Skip to main content

Advertisement

SpringerLink
Log in

Novel Cyclopeptides for the Design of MMP Directed Delivery Devices: A Novel Smart Delivery Paradigm

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Matrix metalloproteinases (MMP) are a family of proteolytic enzymes, the expression of which in a key step of tumor progression has been better defined recently. The studies highlighted the ongoing need for very specific inhibitors, substrates or release devices designed to be selective for one or at least very few MMPs.

Methods

This report deals with the design, synthesis and in vitro evaluation of linear and especially novel cyclic peptidic moieties, embodying MMP cleavable sequences designed to answer these questions. FRET (fluorescence resonance energy transfer) labelling via chromophore-modified amino-acids was used to give access to enzyme kinetics.

Results

Evaluation of these peptides showed that cyclisation gives rise to high specificity for certain MMP, suggesting that this approach could provide very specific MMP substrate. Moreover, cyclic structures present a very good plasma stability.

Conclusions

These original derivatives could allow the design of MMP-controlled delivery devices, the specificity of which will be retained in complex biological media and in vivo.

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
Fig. 6

Similar content being viewed by others

Abbreviations

ACN:

acetonitrile

APMA:

4-aminophenylmercuric acetate

DAC:

7-diethylamino coumarin-3-carboxylic acid

DCM:

methylene chloride

DIEA:

N,N′-diisopropyldiethylamine

DMF:

N,N-dimethylformamide

DMSO:

dimethylsulfoxide

EDC:

1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride

ECM:

extracellular matrix

Et2O:

diethyl ether

Fmoc:

(9H-fluoren-9-ylmethoxycarbonyl)

FRET:

fluorescence resonance energy transfer

HBTU:

N-[1H-benzotriazol-1-yl)dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide

HOBt:

N-hydroxybenzotriazole

HPLC:

high performance liquid chromatography

MALDI-TOF:

matrix-assisted laser desorption/ionization—time of flight

MC:

7-methoxy coumarin-3-carboxylic acid

MMP:

Matrix metalloprotease

MMPI:

MMP inhibitor

MS:

mass spectrometry

NMM:

N-methylmorpholine

PyBOP:

benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium

tBu:

t-butyl

TFA:

Trifluoroacetic acid

THF:

tetrahydrofuran

TIS:

triisopropylsilane

TRIS:

tris(hydroxymethyl)aminomethane

Trt:

trityl

SPPS:

solid phase peptide synthesis

REFERENCES

  1. Liotta LA. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature. 1980;284:67–8.

    Article  PubMed  CAS  Google Scholar 

  2. Stetler-Stevenson WG. Progelatinase A activation during tumor cell invasion. Invasion Metastasis. 1994;14:259–68.

    PubMed  CAS  Google Scholar 

  3. Nagaseand H, Woessner JF. Matrix metalloproteinases. J Biol Chem. 1999;274:21491–4.

    Article  Google Scholar 

  4. Lucio-Eterovic AK, Piao Y, de Groot JF. Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin Cancer Res. 2009;15:4589–99.

    Article  PubMed  CAS  Google Scholar 

  5. Roy R, Louis G, Loughlin KR, Wiederschain D, Kilroy SM, Lamb CC et al. Tumor-specific urinary matrix metalloproteinase fingerprinting: identification of high molecular weight urinary matrix metalloproteinase species. Clin Cancer Res. 2008;14:6610–7.

    Article  PubMed  CAS  Google Scholar 

  6. Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell. 1996;85:683–93.

    Article  PubMed  CAS  Google Scholar 

  7. Zucker S, Cao J, Chen WT. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene. 2000;19:6642–50.

    Article  PubMed  CAS  Google Scholar 

  8. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science (New York, NY). 2002;295:2387–92.

    CAS  Google Scholar 

  9. Overall CM. Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites. Mol Biotechnol. 2002;22:51–86.

    Article  PubMed  CAS  Google Scholar 

  10. Fingleton B. Matrix metalloproteinase inhibitors for cancer therapy: the current situation and future prospects. Expert Opin Ther Targets. 2003;7:385–97.

    Article  PubMed  CAS  Google Scholar 

  11. McCawley LJ, Matrisian LM. Matrix metalloproteinases: they’re not just for matrix anymore! Curr Opin Cell Biol. 2001;13:534–40.

    Article  PubMed  CAS  Google Scholar 

  12. Aoki T, Sumii T, Mori T, Wang X, Lo EH. Blood-brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats. Stroke. 2002;33:2711–7.

    Article  PubMed  Google Scholar 

  13. Overall CM. Dilating the degradome: matrix metalloproteinase-2 cuts to the heart of the matter. Biochem J. 2004;383:E5–7.

    Article  PubMed  CAS  Google Scholar 

  14. Parks WC, Wilson CL, Lopez-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nature Rev Immunol. 2004;4:617–29.

    Article  CAS  Google Scholar 

  15. Minn AJ. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436:518–24.

    Article  PubMed  CAS  Google Scholar 

  16. Minn AJ, Kang Y, Serganova I, Gupta GP, Giri DD, Doubrovin M et al. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest. 2005;115:44–55.

    PubMed  CAS  Google Scholar 

  17. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436:123–7.

    Article  PubMed  CAS  Google Scholar 

  18. Weigelt B, Peterse JL, van 't Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5:591–602.

    Article  PubMed  CAS  Google Scholar 

  19. Lauer-Fields JL, Broder T, Sritharan T, Chung L, Nagase H, Fields GB. Kinetic analysis of matrix metalloproteinase activity using fluorogenic triple-helical substrates. Biochemistry. 2001;40:5795–803.

    Article  PubMed  CAS  Google Scholar 

  20. Vartak DG, Gemeinhart RA. Matrix metalloproteases: underutilized targets for drug delivery. J Drug Target. 2007;15:1–20.

    Article  PubMed  CAS  Google Scholar 

  21. Chau Y, Tan FE, Langer R. Synthesis and characterization of dextran-peptide-methotrexate conjugates for tumor targeting via mediation by matrix metalloproteinase II and matrix metalloproteinase IX. Bioconjug Chem. 2004;15:931–41.

    Article  PubMed  CAS  Google Scholar 

  22. Tauro JR, Lee BS, Lateef SS, Gemeinhart RA. Matrix metalloprotease selective peptide substrates cleavage within hydrogel matrices for cancer chemotherapy activation. Peptides. 2008;29:1965–73.

    Article  PubMed  CAS  Google Scholar 

  23. Tauro JR, Gemeinhart RA. Matrix metalloprotease triggered delivery of cancer chemotherapeutics from hydrogel matrices. Bioconjug Chem. 2005;16:1133–9.

    Article  PubMed  CAS  Google Scholar 

  24. Tauro JR, Gemeinhart RA. Extracellular protease activation of chemotherapeutics from hydrogel matrices: a new paradigm for local chemotherapy. Mol Pharm. 2005;2:435–8.

    Article  PubMed  CAS  Google Scholar 

  25. Murray GI, Duncan ME, O'Neil P, Melvin WT, Fothergill JE. Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer. Nature Med. 1996;2:461–2.

    Article  PubMed  CAS  Google Scholar 

  26. Overall CM, Kleifeld O. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6:227–39.

    Article  PubMed  CAS  Google Scholar 

  27. Folgueras AR, Pendas AM, Sanchez LM, Lopez-Otin C. Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol. 2004;48:411–24.

    Article  PubMed  CAS  Google Scholar 

  28. Berthelot T, Lain G, Latxague L, Deleris G. Synthesis of novel fluorogenic L-Fmoc lysine derivatives as potential tools for imaging cells. J Fluoresc. 2004;14:671–5.

    Article  PubMed  CAS  Google Scholar 

  29. Berthelot T, Talbot JC, Lain G, Deleris G, Latxague L. Synthesis of N epsilon-(7-diethylaminocoumarin-3-carboxyl)- and N epsilon-(7-methoxycoumarin-3-carboxyl)-L-Fmoc lysine as tools for protease cleavage detection by fluorescence. J Pept Sci. 2005;11:153–60.

    Article  PubMed  CAS  Google Scholar 

  30. Nagase H, Gregg BF. Human matrix metalloproteinase specificity studies using collagen sequence-based synthetic peptides. Pept Sci. 1996;40:399–416.

    CAS  Google Scholar 

  31. Fields GB. A model for interstitial collagen catabolism by mammalian collagenases. J Theor Biol. 1991;153:585–602.

    Article  PubMed  CAS  Google Scholar 

  32. Ochieng J, Fridman R, Nangia-Makker P, Kleiner DE, Liotta LA, Stetler-Stevenson WG et al. Galectin-3 Is a Novel Substrate for Human Matrix Metalloproteinases-2 and-9. Biochemistry. 2002;33:14109–14.

    Article  Google Scholar 

  33. Niyibizi C, Chan R, Wu JJ, Eyre D. A 92 kDa gelatinase (MMP-9) cleavage site in native type V collagen. Biochem Biophys Res Commun. 1994;202:328–33.

    Article  PubMed  CAS  Google Scholar 

  34. Flouzat C, Marguerite F, Croizet F, Percebois M, Monteil A, Combourieu M. Solid-phase synthesis of “head-to-side chain” cyclic tripeptides using allyl deprotection. Tetrahedron Lett. 1997;38:1191–4.

    Article  CAS  Google Scholar 

  35. Planas M, Bardají E, Barany G. Synthesis of cyclic peptide hybrids with amino acid and nucleobase side-chains. Tetrahedron Lett. 2000;41:4097–100.

    Article  CAS  Google Scholar 

  36. Napolitano A, Bruno I, Rovero P, Lucas R, Peris MP, Gomez-Paloma L et al. Synthesis, structural aspects and bioactivity of the marine cyclopeptide hymenamide C. Tetrahedron. 2001;57:6249–55.

    Article  CAS  Google Scholar 

  37. Gogly B, Groult N, Hornebeck W, Godeau G, Pellat B. Collagen Zymography as a Sensitive and Specific Technique for the Determination of Subpicogram Levels of Interstitial Collagenase. Anal Biochem. 1998;255:211–6.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

Authors wish to warmly thank Dr. Pierre Voisin and Dr. Philippe Mellet for helpful discussions, Collectivité Départementale de Mayotte, Conseil Régional d’Aquitaine and Ligue Contre le Cancer for financial support.

Author information

Authors and Affiliations

  1. Université Victor Segalen Bordeaux 2, CNRS UMR 5084 Bio-Organic Chemistry Group, 146 rue Léo Saignat, F-33076, Bordeaux Cedex, France

    El-Farouck Moustoifa, Mohamed-Anis Alouini, Arnaud Salaün, Sandra Albenque-Rubio & Gérard Déléris

  2. CEA, IRAMIS, LSI Irradiated Polymers Group, UMR 7642 CEA/CNRS/Ecole Polytechnique, F-91128, Palaiseau Cedex, France

    Mohamed-Anis Alouini & Thomas Berthelot

  3. Unité de Recherche 02/UR/09-01 Biochimie des Protéines et Interactions Moléculaires, Avenue Taher Hadda, BP 74, Monastir, 5000, Tunisie

    Mohamed-Anis Alouini & Aghleb Bartegi

Authors
  1. El-Farouck Moustoifa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohamed-Anis Alouini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arnaud Salaün
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Berthelot
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aghleb Bartegi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandra Albenque-Rubio
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gérard Déléris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gérard Déléris.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moustoifa, EF., Alouini, MA., Salaün, A. et al. Novel Cyclopeptides for the Design of MMP Directed Delivery Devices: A Novel Smart Delivery Paradigm. Pharm Res 27, 1713–1721 (2010). https://doi.org/10.1007/s11095-010-0164-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0164-0

KEY WORDS

Search

Navigation