Skip to main content

Advertisement

SpringerLink
Log in

Noninvasive Detection and Imaging of Matrix Metalloproteinases for Cancer Diagnosis

  • Review
  • Published:
Journal of Analysis and Testing Aims and scope Submit manuscript

Abstract

Matrix metalloproteinases (MMPs) are important cancer biomarkers and the sensitive detection of MMPs is of great importance to improve clinical diagnosis and therapy of cancer at its early stage. Molecular imaging, including fluorescent optical imaging, radiolabeled imaging, and magnetic resonance imaging, is a powerful tool to visualize and characterize biological processes at the cellular and molecular level. The recognition of MMPs via imaging strategies by utilizing MMP-responsive probes has been a hot pursuit in recent years. Probes designed for MMP detection commonly have two features: (1) off-then-on state in detection signal response to the appearance of MMPs, which has been applied in optical imaging and magnetic resonance imaging; (2) specific retention upon sensing MMPs, which has been applied in radiolabeled imaging. The development of theory and technology in the field of biomarker probes will be beneficial to the accurate diagnosis and effective treatment of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Georgakilas AG. From chemistry of DNA damage to repair and biological significance. Comprehending the future. Mutat Res. 2011;711:1–2.

    Article  CAS  Google Scholar 

  2. Kleiner DE, Stetler-Stevenson WG. Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol. 1999;43(Suppl):S42–51.

    Article  CAS  Google Scholar 

  3. Caley MP, Martins VL, O’Toole EA. Metalloproteinases and wound healing. Adv Wound Care (New Rochelle). 2015;4:225–34.

    Article  Google Scholar 

  4. Khokha R, Murthy A, Weiss A. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol. 2013;13:649–65.

    Article  CAS  Google Scholar 

  5. Maxwell PR, Timms PM, Chandran S, Gordon D. Peripheral blood level alterations of TIMP-1, MMP-2 and MMP-9 in patients with type 1 diabetes. Diabet Med. 2001;18:777–80.

    Article  CAS  Google Scholar 

  6. DeLano FA, Schmid-Schönbein GW. Proteinase activity and receptor cleavage: mechanism for insulin resistance in the spontaneously hypertensive rat. Hypertension. 2008;52:415–23.

    Article  CAS  Google Scholar 

  7. Remacle AG, Noel A, Duggan C, MaDermott E, O’Higgins N, Foidart JM, Duffy MJ. Assay of matrix metalloproteinases types 1, 2, 3 and 9 in breast cancer. Br J Cancer. 1998;77:926–31.

    Article  CAS  Google Scholar 

  8. Baker EA, Bergin FG, Leaper DJ. Matrix metalloproteinases, their tissue inhibitors and colorectal cancer staging. Br J Surg. 2000;87:1215–21.

    Article  CAS  Google Scholar 

  9. Baker EA, Leaper DJ. Measuring gelatinase activity in colorectal cancer. Eur J Surg Oncol. 2002;28:24–9.

    Article  CAS  Google Scholar 

  10. Kuniyasu H, Troncoso P, Johnston D, Bucana CD, Tahara E, Fidler IJ, Pettaway CA. Relative expression of type IV collagenase, E-cadherin, and vascular endothelial growth factor/vascular permeability factor in prostatectomy specimens distinguishes organ-confined from pathologically advanced prostate cancers. Clin Cancer Res. 2000;6:2295–308.

    CAS  Google Scholar 

  11. Zucker S, Hymowitz M, Conner C, Zarrabi HM, Hurewitz AN, Matrisian L, Boyd D, Nicolson G, Montana S. Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications. Ann NY Acad Sci. 1999;878:212–27.

    Article  CAS  Google Scholar 

  12. Sier CF, Kubben FJ, Ganesh S, Heerding MM, Griffioen G, Hanemaaijer R, van Krieken JH, Lamers CB, Verspaget HW. Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. Br J Cancer. 1996;74:413–7.

    Article  CAS  Google Scholar 

  13. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141:52–67.

    Article  CAS  Google Scholar 

  14. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14:163–76.

    Google Scholar 

  15. Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, Sheppard D, Broaddus VC, Nishimura SL. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol. 2002;157:493–507.

    Article  CAS  Google Scholar 

  16. Cowden Dahl KD, Symowicz J, Ning Y, Gutierrez E, Fishman DA, Adley BP, Stack MS, Hudson LG. Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent e-cadherin loss in ovarian carcinoma cells. Cancer Res. 2008;68:4606–13.

    Article  CAS  Google Scholar 

  17. Patel S, Sumitra G, Koner BC, Saxena A. Role of serum matrix metalloproteinase-2 and-9 to predict breast cancer progression. Clin Biochem. 2011;44:869–72.

    Article  CAS  Google Scholar 

  18. Parsons SL, Watson SA, Collins HM, Griffin NR, Clarke PA, Steele RJC. Gelatinase (MMP-2 and -9) expression in gastrointestinal malignancy. Br J Cancer. 1998;78:1495–502.

    Article  CAS  Google Scholar 

  19. Hawkridge AM, Muddiman DC. Mass spectrometry-based biomarker discovery: toward a global proteome index of individuality. Annul Rev Anal Chem. 2009;2:265–77.

    Article  CAS  Google Scholar 

  20. Scherer RL, McIntyre JO, Matrisian LM. Imaging matrix metalloproteinases in cancer. Cancer Metastasis Rev. 2008;27:679–90.

    Article  Google Scholar 

  21. Chen YF, Hong J, Wu DY, Zhou YY, D’Ortenzio M, Ding Y, Xia XH. In vivo mapping and assay of matrix metalloproteases for liver tumor diagnosis. RSC Adv. 2016;6:8336–45.

    Article  CAS  Google Scholar 

  22. Yun CS, Javier A, Jennings T, Fisher M, Hira S, Peterson S, Hopkins S, Reich NO, Strouse GF. Nanometal surface energy transfer in optical rulers, breaking the FRET barrier. J Am Chem Soc. 2005;127:3115–9.

    Article  CAS  Google Scholar 

  23. Hilderbrand SA, Weissleder R. Near-infrared fluorescence: application to in vivo molecular imaging. Curr Opin Chem Biol. 2010;14:71–9.

    Article  CAS  Google Scholar 

  24. Kim JH, Chung BH. Proteolytic fluorescent signal amplification on gold nanoparticles for a highly sensitive and rapid protease assay. Small. 2010;6:126–31.

    Article  CAS  Google Scholar 

  25. Wang X, Xia YQ, Liu YY, Qi WX, Sun QQ, Zhao Q, Tang B. Dual-luminophore-labeled gold nanoparticles with completely resolved emission for the simultaneous imaging of MMP-2 and MMP-7 in living cells under single wavelength excitation. Chem Eur J. 2012;18:7189–95.

    Article  CAS  Google Scholar 

  26. Myochin T, Hanaoka K, Komatsu T, Terai T, Nagano T. Design strategy for a near-infrared fluorescence probe for matrix metalloproteinase utilizing highly cell permeable boron dipyrromethene. J Am Chem Soc. 2012;134:13730–7.

    Article  CAS  Google Scholar 

  27. Yoon SM, Myung S-J, Kim I-W, Do E-J, Ye BD, Ryu JH, Park K, Kim K, Kwon IC, Kim MJ, Moon DH, Yang D-H, Kim KJ, Byeon J-S, Yang S-K, Kim J-H. Application of near-infrared fluorescence imaging using a polymeric nanoparticle-based probe for the diagnosis and therapeutic monitoring of colon cancer. Dig Dis Sci. 2011;56:3005–13.

    Article  CAS  Google Scholar 

  28. Li SY, Liu LH, Cheng H, Li B, Qiu WX, Zhang XZ. A dual-FRET based fluorescence probe for sequential detection of MMP-2 and caspase-3. Chem Commun. 2015;51:14520–3.

    Article  CAS  Google Scholar 

  29. Akers WJ, Xu BG, Lee H, Sudlow GP, Fields GB, Achilefu S, Edwards WB. Detection of MMP-2 and MMP-9 activity in vivo with a triple-helical peptide optical probe. Bioconjugate Chem. 2012;23:656–63.

    Article  CAS  Google Scholar 

  30. Zhang X, Bresee J, Cheney PP, Xu BG, Bhowmick M, Cudic M, Fields GB, Edwards WB. Evaluation of a triple-helical peptide with quenched fluorophores for optical imaging of MMP-2 and MMP-9 proteolytic activity. Molecules. 2014;19:8571–88.

    Article  Google Scholar 

  31. Radwan SH, Azzay HM. Gold nanoparticles for molecular diagnostics. Expert Rev Mol Diagn. 2009;9:511–24.

    Article  CAS  Google Scholar 

  32. Xia XH, Yang MX, Oetjen LK, Zhang Y, Li QG, Chen JY, Xia YN. An enzyme-sensitive probe for photoacoustic imaging and fluorescence detection of protease activity. Nanoscale. 2011;3:950–3.

    Article  Google Scholar 

  33. Hong Y, Ku M, Heo D, Hwang S, Lee E, Park J, Choi J, Lee HJ, Seo M, Lee EJ, Yook JI, Haam S, Huh Y-M, Yoon DS, Suh J-S, Yang J. Molecular recognition of proteolytic activity in metastatic cancer cells using fluorogenic gold nanoprobes. Biosens Bioelectron. 2014;57:171–8.

    Article  CAS  Google Scholar 

  34. Ku M, Hong Y, Heo D, Lee E, Hwang S, Suh J-S, Yang J. In vivo sensing of proteolytic activity with an NSET-based NIR fluorogenic nanosensor. Biosens Bioelectron. 2016;77:471–7.

    Article  CAS  Google Scholar 

  35. Achatz DE, Mezö G, Kele P, Wolfbeis OS. Probing the activity of matrix metalloproteinase II with a sequentially click-labeled silica nanoparticle FRET probe. ChemBioChem. 2009;10:2316–20.

    Article  CAS  Google Scholar 

  36. Feng D, Zhang YY, Feng TT, Shi W, Li XH, Ma HM. A graphene oxide-peptide fluorescence sensor tailor-made for simple and sensitive detection of matrix metalloproteinase 2. Chem Commun. 2011;47:10680–2.

    Article  CAS  Google Scholar 

  37. Nguyen P-D, Cong VT, Baek C, Min J. Fabrication of peptide stabilized fluorescent gold nanocluster/graphene oxide nanocomplex and its application in turn-on detection of metalloproteinase-9. Biosens Bioelectron. 2017;89:666–72.

    Article  CAS  Google Scholar 

  38. Wang YH, Shen P, Li CY, Wang YY, Liu ZH. Upconvension fluorescence resonance energy transfer based biosensor for ultrasensitive detection of matrix metalloproteinase-2 in blood. Anal Chem. 2012;84:1466–73.

    Article  CAS  Google Scholar 

  39. Wang Z, Li XH, Feng D, Li LH, Shi W, Ma HM. Poly(m-phenylenediamine)-based fluorescent nanoprobe for ultrasensitive detection of matrix metalloproteinase 2. Anal Chem. 2014;86:7719–25.

    Article  CAS  Google Scholar 

  40. Kim J, Cote LJ, Kim F, Huang JX. Visualizing graphene based sheets by fluorescence quenching microscopy. J Am Chem Soc. 2010;132:260–7.

    Article  CAS  Google Scholar 

  41. Shimizu Y, Temma T, Sano K, Ono M, Saji H. Development of membrane type-1 matrix metalloproteinase-specific activatable fluorescent probe for malignant tumor detection. Cancer Sci. 2011;102:1897–903.

    Article  CAS  Google Scholar 

  42. 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.

    Article  CAS  Google Scholar 

  43. Kapoor V, McCook BM, Torok FS. An introduction to PET-CT imaging. Radiographics. 2004;24:523–43.

    Article  Google Scholar 

  44. Jiang T, Olson ES, Nguyen QT, Roy M, Jennings PA, Tsien RY. Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc Natl Acad Sci USA. 2004;101:17867–72.

    Article  CAS  Google Scholar 

  45. Van Duijnhoven SMJ, Robillard MS, Nicolay K, Grüll H. Tumor targeting of MMP-2/9 activatable cell-penetrating imaging probes is caused by tomor-independent activation. J Nucl Med. 2011;52:279–86.

    Article  Google Scholar 

  46. Van Duijnhoven SMJ, Robillard MS, Nicolay K, Grüll 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.

    Article  Google Scholar 

  47. Liu QH, Pan DH, Cheng C, Zhang DZ, Zhang AY, Wang LZ, Jiang HD, Wang T, Liu HR, Xu YP, Yang RL, Chen F, Yang M, Zuo CJ. Development of a novel-PET tracer [18F]AlF-NOTA-C6 targeting MMP2 for tumor imaging. PLoS One. 2015;10:1–15.

    Google Scholar 

  48. Grams F, Brandstetter H, D’Alo S, Geppert D, Krell HW, Leinert H, Live V, Menta E, Oliva A, Zimmermann G. Pyrimidine-2,4,6-triones: a new effective and selective class of matrix metalloproteinase inhibitors. Biol Chem. 2001;382:1277–85.

    Article  CAS  Google Scholar 

  49. Breyholz H-J, Wagner S, Faust A, Riemann B, Höltke C, Hermann S, Schober O, Schäfers M, Kopka K. Radiofluorinated pyrimidine-2,4,6-triones as molecular probes for noninvasive MMP-targeted imaging. ChemMedChem. 2010;5:777–89.

    Article  CAS  Google Scholar 

  50. Schrigten D, Breyholz H-J, Wagner S, Hermann S, Schober O, Schäfers M, Haufe G, Kopka K. A new generation of radiofluorinated pyrimidine-2,4,6-triones as MMP-targeted radiotracter for positron emission tomography. J Med Chem. 2012;55:223–32.

    Article  CAS  Google Scholar 

  51. Hugenberg V, Breyholz H-J, Riemann B, Hermann S, Schober O, Schäfers M, Gangadharmath U, Mocharla V, Kolb H, Walsh J, Zhang W, Kopka K, Wagner S. A new class of highly potent matrix metalloproteinase inhibitors based on triazole-substituted hydroxamates: (radio) synthesis and in vitro. J Med Chem. 2012;55:4714–27.

    Article  CAS  Google Scholar 

  52. Beutel B, Daniliuc CG, Riemann B, Schäfers M, Haufe G. Fluorinated matrix metalloproteinases inhibitors—phosphonate based potential probes for positron emission tomography. Bioorg Med Chem. 2016;24:902–9.

    Article  CAS  Google Scholar 

  53. Kalinin DV, Wagner S, Riemann B, Hermann S, Schmidt F, Becker-Pauly C, Rose-John S, Schäfers M, Holl R. Novel potent proline-based metalloproteinase inhibitors: design, (radio) synthesis, and first in vivo evaluation as radiotracer for positron emission tomography. J Med Chem. 2016;59:9541–59.

    Article  CAS  Google Scholar 

  54. Huang CW, Li ZB, Conti PS. Radioactive smart probe for potential corrected matrix metalloproteinase imaging. Bioconjuate Chem. 2012;23:2159–67.

    Article  CAS  Google Scholar 

  55. Kondo N, Temma T, Deguchi J, Sano K, Ono M, Saji H. Development of PEGylated peptide probes conjugated with 18F-labeled BODIPY for PET/optical imaging of MT1-MMP activity. J Control Release. 2015;220:476–83.

    Article  CAS  Google Scholar 

  56. Kondo N, Temma T, Shimizu Y, Ono M, Saji H. Radioiodinated peptidic imaging probes for in vivo detection of membrane type-1 matrix metalloproteinase in cancers. Biol Pharm Bull. 2015;38:1375–82.

    Article  CAS  Google Scholar 

  57. Min KY, Ji B, Zhao M, Ji TF, Chen B, Fang XD, Ma QJ. Development of a radiolabeled peptide-based probe targeting MT1-MMP for breast cancer detection. PLoS One. 2015;10:1–12.

    Google Scholar 

  58. Zhao LZ, Zhu JY, Cheng YJ, Xiong ZJ, Tang YQ, Guo LL, Shi XY, Zhao JH. Chlorotoxin-conjugated multifunctional dendrimers labeled with radionuclide 131I for single photon emission computed tomography imaging and radiotherapy of gliomas. ACS Appl Mater Interfaces. 2015;7:19798–808.

    Article  CAS  Google Scholar 

  59. Hussain T, Nguyen QT. Molecular imaging for cancer diagnosis and surgery. Adv Drug Deliv Rev. 2014;66:90–100.

    Article  CAS  Google Scholar 

  60. Lebel R, Jastrzebska B, Therriault H, Cournoyer M-M, McIntyre JO, Escher E, Neugebauer W, Paquette B, Lepage M. Novel solubility-switchable MRI agent allows the noninvasive detection of matrix metalloproteinase-2 activity in vivo in a mouse model. Magn Reson Med. 2008;60:1056–65.

    Article  CAS  Google Scholar 

  61. Jastrzebska B, Lebel R, Therriault H, McIntyre JO, Escher E, Guérin B, Paquette B, Neugebauer WA, Lepage M. New enzyme-activated solubility-switchable contrast agent for magnetic resonance imaging: from synthesis to in vivo imaging. J Med Chem. 2009;52:1576–81.

    Article  CAS  Google Scholar 

  62. Gringeri CV, Menchise V, Rizzitelli S, Cittadino E, Catanzaro V, Dati G, Chaabane L, Digilio G, Aime S. Novel-Gd(III) based probes for MR molecular imaging of matrix metalloproteinases. Contrast Media Mol Imaging. 2012;7:175–84.

    Article  CAS  Google Scholar 

  63. Kobayashi H, Brechbiel MW. Dendrimer-based macromolecular MRI contrast agents: characteristics and application. Mol Imaging. 2003;2:1–10.

    Article  CAS  Google Scholar 

  64. Olson ES, Jiang T, Aguilera TA, Nguyen QT, Ellies LG, Scadeng M, Tsien RY. Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases. Proc Natl Acad Sci USA. 2010;107:4311–6.

    Article  CAS  Google Scholar 

  65. Malone CD, Olson ES, Mattrey RF, Jiang T, Tsien RY, Nguyen QT. Tumor detection at 3 Tesla with an activatable cell penetrating peptide dentrimer (ACPPD-Gd), a T1 magnetic resonance (MR) molecular imaging agent. PLoS One. 2015;1:1–15.

    Google Scholar 

  66. Cunningham CH, Arai T, Yang PC, McConnell MV, Pauly JM, Conolly SM. Positive contrast magnetic resonance imaging of cells labeled with magnetic nanoparticles. Magn Reson Med. 2005;53:999–1005.

    Article  CAS  Google Scholar 

  67. Gallo J, Kamaly N, Lavdas I, Stevens E, Nguyen Q-D, Wylezinska-Arridge M, Aboagye EO, Long NJ. CXCR4-trageted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging. Angew Chem Int Ed. 2014;53:9550–4.

    Article  CAS  Google Scholar 

  68. Ntziachristos V, Yoo JS, van Dam GM. Current concepts and future perspectives on surgical optical imaging in cancer. J Biomed Opt. 2010;15:066024.

    Article  Google Scholar 

Download references

Acknowledgements

This research study was financially supported by the Natural Science Foundation of China (31470916, 31500769), the Fundamental Research Funds for the Central Universities (2015PT036, 2016PT014), and the Priority Academic Program Development of Jiangsu Higher Education Institutions, and the Open Project Program of MOE Key Laboratory of Drug Quality Control and Pharmacovigilance (DQCP2015MS01).

Author information

Authors and Affiliations

  1. Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, 21009, China

    Jin Hong, Yu-Feng Chen, Jia-Jia Shen & Ya Ding

  2. Key Laboratory of Biomedical Functional Materials, School of Sciences, China Pharmaceutical University, Ministry of Education, Nanjing, 211198, China

    Jin Hong

Authors
  1. Jin Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu-Feng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jia-Jia Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ya Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ya Ding.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hong, J., Chen, YF., Shen, JJ. et al. Noninvasive Detection and Imaging of Matrix Metalloproteinases for Cancer Diagnosis. J. Anal. Test. 1, 203–212 (2017). https://doi.org/10.1007/s41664-017-0036-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s41664-017-0036-2

Keywords

Search

Navigation