Biotinylated polyurethane-urea nanoparticles for targeted theranostics in human hepatocellular carcinoma
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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.
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Biotinylated polyurethane-urea nanoparticles for targeted theranostics in human hepatocellular carcinoma
)
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.
References(42)
Brannon-Peppas, L.; Blanchette, J.O. Nanoparticle and targeted systems for cancer therapy. Adv. Drug. Deliver. Rev. 2004, 56, 1649–1659.
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.
Morral-Ruíz, G.; Melgar-Lesmes, P.; Solans, C.; GarcíaCelma, 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.
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.
Moghimi, S. M.; Hunter, A. C.; Murray, J. C. Long- circulating and target-specific nanoparticles: Theory to practice. Pharmacol. Rev. 2001, 53, 283–318.
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.
Brannon-Peppas, L.; Blanchette, J. O. Nanoparticle and targeted systems for cancer therapy. Adv. Drug. Deliver. Rev. 2012, 64, 206–212.
Blanpain, C. Tracing the cellular origin of cancer. Nat. Cell. Biol. 2013, 15, 126–134.
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.
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.
Zempleni, J. Uptake, localization, and noncarboxylase roles of biotin. Annu. Rev. Nutr. 2005, 25, 175–196.
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.
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.
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.
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.
Forner, A.; Llovet, J. M.; Bruix, J. Hepatocellular carcinoma. Lancet 2012, 379, 1245–1255.
Lu, C. H.; Willner, B.; Willner, I. DNA nanotechnology: From sensing and DNA machines to drug-delivery systems. ACS Nano 2013, 7, 8320–8332.
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.
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.
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.
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.
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.
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.
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.
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.
Melgar-Lesmes, P.; Morral-Ruíz, G.; Solans, C.; GarcíaCelma, M. J. Quantifying the bioadhesive properties of surface-modified polyurethane-urea nanoparticles in the vascular network. Colloids Surf. B 2014, 118, 280–288.
Vonarbourg, A.; Passirani, C.; Saulnier, P.; Benoit, J. P. Parameters influencing the stealthiness of colloidal drug delivery Systems. Biomaterials 2006, 27, 4356–4373.
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.
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.
Ferrari, M. Cancer nanotechnology: Opportunities and challenges. Nat. Rev. Cancer 2005, 5, 161–171.
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.
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.
Kaneda, Y. Virosome: A novel vector to enable multi-modal strategies for cancer therapy. Adv. Drug Deliv. Rev. 2012, 64, 730–738.
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.
Gan, H. K.; Seruga, B.; Knox, J. J. Sunitinib in solid tumors. Expert Opin. Investig. Drugs. 2009, 18, 821–834.
Killock, D. Kidney cancer: Sunitinib has similar efficacy irrespective of age in mRCC. Nat. Rev. Clin. Oncol. 2014, 11, 122.
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.
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.
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.
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.
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.
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.
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Acknowledgements
The authors wish to acknowledge the sponsorship of the Spanish Ministry of Education and Science, DGI (CTQ 2011-29336-C03/PPQ), "Generalitat de Catalunya" DURSI (Grant 2009 SGR-961) and CIBER-BBN. CIBER- BBN is an initiative funded by the VI National R & D & i Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fundation.
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