Targeting pancreatic cancer with magneto-fluorescent theranostic gold nanoshells.

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.

[1]  Mostafa A. El-Sayed,et al.  Beating cancer in multiple ways using nanogold. , 2011, Chemical Society reviews.

[2]  A. Naylor,et al.  Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption. , 2000, Stroke.

[3]  A. Leonardi,et al.  The neutrophil gelatinase-associated lipocalin (NGAL), a NF-κB-regulated gene, is a survival factor for thyroid neoplastic cells , 2008, Proceedings of the National Academy of Sciences.

[4]  M. Goumans,et al.  Molecular MRI of murine atherosclerotic plaque targeting NGAL: a protein associated with unstable human plaque characteristics. , 2011, Cardiovascular research.

[5]  Philippe C. Besse,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. , 2006, World journal of gastroenterology.

[6]  P. Libby,et al.  Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. , 1994, The Journal of clinical investigation.

[7]  S. Ohlson,et al.  Interactions between neutrophil gelatinase-associated lipocalin and natural lipophilic ligands. , 1999, Biochimica et biophysica acta.

[8]  Robia G. Pautler,et al.  Tracking of multimodal therapeutic nanocomplexes targeting breast cancer in vivo. , 2010, Nano letters.

[9]  Naomi J Halas,et al.  Theranostic nanoshells: from probe design to imaging and treatment of cancer. , 2011, Accounts of chemical research.

[10]  L. Kjeldsen,et al.  Subcellular localization and translocation of the receptor for N-formylmethionyl-leucyl-phenylalanine in human neutrophils. , 1994, The Biochemical journal.

[11]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[12]  Jun Li,et al.  Multifunctional Nanoparticles Delivering Small Interfering RNA and Doxorubicin Overcome Drug Resistance in Cancer* , 2010, The Journal of Biological Chemistry.

[13]  Susan M. Kilroy,et al.  Tumor-Specific Urinary Matrix Metalloproteinase Fingerprinting: Identification of High Molecular Weight Urinary Matrix Metalloproteinase Species , 2008, Clinical Cancer Research.

[14]  E. Raines,et al.  Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. , 2005, The Journal of clinical investigation.

[15]  M. Mizumoto,et al.  Identification of a neutrophil gelatinase-associated lipocalin mRNA in human pancreatic cancers using a modified signal sequence trap method. , 1998, Cancer letters.

[16]  Valery V Tuchin,et al.  Circulation and distribution of gold nanoparticles and induced alterations of tissue morphology at intravenous particle delivery , 2009, Journal of biophotonics.

[17]  Robia G. Pautler,et al.  Nanoshells with Targeted Simultaneous Enhancement of Magnetic and Optical Imaging and Photothermal Therapeutic Response , 2009 .

[18]  J. D. Payne,et al.  Application of INAA to the build-up and clearance of gold nanoshells in clinical studies in mice , 2007 .

[19]  L. Pusztai,et al.  Inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis. , 2009, Cancer research.

[20]  Naomi J Halas,et al.  A Molecularly Targeted Theranostic Probe for Ovarian Cancer , 2010, Molecular Cancer Therapeutics.

[21]  Douglas B. Evans,et al.  Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy , 2007, Cancer.

[22]  B. Aggarwal,et al.  Neutrophil gelatinase-associated lipocalin: a novel suppressor of invasion and angiogenesis in pancreatic cancer. , 2008, Cancer research.

[23]  G. Rice,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 , 2007, International journal of cancer.

[24]  K. Mori,et al.  Dual action of neutrophil gelatinase-associated lipocalin. , 2007, Journal of the American Society of Nephrology : JASN.

[25]  Tammy Y. Olson,et al.  Synthesis, characterization, and tunable optical properties of hollow gold nanospheres. , 2006, The journal of physical chemistry. B.

[26]  S. Nie,et al.  Molecular imaging of pancreatic cancer in an animal model using targeted multifunctional nanoparticles. , 2009, Gastroenterology.

[27]  Naomi J. Halas,et al.  Nanosphere-in-a-Nanoshell: A Simple Nanomatryushka† , 2010 .

[28]  S. Batra,et al.  Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin , 2009, British Journal of Cancer.

[29]  I. Shmulevich,et al.  NGAL decreases E-cadherin-mediated cell-cell adhesion and increases cell motility and invasion through Rac1 in colon carcinoma cells , 2009, Laboratory Investigation.

[30]  Eva M. Sevick-Muraca,et al.  Improved Excitation Light Rejection Enhances Small-Animal Fluorescent Optical Imaging , 2005, Molecular imaging.

[31]  J. Cameron,et al.  Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma. , 2001, Cancer research.

[32]  D. Winchester,et al.  Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database. , 1999, Journal of the American College of Surgeons.

[33]  Glenn P. Goodrich,et al.  Evaluation of the Toxicity of Intravenous Delivery of Auroshell Particles (Gold–Silica Nanoshells) , 2012, International journal of toxicology.

[34]  P Ghaneh,et al.  Biology and management of pancreatic cancer , 2008, Postgraduate Medical Journal.

[35]  Christine A Iacobuzio-Donahue,et al.  Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. , 2003, Cancer research.

[36]  D. Zurakowski,et al.  Lipocalin 2 promotes breast cancer progression , 2009, Proceedings of the National Academy of Sciences.

[37]  Haiyong Han,et al.  Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. , 2002, Cancer research.

[38]  S. Batra,et al.  Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia , 2008, British Journal of Cancer.

[39]  Eithne Costello,et al.  Analysis of gene expression in cancer cell lines identifies candidate markers for pancreatic tumorigenesis and metastasis , 2004, International journal of cancer.

[40]  P. Kulkarni,et al.  Monitoring of magnetic targeting to tumor vasculature through MRI and biodistribution. , 2010, Nanomedicine.

[41]  Douglas B. Evans,et al.  Prognostic factors in patients with unresectable locally advanced pancreatic adenocarcinoma treated with chemoradiation , 2006, Cancer.

[42]  B. Nielsen,et al.  Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases. , 1996, Gut.