Nano Research

, Volume 8, Issue 5, pp 1729–1745 | Cite as

Biotinylated polyurethane-urea nanoparticles for targeted theranostics in human hepatocellular carcinoma

  • Genoveva Morral-Ruíz
  • Pedro Melgar-Lesmes
  • Andrea López-Vicente
  • Conxita Solans
  • María José García-Celma
Research Article

Abstract

Over the past years, significant efforts have been devoted to explore novel drug delivery and detection strategies for simultaneous therapy and diagnostics. The development of biotinylated polyurethane-urea nanoparticles as theranostic nanocarriers for targeted drug and plasmid delivery, for fluorescence detection of human hepatocellular carcinoma cells, is described herein. These targeted nanoparticles are specifically designed to incorporate biotin into the polymeric matrix, since many tumor types overexpress receptors for biotin as a mechanism to boost uncontrolled cell growth. The obtained nanoparticles were spherical, exhibited an average diameter ranging 110–145 nm, and showed no cytotoxicity in healthy endothelial cells. Biotinylated nanoparticles are selectively incorporated into the perinuclear and nuclear area of the human hepatocellular carcinoma cell line, HepG2, in division, but not into growing, healthy, human endothelial cells. Indeed, the simultaneous incorporation of the anticancer drugs, phenoxodiol or sunitinib, together with plasmid DNA encoding green fluorescent protein, into these nanoparticles allows a targeted pharmacological antitumor effect and furthermore, selective transfection of a reporter gene, to detect these cancer cells. The combined targeted therapy and detection strategy described here could be exploited for liver cancer therapy and diagnostics, with a moderate safety profile, and may also be a potential tool for other types of cancer.

Keywords

cancer therapy DNA nanoparticles polyurethane theranostics 

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References

  1. [1]
    Brannon-Peppas, L.; Blanchette, J.O. Nanoparticle and targeted systems for cancer therapy. Adv. Drug. Deliver. Rev. 2004, 56, 1649–1659.CrossRefGoogle Scholar
  2. [2]
    Wang, S. Y.; Kim, G.; Lee, Y.-E.; Hah, H. J.; Ethirajan, M.; Pandey, R. K.; Kopelman, R. Multifunctional biodegradable polyacrylamide nanocarriers for cancer theranostics-A “see and treat” strategy. ACS Nano 2012, 6, 6843–6851.CrossRefGoogle Scholar
  3. [3]
    Morral-Ruíz, G.; Melgar-Lesmes, P.; Solans, C.; García-Celma, M. J. Multifunctional polyurethane-urea nanoparticles to target and arrest inflamed vascular environment: Apotential tool for cancer therapy and diagnosis. J. Control. Release 2013, 171, 163–171.CrossRefGoogle Scholar
  4. [4]
    Morral-Ruíz, G.; Solans, C.; García, M. L.; García-Celma, M. J. Formation of pegylated polyurethane and lysine-coated polyurea nanoparticles obtained from O/W nano-emulsions. Langmuir 2012, 28, 6256–6264.CrossRefGoogle Scholar
  5. [5]
    Moghimi, S. M.; Hunter, A. C.; Murray, J. C. Long-circulating and target-specific nanoparticles: Theory to practice. Pharmacol. Rev. 2001, 53, 283–318.Google Scholar
  6. [6]
    Bonzani, J. C.; Adhikari, R.; Houshyar, S.; Mayadunne, R.; Gunatillake, P.; Stevens, M. M. Synthesis of two-component injectable polyurethanes for bone tissue engineering. Biomaterials 2007, 28, 423–433.CrossRefGoogle Scholar
  7. [7]
    Brannon-Peppas, L.; Blanchette, J. O. Nanoparticle and targeted systems for cancer therapy. Adv. Drug. Deliver. Rev. 2012, 64, 206–212.CrossRefGoogle Scholar
  8. [8]
    Blanpain, C. Tracing the cellular origin of cancer. Nat. Cell. Biol. 2013, 15, 126–134.CrossRefGoogle Scholar
  9. [9]
    Vadlapudi, A. D.; Vadlapatla, R. -K.; Pal, D.; Mitra, A. K. Biotin uptake by T47D breast cancer cells: Functional and molecular evidence of sodium-dependent multivitamin transporter (SMVT). Int. J. Pharm. 2013, 441, 535–543.CrossRefGoogle Scholar
  10. [10]
    Soininen, S. K.; Lehtolainen-Dalkilic, P.; Karppinen, T.; Puustinen, T.; Dragneva, G.; Kaikkonen, M. U.; Jauhiainen, M.; Allart, B.; Selwood, D. L.; Wirth, T. et al. Targeted delivery via avidin fusion protein: Intracellular fate of biotinylated doxorubicin derivative and cellular uptake kinetics and biodistribution of biotinylated liposomes. Eur. J. Pharm. Sci. 2012, 47, 848–856.CrossRefGoogle Scholar
  11. [11]
    Zempleni, J. Uptake, localization, and noncarboxylase roles of biotin. Annu. Rev. Nutr. 2005, 25, 175–196.CrossRefGoogle Scholar
  12. [12]
    Fang, J.; Nakamura, H.; Maeda, H. The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv. Drug Deliv. Rev. 2011, 63, 136–151.CrossRefGoogle Scholar
  13. [13]
    Sangiovanni, A.; Del Ninno, E.; Fasani, P.; De Fazio, C.; Ronchi, G.; Romeo, R.; Morabito, A.; De Franchis, R.; Colombo, M. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology 2004, 126, 1005–1014.CrossRefGoogle Scholar
  14. [14]
    Llovet, J. M.; Di Bisceglie, A. M.; Bruix, J.; Kramer, B. S.; Lencioni, R.; Zhu, A.X.; Sherman, M.; Schwartz, M.; Lotze, M.; Talwalkar, J. et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J. Natl. Cancer Inst. 2008, 100, 698–711.CrossRefGoogle Scholar
  15. [15]
    Newell, P.; Toffanin, S.; Villanueva, A.; Chiang, D. Y.; Minguez, B.; Cabellos, L.; Savic, R.; Hoshida, Y.; Lim, K. H.; Melgar-Lesmes, P. et al. Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo. J. Hepatol. 2009, 59, 725–733.CrossRefGoogle Scholar
  16. [16]
    Forner, A.; Llovet, J. M.; Bruix, J. Hepatocellular carcinoma. Lancet 2012, 379, 1245–1255.CrossRefGoogle Scholar
  17. [17]
    Lu, C. H.; Willner, B.; Willner, I. DNA nanotechnology: From sensing and DNA machines to drug-delivery systems. ACS Nano 2013, 7, 8320–8332.CrossRefGoogle Scholar
  18. [18]
    Singh, M.; Ariatti, M. Targeted gene delivery into HepG2 cells using complexes containing DNA, cationized asialoorosomucoid and activated cationic liposomes. J. Control. Release 2003, 92, 383–394.CrossRefGoogle Scholar
  19. [19]
    Morral-Ruíz, G.; Melgar-Lesmes, P.; García, M. L.; Solans, C.; García-Celma, M. J. Design of biocompatible surface-modified polyurethane and polyurea nanoparticles. Polymer 2012, 53, 6072–6080.CrossRefGoogle Scholar
  20. [20]
    Chen, C.; Heng, Y. C.; Yu, C. H.; Chan, S. W.; Cheung, M. K.; Yu, P. H. F. In vitro cytotoxicity, hemolysis assay, and biodegradation behaviour of biodegradable poly(3-hydroxybutyrate)-poly(ethylene glycol)-poly (3-hydroxybutyrate) nanoparticles as potential drug carriers. J. Biomed. Mater. Res. A 2008, 87, 290–298.CrossRefGoogle Scholar
  21. [21]
    Faivre, S.; Zappa, M.; Vilgrain, V.; Boucher, E.; Douillard, J.-Y.; Lim, H. Y.; Kim, J. S.; Im, S. A.; Kang, Y.-K.; Bouattour, M. et al. Changes in tumor density in patients with advanced hepatocellular carcinoma treated with sunitinib. Clin. Cancer Res. 2011, 17, 4504–4512.CrossRefGoogle Scholar
  22. [22]
    Silasi, D.-A.; Alvero, A. B.; Rutherford, T. J.; Brown, D.; Mor, G. Phenoxodiol: Pharmacology and clinical experience in cancer monotherapy and in combination with chemotherapeutic drugs. Expert Opin. Pharmacother. 2009, 10, 1059–1067.CrossRefGoogle Scholar
  23. [23]
    Perrault, S. D.; Walkey, C.; Jennings, T.; Fischer, H. C.; Chan, W. C. W. Mediating tumour targeting efficiency of nanoparticles through design. Nano Lett. 2009, 9, 1909–1915.CrossRefGoogle Scholar
  24. [24]
    Yuan, F.; Dellian, M.; Fukumura, D.; Leunig, M.; Berk, D. A.; Torchilin, V. P.; Jain, R. K. Vascular permeability in a human tumor xenograft: Molecular size dependence and cutoff size. Cancer Res. 1995, 17, 3752–3756.Google Scholar
  25. [25]
    Hobbs, S. K.; Monsky, W. L.; Yuan, F.; Roberts, W. G.; Griffith, L.; Torchilin, V. P.; Jain, R. K. Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 4607–4612.CrossRefGoogle Scholar
  26. [26]
    Melgar-Lesmes, P.; Morral-Ruíz, G.; Solans, C.; García-Celma, M. J. Quantifying the bioadhesive properties of surface-modified polyurethane-urea nanoparticles in the vascular network. Colloids Surf. B 2014, 118, 280–288.CrossRefGoogle Scholar
  27. [27]
    Vonarbourg, A.; Passirani, C.; Saulnier, P.; Benoit, J. P. Parameters influencing the stealthiness of colloidal drug delivery Systems. Biomaterials 2006, 27, 4356–4373.CrossRefGoogle Scholar
  28. [28]
    Rapiti, E.; Verkooijen, H. M.; Vlastos, G.; Fioretta, G.; Neyroud-Caspar, I.; Sappino, A. P.; Chappuis, P. O.; Bouchardy, C. Complete excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis. J. Clin. Oncol. 2006, 24, 2743–2749.CrossRefGoogle Scholar
  29. [29]
    Orringer, D. A.; Koo, Y.-E. L.; Chen, T.; Kim, G.; Hah, H. J.; Xu, H.; Wang, S. Y.; Keep, R.; Philbert, M. A.; Kopelman, R. et al. In vitro characterization of a targeted, dye-loaded nanodevice for intraoperative tumor delineation. Neurosurgery 2009, 64, 965–972.CrossRefGoogle Scholar
  30. [30]
    Ferrari, M. Cancer nanotechnology: Opportunities and challenges. Nat. Rev. Cancer 2005, 5, 161–171.CrossRefGoogle Scholar
  31. [31]
    Eyüpoglu, I. Y.; Hore, N.; Savaskan, N. E.; Grummich, P.; Roessler, K.; Buchfelder, M.; Ganslandt, O. Improving the extent of malignant glioma resection by dual intraoperative visualization approach. PLoS ONE 2012, 7, e44885.CrossRefGoogle Scholar
  32. [32]
    Pedraza, C. E.; Basset, D. C.; McKee, M. D.; Nelea, V.; Gbureck, U.; Barralet, J. E. The importance of particle size and DNA condensation salt for calcium phosphate nanoparticle transfection. Biomaterials 2008, 29, 3384–3392.CrossRefGoogle Scholar
  33. [33]
    Kaneda, Y. Virosome: A novel vector to enable multi-modal strategies for cancer therapy. Adv. Drug Deliv. Rev. 2012, 64, 730–738.CrossRefGoogle Scholar
  34. [34]
    Glendenning, J. L.; Barbachano, Y.; Norman, A. R.; Dearnaley, D. P.; Horwich, A.; Huddart, R. A. Long-term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer. Cancer 2010, 116, 2322–2331.Google Scholar
  35. [35]
    Gan, H. K.; Seruga, B.; Knox, J. J. Sunitinib in solid tumors. Expert Opin. Investig. Drugs. 2009, 18, 821–834.CrossRefGoogle Scholar
  36. [36]
    Killock, D. Kidney cancer: Sunitinib has similar efficacy irrespective of age in mRCC. Nat. Rev. Clin. Oncol. 2014, 11, 122.CrossRefGoogle Scholar
  37. [37]
    Lopergolo, A.; Nicolini, V.; Favini, E.; Dal Bo, L.; Tortoreto, M.; Cominetti, D.; Folini, M.; Perego, P.; Castiglioni, V.; Scanziani, E. et al. Synergistic cooperation between sunitinib and Cisplatin promotes apoptotic cell death in human medullary thyroid cancer. J. Clin. Endocrinol. Metab. 2014, 99, 498–509.CrossRefGoogle Scholar
  38. [38]
    Herst, P. M.; Petersen, T.; Jerram, P.; Baty, J.; Berridge M. V. The antiproliferative effects of phenoxodiol are associated with inhibition of plasma membrane electron transport in tumour cell lines and primary immune cells. Biochem. Pharmacol. 2007, 74, 1587–1595.CrossRefGoogle Scholar
  39. [39]
    Aguero, M. F.; Facchinetti, M. M.; Sheleg, Z.; Senderowicz, A. M. Phenoxodiol, a novel isoflavone, induces G1 arrest by specific loss in cyclin-dependent kinase 2 activity by p53-independent induction of p21WAF1/CIP1. Cancer Res. 2005, 65, 3364–3373.Google Scholar
  40. [40]
    Kamsteeg, M.; Rutherford, T.; Sapi, E.; Hanczaruk, B.; Shahabi, S.; Flick, M. Phenoxodiol-an isoflavone analog-induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 2003, 22, 2611–2620.CrossRefGoogle Scholar
  41. [41]
    Yao, C.; Wu, S. J.; Li, D. M.; Wang, Z. Y.; Yang, Y. J.; Yang, S. C.; Gu, Z. P. Co-administration phenoxodiol with doxorubicin synergistically inhibit the activity of sphingosine kinase-1 (SphK1), a potential oncogene of osteosarcoma, to suppress osteosarcoma cell growth both in vivo and in Vitro. Molecular Oncology 2012, 6, 392–404.CrossRefGoogle Scholar
  42. [42]
    Mendel, D. B., Laird, A. D.; Xin, X. H.; Louie, S. G.; Christensen, J. G.; Li, G. M.; Schreck, R. E.; Abrams, T. J.; Ngai, T. J.; Lee, L. B. et al.In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res., 2003, 9, 327–337.Google Scholar

Copyright information

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Genoveva Morral-Ruíz
    • 1
  • Pedro Melgar-Lesmes
    • 1
  • Andrea López-Vicente
    • 1
  • Conxita Solans
    • 2
    • 3
  • María José García-Celma
    • 1
    • 3
  1. 1.Department of Pharmacy and Pharmaceutical Technology, Faculty of PharmacyUniversity of BarcelonaBarcelonaSpain
  2. 2.Institute of Advanced Chemistry of Catalonia (IQAC)CSICBarcelonaSpain
  3. 3.Networking Research Center on Bioengineering, Biomaterials and NanomedicineCIBER-BBNMadridSpain
  4. 4.Institute for Medical Engineering and ScienceMassachusetts Institute of TechnologyCambridgeUSA

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