Aboagye EO, Long NJ. CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonanceimaging. Angew Chem Int Ed Engl. 2014;53:9550–4.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Crisp JL, Savariar EN, Glasgow HL, Ellies LG, Whitney MA, Tsien RY. Dual targeting of integrin avb3 and matrix Metalloproteinase-2 for optical imaging of tumors and chemotherapeutic delivery. Mol Cancer Ther. 2014;13:1514–25.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Ansari C, Tikhomirov GA, Hong SH, Falconer RA, Loadman PM, Gill JH, Castaneda R, Hazard FK, Tong L, Lenkov OD, Felsher DW, Rao J, Daldrup-Link HE. Development of novel tumor-targeted theranostic nanoparticles activated by membrane-type matrix metalloproteinases for combined cancer magnetic resonance imaging and therapy. Small. 2014;10:566–75.PubMedCrossRefGoogle Scholar
  162. 162.
    Matsuo K, Kamada R, Mizusawa K, Imai H, Takayama Y, Narazaki M, Matsuda T, Takaoka Y, Hamachi I. Specific detection and imaging of enzyme activity by signal-amplifiable self-assembling 19F MRI probes. Chem Eur J. 2013;19:12875–83.PubMedCrossRefGoogle Scholar
  163. 163.
    Reiser J, Adair B, Reinheckel T. Specialized roles for cysteine cathepsins in health and disease. J Clin Invest. 2010;120:3421–31.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Mohamed MM, Sloane BF. Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer. 2006;6:764–75.PubMedCrossRefGoogle Scholar
  165. 165.
    Palermo C, Joyce JA. Cysteine cathepsin proteases as pharmacological targets in cancer. Trends Pharmacol Sci. 2008;29:22–8.PubMedCrossRefGoogle Scholar
  166. 166.
    Loeser R, Bergmann R, Frizler M, Mosch B, Dombrowski L, Kuchar M, Steinbach J, Guetschow M, Pietzsch J. Synthesis and radiopharmacological characterisation of a Fluorine-18-labelled Azadipeptide nitrile as a potential PET tracer for in vivo imaging of cysteine cathepsins. ChemMedChem. 2013;8:1330–44.CrossRefGoogle Scholar
  167. 167.
    Ren G, Blum G, Verdoes M, Liu H, Syed S, Edgington LE, Gheysens O, Miao Z, Jiang H, Gambhir SS, Bogyo M, Cheng Z. Non-invasive imaging of cysteine cathepsin activity in solid tumors using a 64Cu-labeled activity-based probe. PLoS One. 2011;6:e28029.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Shi W, Ogbomo SM, Wagh NK, Zhou Z, Jia Y, Brusnahan SK, Garrison JC. The influence of linker length on the properties of cathepsin S cleavable 177Lu-labeled HPMA copolymers for pancreatic cancer imaging. Biomaterials. 2014;35:5760–70.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Haris M, Singh A, Mohammed I, Ittyerah R, Nath K, Nanga RPR, Debrosse C, Kogan F, Cai K, Poptani H, Reddy D, Hariharan H, Reddy R. In vivo magnetic resonance imaging of tumor protease activity. Sci Rep. 2014;4:6081.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Fujii T, Kamiya M, Urano Y. In vivo imaging of Intraperitoneally disseminated tumors in model mice by using activatable fluorescent small-molecular probes for activity of cathepsins. Bioconjug Chem. 2014;25:1838–46.PubMedCrossRefGoogle Scholar
  171. 171.
    Ryu JH, Na JH, Ko HK, You DG, Park S, Jun E, Yeom HJ, Seo DH, Park JH, Jeong SY, Kim I-S, Kim B-S, Kwon IC, Choi K, Kim K. Non-invasive optical imaging of cathepsin B with activatable fluorogenic nanoprobes in various metastatic models. Biomaterials. 2014;35:2302–11.PubMedCrossRefGoogle Scholar
  172. 172.
    Kisin-Finfer E, Ferber S, Blau R, Satchi-Fainaro R, Shabat D. Synthesis and evaluation of new NIR-fluorescent probes for cathepsin B: ICT versus FRET as a turn-ON mode-of-action. Bioorg Med Chem Lett. 2014;24:2453–8.PubMedCrossRefGoogle Scholar
  173. 173.
    Tian R, Li M, Wang J, Yu M, Kong X, Feng Y, Chen Z, Li Y, Huang W, Wu W, Hong Z. An intracellularly activatable, fluorogenic probe for cancer imaging. Org Biomol Chem. 2014;12:5365–74.PubMedCrossRefGoogle Scholar
  174. 174.
    Cuneo KC, Mito JK, Javid MP, Ferrer JM, Kim Y, Lee WD, Bawendi MG, Brigman BE, Kirsch DG. Imaging primary mouse sarcomas after radiation therapy using cathepsin-activatable fluorescent imaging agents. Int J Radiat Oncol Biol Phys. 2013;86:136–42.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    ABD-Elgaliel WR, Cruz-Monserrate Z, Logsdon CD, Tung C-H. Molecular imaging of Cathepsin E-positive tumors in mice using a novel protease-activatable fluorescent probe. Mol BioSyst. 2011;7:3207–13.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Hu H-Y, Vats D, Vizovisek M, Kramer L, Germanier C, Wendt KU, Rudin M, Turk B, Plettenburg O, Schultz C. In vivo imaging of mouse tumors by a lipidated cathepsin substrate. Angew Chem Int Ed Engl. 2014;53:7669–73.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Verdoes M, Edgington LE, Scheeren FA, Leyva M, Blum G, Weiskopf K, Bachmann MH, Ellman JA, Bogyo M. A nonpeptidic cathepsin S activity-based probe for noninvasive optical imaging of tumor-associated macrophages. Chem Biol. 2012;19:619–28.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Goodman SL, Picard M. Integrins as therapeutic targets. Trends Pharmacol Sci. 2012;33:405–12.PubMedCrossRefGoogle Scholar
  179. 179.
    Goswami S. Importance of integrin receptors in the field of pharmaceutical, medical science. Adv Biol Chem. 2013;3:224–52. 29 ppCrossRefGoogle Scholar
  180. 180.
    Danhier F, Breton AL, Préat VR. RGD-based strategies to target alpha (v) beta (3) integrin in cancer therapy and diagnosis. Mol Pharm. 2012;9:2961–73.PubMedCrossRefGoogle Scholar
  181. 181.
    Guo J, Lang L, Hu S, Guo N, Zhu L, Sun Z, Ma Y, Kiesewetter DO, Niu G, Xie Q, Chen X. Comparison of three dimeric 18F-AlF-NOTA-RGD tracers. Mol Imaging Biol. 2014;16:274–83.PubMedCrossRefGoogle Scholar
  182. 182.
    Mena E, Owenius R, Turkbey B, Sherry R, Bratslavsky G, Macholl S, Miller MP, Somer EJ, Lindenberg L, Adler S, Shih J, Choyke P, Kurdziel K. [18F]Fluciclatide in the in vivo evaluation of human melanoma and renal tumors expressing αvβ3 and αvβ5 integrins. Eur J Nucl Med Mol Imaging. 2014;41:1879–88.PubMedCrossRefGoogle Scholar
  183. 183.
    Haubner R, Rangger C, Virgolini IJ, Maschauer S, Prante O, Einsiedel J, Gmeiner P, Eder IE. H-CRRETAWAC-OH, a lead structure for the development of radiotracer targeting integrin α5β1? Biomed Res Int. 2014;2014:243185.PubMedPubMedCentralGoogle Scholar
  184. 184.
    Bao X, Wang M-W, Xu J-Y, Zheng Y-J, Jiang J-J, Zhang Y-J. Biodistribution in healthy KM mice and micro PET/CT imaging in U87MG tumor-bearing nude mice of a new 18F-labeled cyclic RGD dimer. Zhongguo Aizheng Zazhi. 2013;23:408–12.Google Scholar
  185. 185.
    Hackel BJ, Kimura RH, Miao Z, Liu H, Sathirachinda A, Cheng Z, Chin FT, Gambhir SS. 18F-fluorobenzoate-labeled cystine knot peptides for PET imaging of integrin αvβ6. J Nucl Med. 2013;54:1101–5.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Beer AJ, Pelisek J, Heider P, Reeps C, Eckstein HH, Saraste A, Metz S, Seidl S, Kessler H, Wester H-J, Schwaiger M. PET/CT imaging of integrin αvβ3 expression in human carotid atherosclerosis. JACC Cardiovasc Imaging. 2014;7:178–87.PubMedCrossRefGoogle Scholar
  187. 187.
    Bryden F, Rosca EV, Boyle RW. PET/PDT theranostics: synthesis and biological evaluation of a peptide-targeted Ga-68 porphyrin. Dalton Trans. 2014;44:4925–32.CrossRefGoogle Scholar
  188. 188.
    McBride WJ, D’Souza CA, Sharkey RM, Karacay H, Rossi EA, Chang C-H, Goldenberg DM. Improved F-18 labeling of peptides with a fluoride-aluminum-chelate complex. Bioconjug Chem. 2010;21:1331–40.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    WJ MB, Sharkey RM, Goldenberg DM, McBride WJ. Radiofluorination using aluminum-fluoride (Al18F). EJNMMI Res. 2013;3:36.CrossRefGoogle Scholar
  190. 190.
    Hausner SH, Bauer N, Sutcliffe JL. In vitro and in vivo evaluation of the effects of aluminum [18F]fluoride radiolabeling on an integrin αvβ6-specific peptide. Nucl Med Biol. 2014;41:43–50.PubMedCrossRefGoogle Scholar
  191. 191.
    Bejot R, Goggi J, Moonshi SS, Robins EG. A practical synthesis of [18F]FtRGD: an angiogenesis biomarker for PET. J Label Compd Radiopharm. 2013;56:42–9.CrossRefGoogle Scholar
  192. 192.
    Singh AN, McGuire MJ, Li S, Hao G, Kumar A, Sun X, Brown KC. Dimerization of a phage-display selected peptide for imaging of αvβ6- integrin: two approaches to the multivalent effect. Theranostics. 2014;4:745–60.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Hu LY, Bauer N, Knight LM, Li Z, Liu S, Anderson CJ, Conti PS, Sutcliffe JL. Characterization and evaluation of (64)Cu-labeled A20FMDV2 conjugates for imaging the integrin αvβ 6. Mol Imaging Biol. 2014;16:567–77.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Shokeen M, Zheleznyak A, Wilson JM, Jiang M, Liu R, Ferdani R, Lam KS, Schwarz JK, Anderson CJ. Molecular imaging of very late antigen-4 (α4β1 integrin) in the premetastatic niche. J Nucl Med. 2012;53:779–86.PubMedCrossRefGoogle Scholar
  195. 195.
    Ortiz-Arzate Z, Santos-Cuevas CL, Ocampo-Garcia BE, Ferro-Flores G, Garcia-Becerra R, Estrada G, Gomez-Argumosa E, Izquierdo-Sanchez V. Kit preparation and biokinetics in women of 99mTc-EDDA/HYNIC-E-[c(RGDfK)]2 for breast cancer imaging. Nucl Med Commun. 2014;35:423–32.PubMedCrossRefGoogle Scholar
  196. 196.
    Li F, Song Z, Li Q, Wu J, Wang J, Xie C, Tu C, Wang J, Huang X, Lu W. Molecular imaging of hepatic stellate cell activity by visualization of hepatic integrin αvβ3 expression with SPECT in rat. Hepatology. 2011;54:1020–30.PubMedCrossRefGoogle Scholar
  197. 197.
    Liu Z, Liu H, Ma T, Sun X, Shi J, Jia B, Sun Y, Zhan J, Zhang H, Zhu Z, Wang F. Integrin αvβ6-targeted SPECT imaging for pancreatic cancer detection. J Nucl Med. 2014;55:989–94.PubMedCrossRefGoogle Scholar
  198. 198.
    Zhu X, Li J, Hong Y, Kimura RH, Ma X, Liu H, Qin C, Hu X, Hayes TR, Benny P, Gambhir SS, Cheng Z. 99mTc-Labeled cystine knot peptide targeting integrin αvβ6 for tumor SPECT imaging. Mol Pharm. 2014;11:1208–17.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Ueda M, Fukushima T, Ogawa K, Kimura H, Ono M, Yamaguchi T, Ikehara Y, Saji H. Synthesis and evaluation of a radioiodinated peptide probe targeting αvβ6 integrin for the detection of pancreatic ductal adenocarcinoma. Biochem Biophys Res Commun. 2014;445:661–6.PubMedCrossRefGoogle Scholar
  200. 200.
    John AE, Luckett JC, Tatler AL, Awais RO, Desai A, Habgood A, Ludbrook S, Blanchard AD, Perkins AC, Jenkins RG, Marshall JF. Preclinical SPECT/CT imaging of αvβ6 integrins for molecular stratification of idiopathic pulmonary fibrosis. J Nucl Med. 2013;54:2146–52.PubMedCrossRefGoogle Scholar
  201. 201.
    Gao D, Gao L, Zhang C, Liu H, Jia B, Zhu Z, Wang F, Liu Z. A near-infrared phthalocyanine dye-labeled agent for integrin αvβ6-targeted theranostics of pancreatic cancer. Biomaterials. 2015;53:229–38.PubMedCrossRefGoogle Scholar
  202. 202.
    Moore SJ, Hayden GMG, Bergen JM, Su YS, Rayburn H, Scott MP, Cochran JR. Engineered knottin peptide enables noninvasive optical imaging of intracranial medulloblastoma. Proc Natl Acad Sci U S A. 2013;110:14598–603.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Shi H, Liu J, Geng J, Tang BZ, Liu B. Specific detection of integrin αvβ3 by light-up bioprobe with aggregation-induced emission characteristics. J Am Chem Soc. 2012;134:9569–72.PubMedCrossRefGoogle Scholar
  204. 204.
    Kossodo S, Pickarski M, Lin S-A, Gleason A, Gaspar R, Buono C, Ho G, Blusztajn A, Cuneo G, Zhang J, Jensen J, Hargreaves R, Coleman P, Hartman G, Rajopadhye M, Duong LT, Sur C, Yared W, Peterson J, Bednar B. Dual in vivo quantification of integrin-targeted and protease-activated agents in cancer using fluorescence molecular tomography (FMT). Mol Imaging Biol. 2010;12:488–99.PubMedCrossRefGoogle Scholar
  205. 205.
    Satpati D, Hausner SH, Bauer N, Sutcliffe JL. Cerenkov luminescence imaging of αvβ6 integrin expressing tumors using 90Y-labeled peptides. J Label Compd Radiopharm. 2014;57:558–65.CrossRefGoogle Scholar
  206. 206.
    Kawamura W, Miura Y, Kokuryo D, Toh K, Yamada N, Nomoto T, Matsumoto Y, Sueyoshi D, Liu X, Aoki I. Density-tunable conjugation of cyclic RGD ligands with polyion complex vesicles for the neovascular imaging of orthotopic glioblastomas. Sci Technol Adv Mater. 2015;16:1–13.CrossRefGoogle Scholar
  207. 207.
    Yan C, Wu Y, Feng J, Chen W, Liu X, Hao P, Yang R, Zhang J, Lin B, Xu Y, Liu R. Anti-αvβ3 antibody guided three-step pretargeting approach using magnetoliposomes for molecular magnetic resonance imaging of breast cancer angiogenesis. Int J Nanomedicine. 2013;8:245–55.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Marie-Caline Z. Abadjian
    • 1
  • W. Barry Edwards
    • 2
    • 3
  • Carolyn J. Anderson
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of MedicineUniversity of PittsburghPittsburghUSA
  2. 2.Department of RadiologyUniversity of PittsburghPittsburghUSA
  3. 3.Department of BioengineeringUniversity of PittsburghPittsburghUSA
  4. 4.Department of Pharmacology & Chemical BiologyUniversity of PittsburghPittsburghUSA

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