Skip to main content

Advertisement

SpringerLink
Log in

Methylene blue covalently loaded polyacrylamide nanoparticles for enhanced tumor-targeted photodynamic therapy

  • Paper
  • Published:
Photochemical & Photobiological Sciences Aims and scope Submit manuscript

Abstract

The use of targeted nanoparticles (NPs) as a platform for loading photosensitizers enables selective accumulation of the photosensitizers in the tumor area, while maintaining their photodynamic therapy (PDT) effectiveness. Here two novel kinds of methylene blue (MB)-conjugated polyacrylamide (PAA) nanoparticles, MBI-PAA NPs and MBII-PAA NPs, based on two separate MB derivatives, are developed for PDT. This covalent conjugation with the NPs (i) improves the loading of MB, (ii) prevents any leaching of MB from the NPs and (iii) protects the MB from the effects of enzymes in the biological environment. The loading of MB into these two kinds of NPs was controlled by the input amount, resulting in concentrations with optimal singlet oxygen production. For each of the MB-NPs, the highest singlet oxygen production was found for an MB loading of around 11 nmol mg-1. After attachment of F3 peptide groups, for targeting, each of these NPs was taken up, selectively, by MDA-MB-435 tumor cells, in vitro. PDT tests demonstrated that both kinds of targeted NPs resulted in effective tumor cell kill, following illumination, while not causing dark toxicity.

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

Similar content being viewed by others

Notes and references

  1. E. Buytaert, M. Dewaele and P. Agostinis, Molecular effectors of multiple cell death pathways initiated by photodynamic therapy, Biochim. Biophys. Acta, Rev. Cancer, 2007, 1776, 86–107.

    Article  CAS  Google Scholar 

  2. M. M. Siegel, K. Tabei, R. S. Tsao, M. J. Pastel, R. K. Pandey, S. Berkenkamp, F. Hillenkamp and M. S. de Vries, Comparative mass spectrometric analyses of photofrin oligomers by fast atom bombardment mass spectrometry, UV and IR matrix-assisted laser desorption ionization mass spectrometry, electrospray ionization mass spectrometry and laser desorption/jet-cooling photoionization mass spectrometry, J. Mass Spectrom., 1999, 34, 661–669.

    Article  CAS  PubMed  Google Scholar 

  3. D. E. J. G. J. Dolmans, D. Fukumura and R. K. Jain, Photodynamic therapy for cancer, Nat. Rev. Cancer, 2003, 3, 380–387.

    CAS  PubMed  Google Scholar 

  4. S. B. Brown, E. A. Brown and I. Walker, The present and future role of photodynamic therapy in cancer treatment, Lancet Oncol., 2004, 5, 497–508.

    Article  CAS  PubMed  Google Scholar 

  5. B. C. Wilson and M. S. Patterson, The physics, biophysics and technology of photodynamic therapy, Phys.Med. Biol., 2008, 53, R61–R109.

    Article  CAS  PubMed  Google Scholar 

  6. A. Juarranz, P. Jaen, F. Sanz-Rodriguez, J. Cuevas and S. Gonzalez, Photodynamic therapy of cancer. Basic principles and applications, Clin. Transl. Oncol., 2008, 10, 148–154.

    Article  CAS  PubMed  Google Scholar 

  7. D. Bechet, P. Couleaud, C. Frochot, M. L. Viriot, F. Guillemin and M. Barberi-Heyob, Nanoparticles as vehicles for delivery of photodynamic therapy agents, Trends Biotechnol., 2008, 26, 612–621.

    Article  CAS  PubMed  Google Scholar 

  8. G. S. Trindade, S. L. A. Farias, V. M. Rumjanek and M. A. M. Capella, Methylene blue reverts multidrug resistance: sensitivity of multidrug resistant cells to this dye and its photodynamic action, Cancer Lett., 2000, 151, 161–167.

    Article  CAS  PubMed  Google Scholar 

  9. K. J. Mellish, R. D. Cox, D. I. Vernon, J. Griffiths and S. B. Brown, In vitro photodynamic activity of a series of methylene blue analogues, Photochem. Photobiol., 2002, 75, 392–397.

    Article  CAS  PubMed  Google Scholar 

  10. D. Gabrielli, E. Belisle, D. Severino, A. J. Kowaltowski and M. S. Baptista, Binding, aggregation and photochemical properties of methylene blue in mitochondrial suspensions, Photochem. Photobiol., 2004, 79, 227–232.

    Article  CAS  PubMed  Google Scholar 

  11. R. D. Bongard, M. P. Merker, R. Shundo, Y. Okamoto, D. L. Roerig, J. H. Linehan and C. A. Dawson, Reduction of thiazine dyes by bovine pulmonary arterial endothelial-cells in culture, Am. J. Physiol., 1995, 13, L78–L84.

    Google Scholar 

  12. J. Umbreit, Methemoglobin—It’s not just blue: A concise review, Am. J. Hematol., 2007, 82, 134–144.

    Article  CAS  PubMed  Google Scholar 

  13. M. Wainwright, Non-porphyrin photosensitizers in biomedicine, Chem. Soc. Rev., 1996, 25, 351–359.

    Article  CAS  Google Scholar 

  14. W. M. Sharman, C. M. Allen and J. E. van Lier, Photodynamic therapeutics: basic principles and clinical applications, Drug Discovery Today, 1999, 4, 507–517.

    Article  CAS  PubMed  Google Scholar 

  15. E. M. Tuite and J. M. Kelly, Photochemical Interactions of Methylene-Blue and Analogs with DNA and Other Biological Substrates, J. Photochem. Photobiol., B, 1993, 21, 103–124.

    Article  CAS  Google Scholar 

  16. K. Orth, D. Russ, G. Beck, A. Ruck and H. G. Beger, Photochemotherapy of experimental colonic tumours with intra-tumorally applied methylene blue, Langenbecks Arch. Surg., 1998, 383, 276–281.

    Article  CAS  PubMed  Google Scholar 

  17. K. Orth, A. Rück, A. Stanescu and H. G. Beger, Intraluminal treatment of inoperable oesophageal tumours by intralesional photodynamic therapy with methylene blue, Lancet, 1995, 345, 519–520.

    Article  CAS  PubMed  Google Scholar 

  18. K. Orth, G. Beck, F. Genze and A. Ruck, Methylene blue mediated photodynamic therapy in experimental colorectal tumors in mice, J. Photochem. Photobiol., B, 2000, 57, 186–192.

    Article  CAS  Google Scholar 

  19. J. M. May, Z. C. Qu and C. E. Cobb, Reduction and uptake of methylene blue by human erythrocytes, Am. J. Physiol.: Cell Physiol., 2004, 286, C1390–C1398.

    Article  CAS  Google Scholar 

  20. K. Porkka, P. Laakkonen, J. A. Hoffman, M. Bernasconi and E. Ruoslahti, A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 7444–7449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. S. Christian, J. Pilch, M. E. Akerman, K. Porkka, P. Laakkonen and E. Ruoslahti, Nucleolin expressed at the cell surface is a marker of endothelial cells in angiogenic blood vessels, J. Cell Biol., 2003, 163, 871–878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. H. Maeda, The enhanced permeability and retention (EPR) effect in tumor vasculature: The key role of tumor-selective macromolecular drug targeting, Adv. Enzyme Regul., 2001, 41, 189–207.

    Article  CAS  PubMed  Google Scholar 

  23. W. Tang, H. Xu, R. Kopelman and M. A. Philbert, Photodynamic characterization and in vitro application of methylene blue-containing nanoparticle platforms, Photochem. Photobiol., 2005, 81, 242–249.

    Article  CAS  PubMed  Google Scholar 

  24. J. A. Harrel and R. Kopelman, Biocompatible probes measure intracellular activity, Biophotonics Int., 2000, 7, 22–24.

    Google Scholar 

  25. H. Xu, S. M. Buck, R. Kopelman, M. A. Philbert, M. Brasuel, B. D. Ross and A. Rehemtulla, Photoexcitation-based nano-explorers: Chemical analysis inside live cells and photodynamic therapy, Isr. J. Chem., 2004, 44, 317–337.

    Article  CAS  Google Scholar 

  26. B. Ross, A. Rehemtulla, Y.-E. L. Koo, R. Reddy, G. Kim, C. Behrend, S. Buck, R. J. Schneider, M. A. Philbert, R. Weissleder and R. Kopelman, Photonic and magnetic nanoexplorers for biomedical use: fromsubcellular imaging to cancer diagnostics and therapy, Proc.SPIE, 2004, 5331, 76–83.

    Article  CAS  Google Scholar 

  27. R. Kopelman, Y.-E. L. Koo, M. Philbert, B. A. Moffat, G. R. Reddy, P. McConville, D. E. Hall, T. L. Chenevert, M. S. Bhojani, S. M. Buck, A. Rehemtulla and B. D. Ross, Multifunctional nanoparticle platforms for in vivo MRI enhancement and photodynamic therapy of a rat brain cancer, J. Magn. Magn. Mater., 2005, 293, 404–410.

    Article  CAS  Google Scholar 

  28. G. R. Reddy, M. S. Bhojani, P. McConville, J. Moody, B. A. Moffat, D. E. Hall, G. Kim, Y.-E. L. Koo, M. J. Woolliscroft, J. V. Sugai, T. D. Johnson, M. A. Philbert, R. Kopelman, A. Rehemtulla and B. D. Ross, Vascular targeted nanoparticles for imaging and treatment of brain tumors, Clin. Cancer Res., 2006, 12, 6677–6686.

    Article  CAS  PubMed  Google Scholar 

  29. Y.-E. L. Koo, G. R. Reddy, M. Bhojani, R. Schneider, M. A. Philbert, A. Rehemtulla, B. D. Ross and R. Kopelman, Brain cancer diagnosis and therapy with nanoplatforms, Adv. Drug Delivery Rev., 2006, 58, 1556–1577.

    Article  CAS  Google Scholar 

  30. D. Peer, J. M. Karp, S. Hong, O. C. Farokhzad, R. Margalit and R. Langer, Nanocarriers as an emerging platform for cancer therapy, Nat. Nanotechnol., 2007, 2, 751–760.

    Article  CAS  PubMed  Google Scholar 

  31. M. E. Davis, Z. Chen and D. M. Shin, Nanoparticle therapeutics: an emerging treatment modality for cancer, Nat. Rev. Drug Discovery, 2008, 7, 771–782.

    Article  CAS  PubMed  Google Scholar 

  32. W. Tang, H. Xu, E. J. Park, M. A. Philbert and R. Kopelman, Encapsulation of methylene blue in polyacrylamide nanoparticle platforms protects its photodynamic effectiveness, Biochem. Biophys. Res. Commun., 2008, 369, 579–583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. M. Susa, A. K. Iyer, K. Ryu, F. J. Hornicek, H. Mankin, M. M. Amiji and Z. F. Duan, Doxorubicinloaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma, BMC Cancer, 2009, 9, 399.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. M. D. Chavanpatil, A. Khdair, Y. Patil, H. Handa, G. Z. Mao and J. Panyam, Polymer-surfactant nanoparticles for sustained release of water-soluble drugs, J. Pharm. Sci., 2007, 96, 3379–3389.

    Article  CAS  PubMed  Google Scholar 

  35. A. Khdair, B. Gerard, H. Handa, G. Mao, M. P. V. Shekhar and J. Panyam, Surfactant-polymer nanoparticles enhance the effectiveness of anticancer photodynamic therapy, Mol. Pharmaceutics, 2008, 5, 795–807.

    Article  CAS  Google Scholar 

  36. A. Khdair, H. Handa, G. Z. Mao and J. Panyam, Nanoparticlemediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance in vitro, Eur. J. Pharm. Biopharm., 2009, 71, 214–222.

    Article  CAS  PubMed  Google Scholar 

  37. H. J. Hah, G. Kim, Y.-E. Koo Lee, D. A. Orringer, O. Sagher, M. A. Philbert and R. Kopelman, Methylene blue-conjugated hydrogel nanoparticles and tumor-cell targeted photodynamic therapy, Macromol. Biosci., 2011, 11, 90–99.

    Article  CAS  PubMed  Google Scholar 

  38. M. J. Moreno, E. Monson, R. G. Reddy, A. Rehemtulla, B. D. Ross, M. Philbert, R. J. Schneider and R. Kopelman, Production of singlet oxygen by Ru(dpp(SO3)2)3 incorporated in polyacrylamide PEBBLES, Sens. Actuators, B, 2003, 90, 82–89.

    Article  CAS  Google Scholar 

  39. I. Winer, S. Wang, Y.-E. Koo Lee, W. Fan, Y. Gong, D. Burgos-Ojeda, G. Spahlinger, R. Kopelman and R. J. Buckanovich, F3-targeted cisplatinhydrogel nanoparticles as an effective therapeutic that targets both murine and human ovarian tumor endothelial cells in vivo, Cancer Res., 2010, 70, 8674–8683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. M. K. Carroll, M. A. Unger, A. M. Leach, M. J. Morris, C. M. Ingersoll and F. V. Bright, Interactions between methylene blue and sodium dodecyl sulfate in aqueous solution studied by molecular spectroscopy, Appl. Spectrosc., 1999, 53, 780–784.

    Article  CAS  Google Scholar 

  41. K. Patil, R. Pawar and P. Talap, Self-aggregation ofMethylene Blue in aqueous medium and aqueous solutions of Bu4NBr and urea, Phys. Chem. Chem. Phys., 2000, 2, 4313–4317.

    Article  CAS  Google Scholar 

  42. A. Ghanadzadeh, A. Zeini, A. Kashef and M. Moghadam, Concentration effect on the absorption spectra of oxazine1 and methylene blue in aqueous and alcoholic solutions, J. Mol. Liq., 2008, 138, 100–106.

    Article  CAS  Google Scholar 

  43. D. A. Orringer, Y.-E. L. Koo, T. Chen, G. Kim, H. J. Hah, H. Xu, S. Y. Wang, R. Keep, M. A. Philbert, R. Kopelman and O. Sagher, In vitro characterization of a targeted, dye-loaded nanodevice for intraoperative tumor delineation, Neurosurgery, 2009, 64, 965–971.

    Article  PubMed  Google Scholar 

  44. Y.-E. Koo Lee, E. E. Ulbrich, G. Kim, H. Hah, C. Strollo, W. Z. Fan, R. Gurjar, S. M. Koo and R. Kopelman, Near infrared luminescent oxygen nanosensors with nanoparticlematrix tailored sensitivity, Anal. Chem., 2010, 82, 8446–8455.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. L. E. van Vlerken, T. K. Vyas and M. M. Amiji, Poly(ethylene glycol)-modified nanocarriers for tumor-targeted and intracellular delivery, Pharm. Res., 2007, 24, 1405–1414.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor, Michigan, 48109, USA

    Ming Qin, Hoe Jin Hah, Gwangseong Kim, Guochao Nie, Yong-Eun Koo Lee & Raoul Kopelman

  2. Department of Chemistry and Biology, Yulin Normal University, Yulin City, Guangxi, 537000, China

    Guochao Nie

Authors
  1. Ming Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hoe Jin Hah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gwangseong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guochao Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong-Eun Koo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Raoul Kopelman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raoul Kopelman.

Additional information

This article is published as part of a themed issue on immunological aspects and drug delivery technologies in PDT.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qin, M., Hah, H.J., Kim, G. et al. Methylene blue covalently loaded polyacrylamide nanoparticles for enhanced tumor-targeted photodynamic therapy. Photochem Photobiol Sci 10, 832–841 (2011). https://doi.org/10.1039/c1pp05022b

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1039/c1pp05022b

Search

Navigation