Designing Nanoconjugates to Effectively Target Pancreatic Cancer Cells In Vitro and In Vivo

Background Pancreatic cancer is the fourth leading cause of cancer related deaths in America. Monoclonal antibodies are a viable treatment option for inhibiting cancer growth. Tumor specific drug delivery could be achieved utilizing these monoclonal antibodies as targeting agents. This type of designer therapeutic is evolving and with the use of gold nanoparticles it is a promising approach to selectively deliver chemotherapeutics to malignant cells. Gold nanoparticles (GNPs) are showing extreme promise in current medicinal research. GNPs have been shown to non-invasively kill tumor cells by hyperthermia using radiofrequency. They have also been implemented as early detection agents due to their unique X-ray contrast properties; success was revealed with clear delineation of blood capillaries in a preclinical model by CT (computer tomography). The fundamental parameters for intelligent design of nanoconjugates are on the forefront. The goal of this study is to define the necessary design parameters to successfully target pancreatic cancer cells. Methodology/Principal Findings The nanoconjugates described in this study were characterized with various physico-chemical techniques. We demonstrate that the number of cetuximab molecules (targeting agent) on a GNP, the hydrodynamic size of the nanoconjugates, available reactive surface area and the ability of the nanoconjugates to sequester EGFR (epidermal growth factor receptor), all play critical roles in effectively targeting tumor cells in vitro and in vivo in an orthotopic model of pancreatic cancer. Conclusion Our results suggest the specific targeting of tumor cells depends on a number of crucial components 1) targeting agent to nanoparticle ratio 2) availability of reactive surface area on the nanoparticle 3) ability of the nanoconjugate to bind the target and 4) hydrodynamic diameter of the nanoconjugate. We believe this study will help define the design parameters for formulating better strategies for specifically targeting tumors with nanoparticle conjugates.

[1]  M. McNiven,et al.  A novel endocytic mechanism of epidermal growth factor receptor sequestration and internalization. , 2006, Cancer research.

[2]  R. Stafford,et al.  Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[3]  D. Astruc,et al.  Gold nanoparticles: assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology. , 2004, Chemical reviews.

[4]  H. Lane,et al.  ERBB Receptors and Cancer: The Complexity of Targeted Inhibitors , 2005, Nature Reviews Cancer.

[5]  Chitta Ranjan Patra,et al.  Attaching folic acid on gold nanoparticles using noncovalent interaction via different polyethylene glycol backbones and targeting of cancer cells , 2007 .

[6]  Nanoconjugation modulates the trafficking and mechanism of antibody-induced receptor endocytosis. , 2011, Nanomedicine.

[7]  Chitta Ranjan Patra,et al.  Fabrication of gold nanoparticles for targeted therapy in pancreatic cancer. , 2010, Advanced drug delivery reviews.

[8]  Chitta Ranjan Patra,et al.  Intracellular gold nanoparticles enhance non-invasive radiofrequency thermal destruction of human gastrointestinal cancer cells , 2008, Journal of nanobiotechnology.

[9]  Wolfgang A. Weber,et al.  Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging , 2007, Proceedings of the National Academy of Sciences.

[10]  Petra Krystek,et al.  Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. , 2008, Biomaterials.

[11]  M. El-Sayed,et al.  Chemistry and properties of nanocrystals of different shapes. , 2005, Chemical reviews.

[12]  S. Maiti,et al.  Molecular Effects of Uptake of Gold Nanoparticles in HeLa Cells , 2007, Chembiochem : a European journal of chemical biology.

[13]  Priyabrata Mukherjee,et al.  Biological properties of "naked" metal nanoparticles. , 2008, Advanced drug delivery reviews.

[14]  Ludovic Jullien,et al.  Synthesis and properties of water-soluble gold colloids covalently derivatized with neutral polymer monolayers. , 2002, Journal of the American Chemical Society.

[15]  Stan W. Casteel,et al.  Bombesin functionalized gold nanoparticles show in vitro and in vivo cancer receptor specificity , 2010, Proceedings of the National Academy of Sciences.

[16]  Hak Soo Choi,et al.  Design considerations for tumour-targeted nanoparticles. , 2010, Nature nanotechnology.

[17]  Michael J Yaszemski,et al.  Potential therapeutic application of gold nanoparticles in B-chronic lymphocytic leukemia (BCLL): enhancing apoptosis , 2007, Journal of nanobiotechnology.

[18]  Keishiro Tomoda,et al.  Biodistribution of colloidal gold nanoparticles after intravenous administration: effect of particle size. , 2008, Colloids and surfaces. B, Biointerfaces.

[19]  M. El-Sayed,et al.  Nuclear targeting of gold nanoparticles in cancer cells induces DNA damage, causing cytokinesis arrest and apoptosis. , 2010, Journal of the American Chemical Society.

[20]  J F Hainfeld,et al.  Gold nanoparticles: a new X-ray contrast agent. , 2006, The British journal of radiology.

[21]  Ulrik B Nielsen,et al.  Anti-HER2 immunoliposomes: enhanced efficacy attributable to targeted delivery. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  Chitta Ranjan Patra,et al.  Gold Nanoparticles Inhibit the Proliferation of Multiple Myeloma Cells , 2007 .

[23]  M. K. Brennaman,et al.  Critical flocculation concentrations, binding isotherms, and ligand exchange properties of peptide-modified gold nanoparticles studied by UV-visible, fluorescence, and time-correlated single photon counting spectroscopies. , 2003, Analytical chemistry.

[24]  D. Mukhopadhyay,et al.  Effect of Rapamycin Alone and in Combination with Antiangiogenesis Therapy in an Orthotopic Model of Human Pancreatic Cancer , 2004, Clinical Cancer Research.

[25]  D. Mukhopadhyay,et al.  Targeted delivery of gemcitabine to pancreatic adenocarcinoma using cetuximab as a targeting agent. , 2008, Cancer research.

[26]  Vincent M Rotello,et al.  Functionalized gold nanoparticles for drug delivery. , 2007, Nanomedicine.

[27]  R. Singal,et al.  EGFR targeting of solid tumors. , 2007, Cancer control : journal of the Moffitt Cancer Center.

[28]  Mark E. Davis,et al.  Mechanism of active targeting in solid tumors with transferrin-containing gold nanoparticles , 2009, Proceedings of the National Academy of Sciences.

[29]  Xiaohua Huang,et al.  Gold nanoparticles surface plasmon field effects on the proton pump process of the bacteriorhodopsin photosynthesis. , 2009, Journal of the American Chemical Society.

[30]  P. Jeffrey,et al.  Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. , 2005, Cancer cell.

[31]  Lauren A Austin,et al.  Dynamic light scattering as a powerful tool for gold nanoparticle bioconjugation and biomolecular binding studies. , 2009, Analytical chemistry.

[32]  M. Ferrari.  Cancer nanotechnology: opportunities and challenges , 2005, Nature Reviews Cancer.

[33]  G. Whitesides.  The 'right' size in nanobiotechnology , 2003, Nature Biotechnology.

[34]  James L. McGrath,et al.  The influence of protein adsorption on nanoparticle association with cultured endothelial cells. , 2009, Biomaterials.

[35]  Warren C W Chan,et al.  Mediating tumor targeting efficiency of nanoparticles through design. , 2009, Nano letters.

[36]  Ling Wang,et al.  Antiangiogenic Properties of Gold Nanoparticles , 2005, Clinical Cancer Research.

[37]  H. Scher,et al.  Anti-epidermal growth factor receptor monoclonal antibody cetuximab plus Doxorubicin in the treatment of metastatic castration-resistant prostate cancer. , 2009, Clinical genitourinary cancer.

[38]  G. Carpenter,et al.  Cetuximab/C225-induced intracellular trafficking of epidermal growth factor receptor. , 2009, Cancer research.

[39]  G. Mills,et al.  Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximab. , 2007, Cancer research.

[40]  J. Mendelsohn,et al.  The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression , 2005, Oncogene.

[41]  M. El-Sayed,et al.  Photocatalysis in gold nanocage nanoreactors. , 2009, The journal of physical chemistry. A.

[42]  T. Libermann,et al.  Biological role of epidermal growth factor-receptor clustering. Investigation with monoclonal anti-receptor antibodies. , 1983, The Journal of biological chemistry.