Skip to main content

Advertisement

SpringerLink
Log in

bFGF interaction and in vivo angiogenesis inhibition by self-assembling sulfonic acid-based copolymers

  • Published:
Journal of Materials Science: Materials in Medicine Aims and scope Submit manuscript

Abstract

The antiangiogenic activity of different families of biocompatible and non-toxic polymer drugs based on 2-acrylamido-2-methylpropane sulfonic acid (AMPS) or polymethacrylic derivatives of 5-aminonaphthalen sulfonic acid (MANSA) is analyzed using directed in vivo angiogenesis assay and correlated with in vitro results. These active compounds were copolymerized with butylacrylate (BA) and N-vinylpyrrolidone in order to obtain two families of copolymers with different properties in aqueous media. The most hydrophobic copolymers poly(BA-co-MANSA) and poly(BA-co-AMPS) formed amphiphilic copolymers and presented micellar morphology in aqueous media. This supramolecular organization of the copolymers had a clear effect on bioactivity. Poly(BA-co-MANSA) copolymers showed the best antiangiogenic activity and very low toxicity at relatively low dose, with the possibility to be injected directly in the solid tumors alone or in combination with other therapeutic agents such as anti-VEGF drugs. The obtained results demonstrate that not only the chemical structure but also the supramolecular organization of the macromolecules plays a key role in the anti-angiogenic activity of these active polymers.

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

Similar content being viewed by others

References

  1. Augustin HG. Translating angiogenesis research into the clinic: the challenges ahead. Br J Radiol. 2003;76(1):S3–S10. doi:10.1259/bjr/68078705.

    Google Scholar 

  2. Lange C, Ehlken C, Martin G, Konzok K, Moscoso del Prado J, Hansen LL, et al. Intravitreal injection of the heparin analog 5-amino-2-naphthalenesulfonate reduces retinal neovascularization in mice. Exp Eye Res. 2007;85(3):323–7.

    Article  CAS  Google Scholar 

  3. Quesada AR, Oz C, Medina MA. Anti-angiogenic drugs: From bench to clinical trials. Med Res Rev. 2006;26(4):483–530.

    Article  CAS  Google Scholar 

  4. Distler JHW, Hirth A, Kurowska-Stolarska M, Gay RE, Gay S, Distler O. Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med. 2003;47(3):149–61.

    CAS  Google Scholar 

  5. Fernández IS, Cuevas P, Angulo J, López-Navajas P, Canales-Mayordomo Á, González-Corrochano R, et al. Gentisic acid, a compound associated with plant defense and a metabolite of aspirin, heads a new class of in vivo fibroblast growth factor inhibitors. J Biol Chem. 2010;285(15):11714–29.

    Article  Google Scholar 

  6. Chen EX, Siu LL. Development of molecular targeted anticancer agents: Successes, failures and future directions. Curr Pharm Des. 2005;11(2):265–72.

    Article  CAS  Google Scholar 

  7. Scappaticci FA. The therapeutic potential of novel antiangiogenic therapies. Expert Opin Investig Drugs. 2003;12(6):923–32.

    Article  CAS  Google Scholar 

  8. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349(5):427–34.

    Article  CAS  Google Scholar 

  9. Benelli R, Ferrari N. Angiogenesis inhibition: state of the art, forgotten strategies and new perspectives in cancer therapy. Curr Cancer Ther Rev. 2009;5(3):203–16.

    Article  CAS  Google Scholar 

  10. Javerzat S, Auguste P, Bikfalvi A. The role of fibroblast growth factors in vascular development. Trends Mol Med. 2002;8(10):483–9.

    Article  CAS  Google Scholar 

  11. Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99(17):11393–8.

    Article  CAS  Google Scholar 

  12. Petersen I. Antiangiogenesis, anti-VEGF(R) and outlook. Recent Results Cancer Res. 2007;176:189–99.

    Article  CAS  Google Scholar 

  13. Ignoffo RJ. Overview of bevacizumab: a new cancer therapeutic strategy targeting vascular endothelial growth factor. Am J Health Syst Pharm. 2004;61(21):S21–S26.

    Google Scholar 

  14. Dempke WCM, Heinemann V. Resistance to EGF-R (erbB-1) and VEGF-R modulating agents. Eur J Cancer. 2009;45(7):1117–28.

    Article  CAS  Google Scholar 

  15. Alessi P, Leali D, Camozzi M, Cantelmo A, Albini A, Presta M. Anti-FGF2 approaches as a strategy to compensate resistance to anti-VEGF therapy: long-pentraxin 3 as a novel antiangiogenic FGF2-antagonist. Eur Cytokine Netw. 2009;20(4):225–34.

    CAS  Google Scholar 

  16. Knights V, Cook SJ. De-regulated FGF receptors as therapeutic targets in cancer. Pharm Ther. 2010;125(1):105–17.

    Article  CAS  Google Scholar 

  17. Nilsson EM, Brokken LJS, Härkönen PL. Fibroblast growth factor 8 increases breast cancer cell growth by promoting cell cycle progression and by protecting against cell death. Exp Cell Res. 2010;316(5):800–12.

    Article  CAS  Google Scholar 

  18. Pike DB, Cai S, Pomraning KR, Firpo MA, Fisher RJ, Shu XZ, et al. Heparin-regulated release of growth factors in vitro and angiogenic response in vivo to implanted hyaluronan hydrogels containing VEGF and bFGF. Biomaterials. 2006;27(30):5242–51.

    Article  CAS  Google Scholar 

  19. García-Fernández L, Aguilar MaR, Fernández MaM, Lozano RM, Giménez G, Román JS. Antimitogenic polymer drugs based on AMPS: monomer distribution–bioactivity relationship of water-soluble macromolecules. Biomacromolecules. 2010;11(3):626–34. doi:10.1021/bm901194e.

    Article  Google Scholar 

  20. Garcia-Fernandez L, Aguilar MR, Fernandez MM, Lozano RM, Gimenez G, Valverde S, et al. Structure, morphology, and bioactivity of biocompatible systems derived from functionalized acrylic polymers based on 5-amino-2-naphthalene sulfonic acid. Biomacromolecules. 2010;11(7):1763–72.

    Article  CAS  Google Scholar 

  21. Fernández-Tornero C, Lozano RM, Redondo-Horcajo M, Gómez AM, López JC, Quesada E, et al. Leads for development of new naphthalenesulfonate derivatives with enhanced antiangiogenic activity. Crystal structure of acidic fibroblast growth factor in complex with 5-amino-2-naphthalenesulfonate. J Bio Chem. 2003;278(24):21774–81.

    Article  Google Scholar 

  22. Liekens S, Leali D, Neyts J, Esnouf R, Rusnati M, Dell’era P, et al. Modulation of fibroblast growth factor-2 receptor binding, signaling, and mitogenic activity by heparin-mimicking polysulfonated compounds. Mol Pharm. 1999;56(1):204–13.

    CAS  Google Scholar 

  23. Liekens S, Neyts J, Dégrève B, De Clercq E. The sulfonic acid polymers PAMPS [Poly(2-acrylamido-2-methyl-1-propanesuifonie acid)] and related analogues are highly potent inhibitors of angiogenesis. Onco Res. 1997;9(4):173–81.

    CAS  Google Scholar 

  24. Bloor DM, Li Y, Wyn-Jones E. Binding of sodium alkyl sulfates to a polymer labeled with a covalently bonded solvatochromic probe. Langmuir. 1995;11(10):3778–81.

    Article  CAS  Google Scholar 

  25. Brown W, Fundin J, Da Graça Miguel M. Poly(ethylene oxide)-sodium dodecyl sulfate interactions studied using static and dynamic light scattering. Macromolecules. 1992;25(26):7192–8.

    Article  CAS  Google Scholar 

  26. Wang G, Olofsson G. Titration calorimetric study of the interaction between ionic surfactants and uncharged polymers in aqueous solution. J Phys Chem B. 1998;102(46):9276–83.

    Article  CAS  Google Scholar 

  27. Rodenhiser AP, Kwak JCT. Application of size exclusion chromatography with surfactant eluent to the study of polymer-surfactant interactions: oligomeric and micellar chromatographic effects. Colloids Surf A. 1999;150(1–3):191–206.

    Article  CAS  Google Scholar 

  28. Ladbury JE. Isothermal titration calorimetry: application to structure-based drug design. Thermochim Acta. 2001;380(2):209–15.

    Article  CAS  Google Scholar 

  29. Pierce MM, Raman CS, Nall BT. Isothermal titration calorimetry of protein–protein interactions. Methods. 1999;19(2):213–21.

    Article  CAS  Google Scholar 

  30. Martínez A, Vos M, Guédez L, Kaur G, Chen Z, Garayoa M, et al. The effects of adrenomedullin overexpression in breast tumor cells. J Nat Cancer Inst. 2002;94(16):1226–37.

    Article  Google Scholar 

  31. García-Fernández L, Halstenberg S, Unger RE, Aguilar MR, Kirkpatrick CJ, San Román J. Anti-angiogenic activity of heparin-like polysulfonated polymeric drugs in 3D human cell culture. Biomaterials. 2010;31(31):7863–72.

    Article  Google Scholar 

  32. Wiseman T, Williston S, Brandts JF, Lin LN. Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Anal Biochem. 1989;179(1):131–7.

    Article  CAS  Google Scholar 

  33. Campoy AV, Freire E. ITC in the post-genomic era…? Priceless. Biophys Chem. 2005;115 (2–3):115–124.

    Google Scholar 

  34. Chaires JB, Dattagupta N, Crothers DM. Studies on interaction of anthracycline antibiotics and deoxyribonucleic acid: equilibrium binding studies on the interaction of daunomycin with deoxyribonucleic acid. Biochem. 1982;21(17):3933–40. doi:10.1021/bi00260a005.

    Article  CAS  Google Scholar 

  35. Gonzalez-Jimenez J, Frutos G, Cayre I, Cortijo M. Chlorpheniramine binding to human serum albumin by fluorescence quenching measurements. Biochim. 1991;73(5):551–6.

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This work was partially supported by grants from the Spanish Ministry of Science and Innovation (SAF2009-13240-C02-01 and MAT2010-18155) and CIBER-BBN.

Author information

Authors and Affiliations

  1. Department of Biomaterials, Institute of Polymer Science and Technology, Juan de la Cierva 3, 28006, Madrid, Spain

    L. García-Fernández, M. R. Aguilar & J. San Román

  2. Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain

    L. García-Fernández, M. R. Aguilar & J. San Román

  3. Angiogenesis Study Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006, Logroño, Spain

    L. Ochoa-Callejero & A. Martínez

  4. Department of Chemistry, Faculty of Pharmacy, San Pablo CEU University, Urbanización Montepríncipe, 28668, Boadilla del Monte, Madrid, Spain

    C. Abradelo

Authors
  1. L. García-Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. R. Aguilar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Ochoa-Callejero
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Abradelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. San Román
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. García-Fernández.

Rights and permissions

Reprints and permissions

About this article

Cite this article

García-Fernández, L., Aguilar, M.R., Ochoa-Callejero, L. et al. bFGF interaction and in vivo angiogenesis inhibition by self-assembling sulfonic acid-based copolymers. J Mater Sci: Mater Med 23, 129–135 (2012). https://doi.org/10.1007/s10856-011-4497-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10856-011-4497-y

Keywords

Search

Navigation