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Research Article

Targeting pancreatic cancer with magneto-fluorescent theranostic gold nanoshells

    Wenxue Chen

    Division of Molecular Imaging, Department of Radiology, Baylor College of Medicine, Mail: BCM 360, One Baylor Plaza, Houston, TX 77030, USA and Department of Diagnostic Imaging, The Fourth Hospital of Hebei Medical University/Hebei Province Tumor Hospital, 12 Jiankang Road, Shijiazhuang, Hebei Province 050011, China

    Authors contributed equally

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    ,
    Ciceron Ayala-Orozco

    Department of Chemistry, Rice University, 6100 Main Street, Houston, TX 77005, USA

    Authors contributed equally

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    ,
    Nrusingh C Biswal

    Division of Molecular Imaging, Department of Radiology, Baylor College of Medicine, Mail: BCM 360, One Baylor Plaza, Houston, TX 77030, USA

    ,
    Carlos Perez-Torres

    Department of Molecular Physiology & Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

    ,
    Marc Bartels

    Division of Molecular Imaging, Department of Radiology, Baylor College of Medicine, Mail: BCM 360, One Baylor Plaza, Houston, TX 77030, USA

    ,
    Rizia Bardhan

    Department of Chemistry, Rice University, 6100 Main Street, Houston, TX 77005, USA

    ,
    Gary Stinnet

    Department of Molecular Physiology & Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

    ,
    Xian-De Liu

    Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA

    ,
    Baoan Ji

    Department of Biochemistry & Molecular Biology, Guggenheim 13-21B. Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

    ,
    Amit Deorukhkar

    Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA

    ,
    Lisa V Brown

    Department of Chemistry, Rice University, 6100 Main Street, Houston, TX 77005, USA

    ,
    Sushovan Guha

    Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA

    ,
    Robia G Pautler

    Department of Molecular Physiology & Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

    ,
    Sunil Krishnan

    Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA

    ,
    Naomi J Halas

    Department of Chemistry, Rice University, 6100 Main Street, Houston, TX 77005, USA and Department of Electrical & Computer Engineering, Rice University, 6100 Main Street, Houston, TX 77005, USA

    &
    Amit Joshi

    * Author for correspondence:

    E-mail Address: amitj@bcm.edu

    Division of Molecular Imaging, Department of Radiology, Baylor College of Medicine, Mail: BCM 360, One Baylor Plaza, Houston, TX 77030, USA

    Published Online:https://doi.org/10.2217/nnm.13.84

    Aim: We report a magneto-fluorescent theranostic nanocomplex targeted to neutrophil gelatinase-associated lipocalin (NGAL) for imaging and therapy of pancreatic cancer. Materials & methods: Gold nanoshells resonant at 810 nm were encapsulated in silica epilayers doped with iron oxide and the near-infrared (NIR) dye indocyanine green, resulting in theranostic gold nanoshells (TGNS), which were subsequently conjugated with antibodies targeting NGAL in AsPC-1-derived xenografts in nude mice. Results: Anti-NGAL-conjugated TGNS specifically targeted pancreatic cancer cells in vitro and in vivo providing contrast for both NIR fluorescence and T2-weighted MRI with higher tumor contrast than can be obtained using long-circulating, but nontargeted, PEGylated nanoparticles. The nanocomplexes also enabled highly specific cancer cell death via NIR photothermal therapy in vitro. Conclusion: TGNS with embedded NIR and magnetic resonance contrasts can be specifically targeted to pancreatic cancer cells with expression of early disease marker NGAL, and enable molecularly targeted imaging and photothermal therapy.

    Original submitted 6 November 2012; Revised submitted 25 March 2013

    Papers of special note have been highlighted as: • of interest

    References

    • Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J. Clin.58(2),71–96 (2008).
    • Sener SF, Fremgen A, Menck HR, Winchester DP. Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985–1995, using the national cancer database. J. Am. Coll. Surg.189(1),1–7 (1999).
    • Krishnan S, Rana V, Janjan NA et al. Prognostic factors in patients with unresectable locally advanced pancreatic adenocarcinoma treated with chemoradiation. Cancer107(11),2589–2596 (2006).
    • Krishnan S, Rana V, Janjan NA et al. Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer110(1),47–55 (2007).
    • Bafna S, Kaur S, Momi N, Batra SK. Pancreatic cancer cells resistance to gemcitabine: the role of muc4 mucin. Brit. J. Cancer101(7),1155–1161 (2009).
    • Yang L, Mao H, Cao Z et al. Molecular imaging of pancreatic cancer in an animal model using targeted multifunctional nanoparticles. Gastroenterology136(5),1514.e2–1525.e2 (2009).
    • Chen Y, Bathula SR, Li J, Huang L. Multifunctional nanoparticles delivering small interfering RNA and doxorubicin overcome drug resistance in cancer. J. Biol. Chem.285(29),22639–22650 (2010).
    • Gultepe E, Reynoso FJ, Jhaveri A et al. Monitoring of magnetic targeting to tumor vasculature through MRI and biodistribution. Nanomedicine (Lond.)5(8),1173–1182 (2010).
    • Dreaden EC, MacKey MA, Huang X, Kang B, El-Sayed MA. Beating cancer in multiple ways using nanogold. Chem. Soc. Rev.40(7),3391–3404 (2011).• Gold nanoparticle-mediated therapy.
    • 10  Bardhan R, Lal S, Joshi A, Halas NJ. Theranostic nanoshells: from probe design to imaging and treatment of cancer. Accounts Chem. Res.44(10),936–946 (2011).• Gold nanoshell synthesis and imaging contrast engineering.
    • 11  Chen W, Bardhan R, Bartels M et al. A molecularly targeted theranostic probe for ovarian cancer. Mol. Cancer Ther.9(4),1028–1038 (2010).
    • 12  Bardhan R, Chen W, Bartels M et al. Tracking of multimodal therapeutic nanocomplexes targeting breast cancer in vivo. Nano Lett.10(12),4920–4928 (2010).
    • 13  Bardhan R, Chen W, Perez-Torres C et al. Nanoshells with targeted simultaneous enhancement of magnetic and optical imaging and photothermal therapeutic response. Adv. Func. Mater.19(24),3901–3909 (2009).• Magneto-fluorescent gold nanoshells.
    • 14  Argani P, Rosty C, Reiter RE et al. Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma. Cancer Res.61(11),4320–4324 (2001).
    • 15  Han H, Bearss DJ, Browne LW, Calaluce R, Nagle RB, Von Hoff DD. Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res.62(10),2890–2896 (2002).
    • 16  Iacobuzio-Donahue CA, Ashfaq R, Maitra A et al. Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. Cancer Res.63(24),8614–8622 (2003).
    • 17  Laurell H, Bouisson M, Berthelémy P et al. Identification of biomarkers of human pancreatic adenocarcinomas by expression profiling and validation with gene expression analysis in endoscopic ultrasound-guided fine needle aspiration samples. World J. Gastroenterol.12(21),3344–3351 (2006).
    • 18  Missiaglia E, Blaveri E, Terris B et al. Analysis of gene expression in cancer cell lines identifies candidate markers for pancreatic tumorigenesis and metastasis. Int. J. Cancer112(1),100–112 (2004).
    • 19  Moniaux N, Chakraborty S, Yalniz M et al. Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia. Brit. J. Cancer98(9),1540–1547 (2008).• Clinical validation of neutrophil gelatinase-associated lipocalin as an early pancreatic cancer diagnostic marker.
    • 20  Furutani M, Arii S, Mizumoto M, Kato M, Imamura M. Identification of a neutrophil gelatinase-associated lipocalin mRNA in human pancreatic cancers using a modified signal sequence trap method. Cancer Lett.122(1–2),209–214 (1998).
    • 21  Tong Z, Kunnumakkara AB, Wang H et al. Neutrophil gelatinase-associated lipocalin: a novel suppressor of invasion and angiogenesis in pancreatic cancer. Cancer Res.68(15),6100–6108 (2008).
    • 22  Roy R, Louis G, Loughlin KR et al. Tumor-specific urinary matrix metalloproteinase fingerprinting: identification of high molecular weight urinary matrix metalloproteinase species. Clin. Cancer Res.14(20),6610–6617 (2008).
    • 23  Iannetti A, Pacifico F, Acquaviva R et al. The neutrophil gelatinase-associated lipocalin (NGAL), a NF-κB-regulated gene, is a survival factor for thyroid neoplastic cells. Proc. Natl Acad. Sci. USA105(37),14058–14063 (2008).
    • 24  Lim R, Ahmed N, Borregaard N et al. Neutrophil gelatinase-associated lipocalin (NGAL) an early-screening biomarker for ovarian cancer: NGAL is associated with epidermal growth factor-induced epithelio-mesenchymal transition. Int. J. Cancer120(11),2426–2434 (2007).
    • 25  Hu L, Hittelman W, Lu T et al. NGAL decreases E-cadherin-mediated cell–cell adhesion and increases cell motility and invasion through Rac1 in colon carcinoma cells. Lab. Invest.89(5),531–548 (2009).
    • 26  Yang J, Bielenberg DR, Rodig SJ et al. Lipocalin 2 promotes breast cancer progression. Proc. Natl Acad. Sci. USA106(10),3913–3918 (2009).
    • 27  Leng X, Ding T, Lin H et al. Inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis. Cancer Res.69(22),8579–8584 (2009).
    • 28  Hwang K, Houston JP, Rasmussen JC et al. Improved excitation light rejection enhances small-animal fluorescent optical imaging. Mol. Imaging4(3),194–204 (2005).
    • 29  Gad SC, Sharp KL, Montgomery C, Payne JD, Goodrich GP. Evaluation of the toxicity of intravenous delivery of auroshell particles (gold–silica nanoshells). Int. J. Toxicol.31(6),584–594 (2012).
    • 30  Terentyuk GS, Maslyakova GN, Suleymanova LV et al. Circulation and distribution of gold nanoparticles and induced alterations of tissue morphology at intravenous particle delivery. J. Biophotonics2(5),292–302 (2009).
    • 31  James WD, Hirsch LR, West JL, O’Neal PD, Payne JD. Application of INAA to the build-up and clearance of gold nanoshells in clinical studies in mice. J. Radioanal. Nucl. Chem.271(2),455–459 (2007).
    • 32  Sengelov H, Boulay F, Kjeldsen L, Borregaard N. Subcellular localization and translocation of the receptor for N-formylmethionyl-leucyl-phenylalanine in human neutrophils. Biochem. J.299(2),473–479 (1994).
    • 33  Nielsen BS, Borregaard N, Bundgaard JR, Timshel S, Sehested M, Kjeldsen L. Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases. Gut38(3),414–420 (1996).
    • 34  Bratt T, Ohlson S, Borregaard N. Interactions between neutrophil gelatinase-associated lipocalin and natural lipophilic ligands. Biochim. Biophys. Acta1472(1–2),262–269 (1999).
    • 35  Schmidt-Ott KM, Mori K, Jau YL et al. Dual action of neutrophil gelatinase-associated lipocalin. J. Am. Soc. Nephrol.18(2),407–413 (2007).
    • 36  Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Invest.94(6),2493–2503 (1994).
    • 37  Gough PJ, Gomez IG, Wille PT, Raines EW. Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. J. Clin. Invest.116(1),59–69 (2006).
    • 38  Loftus IM, Naylor AR, Goodall S et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques: a potential role in acute plaque disruption. Stroke31(1),40–47 (2000).
    • 39  Te Boekhorst BC, Bovens SM, Hellings WE et al. Molecular MRI of murine atherosclerotic plaque targeting NGAL: a protein associated with unstable human plaque characteristics. Cardiovascular Res.89(3),680–688 (2011).
    • 40  Ghaneh P, Costello E, Neoptolemos JP. Biology and management of pancreatic cancer. Postgrad. Med. J.84(995),478–497 (2008).
    • 41  Schwartzberg AM, Olson TY, Talley CE, Zhang JZ. Synthesis, characterization, and tunable optical properties of hollow gold nanospheres. J. Phys. Chem. B110(40),19935–19944 (2006).
    • 42  Bardhan R, Mukherjee S, Mirin NA, Levit SD, Nordlander P, Halas NJ. Nanosphere-in-a-nanoshell: a simple nanomatryushka. J. Phys. Chem. C114(16),7378–7383 (2010).