Dendrimer-entrapped gold nanoparticles as potential CT contrast agents for blood pool imaging

The purpose of this study was to evaluate dendrimer-entrapped gold nanoparticles [Au DENPs] as a molecular imaging [MI] probe for computed tomography [CT]. Au DENPs were prepared by complexing AuCl4- ions with amine-terminated generation 5 poly(amidoamine) [G5.NH2] dendrimers. Resulting particles were sized using transmission electron microscopy. Serial dilutions (0.001 to 0.1 M) of either Au DENPs or iohexol were scanned by CT in vitro. Based on these results, Au DENPs were injected into mice, either subcutaneously (10 μL, 0.007 to 0.02 M) or intravenously (300 μL, 0.2 M), after which the mice were imaged by micro-CT or a standard mammography unit. Au DENPs prepared using G5.NH2 dendrimers as templates are quite uniform and have a size range of 2 to 4 nm. At Au concentrations above 0.01 M, the CT value of Au DENPs was higher than that of iohexol. A 10-μL subcutaneous dose of Au DENPs with [Au] ≥ 0.009 M could be detected by micro-CT. The vascular system could be imaged 5 and 20 min after injection of Au DENPs into the tail vein, and the urinary system could be imaged after 60 min. At comparable time points, the vascular system could not be imaged using iohexol, and the urinary system was imaged only indistinctly. Findings from this study suggested that Au DENPs prepared using G5.NH2 dendrimers as templates have good X-ray attenuation and a substantial circulation time. As their abundant surface amine groups have the ability to bind to a range of biological molecules, Au DENPs have the potential to be a useful MI probe for CT.

[1]  R. Shukla,et al.  Biocompatibility of gold nanoparticles and their endocytotic fate inside the cellular compartment: a microscopic overview. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[2]  J. West,et al.  Immunotargeted nanoshells for integrated cancer imaging and therapy. , 2005, Nano letters.

[3]  T L Chenevert,et al.  Magnetic resonance angiography with gadomer-17. An animal study original investigation. , 1998, Investigative radiology.

[4]  Xiangyang Shi,et al.  Acetylation of dendrimer-entrapped gold and silver nanoparticles , 2008 .

[5]  Rui Guo,et al.  X-ray Attenuation Property of Dendrimer-Entrapped Gold Nanoparticles , 2010 .

[6]  Jing Lin,et al.  Protein-directed one-pot synthesis of Ag microspheres with good biocompatibility and enhancement of radiation effects on gastric cancer cells. , 2011, Nanoscale.

[7]  S. Gambhir,et al.  Molecular imaging in living subjects: seeing fundamental biological processes in a new light. , 2003, Genes & development.

[8]  Thommey P. Thomas,et al.  PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality. , 2006, Biomacromolecules.

[9]  J. H. Hubbell,et al.  Tables of X-Ray Mass Attenuation Coefficients and Mass Energy-Absorption Coefficients 1 keV to 20 MeV for Elements Z = 1 to 92 and 48 Additional Substances of Dosimetric Interest , 1995 .

[10]  Chenjie Xu,et al.  Size and Concentration Effect of Gold Nanoparticles on X-ray Attenuation As Measured on Computed Tomography. , 2008, Chemistry of materials : a publication of the American Chemical Society.

[11]  J. Hainfeld,et al.  The use of gold nanoparticles to enhance radiotherapy in mice. , 2004, Physics in medicine and biology.

[12]  Claudia Calcagno,et al.  Nanocrystal core high-density lipoproteins: a multimodality contrast agent platform. , 2008, Nano letters.

[13]  G. Tromba,et al.  Synchrotron-based in vivo tracking of implanted mammalian cells. , 2008, European journal of radiology.

[14]  M Geso,et al.  Gold nanoparticles: a new X-ray contrast agent. , 2007, The British journal of radiology.

[15]  James R Baker,et al.  Dendrimer-entrapped gold nanoparticles as a platform for cancer-cell targeting and imaging. , 2007, Small.

[16]  Tristan Barrett,et al.  Macromolecular MRI contrast agents for imaging tumor angiogenesis. , 2006, European journal of radiology.

[17]  C. Murphy,et al.  Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. , 2005, Small.

[18]  Haixia Wu,et al.  Synthesis of ultrasmall nucleotide-functionalized superparamagnetic γ-Fe2O3 nanoparticles , 2011 .

[19]  Xiangyang Shi,et al.  Improved biocompatibility of surface functionalized dendrimer-entrapped gold nanoparticles. , 2006, Soft matter.

[20]  M. Brechbiel,et al.  Pharmacokinetics and enhancement patterns of macromolecular MR contrast agents with various sizes of polyamidoamine dendrimer cores , 2001, Magnetic resonance in medicine.

[21]  Hisataka Kobayashi,et al.  Nano-sized MRI contrast agents with dendrimer cores. , 2005, Advanced drug delivery reviews.

[22]  K. Sun,et al.  Characterization of crystalline dendrimer-stabilized gold nanoparticles , 2006 .

[23]  R. Weissleder,et al.  A DNA-binding Gd chelate for the detection of cell death by MRI. , 2009, Chemical communications.

[24]  R. Weissleder.  Molecular imaging: exploring the next frontier. , 1999, Radiology.

[25]  Daxiang Cui,et al.  Dual Phase‐Controlled Synthesis of Uniform Lanthanide‐Doped NaGdF4 Upconversion Nanocrystals Via an OA/Ionic Liquid Two‐Phase System for In Vivo Dual‐Modality Imaging , 2011 .

[26]  Jing Lin,et al.  Photosensitizer-conjugated magnetic nanoparticles for in vivo simultaneous magnetofluorescent imaging and targeting therapy. , 2011, Biomaterials.

[27]  Kan Wang,et al.  Electrochemical Property and Cell Toxicity of Gold Electrode Modified by Monolayer PAMAM Encapsulated Gold Nanorods , 2010 .

[28]  Changxiao Liu.  Research and Development of Nanopharmaceuticals in China , 2009 .

[29]  Seungpyo Hong,et al.  Interaction of poly(amidoamine) dendrimers with supported lipid bilayers and cells: hole formation and the relation to transport. , 2004, Bioconjugate chemistry.

[30]  Rakesh K. Jain,et al.  Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors , 2004, Cancer Research.

[31]  Harvey R Herschman,et al.  Molecular Imaging: Looking at Problems, Seeing Solutions , 2003, Science.

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

[33]  Sangjin Park,et al.  Antibiofouling polymer-coated gold nanoparticles as a contrast agent for in vivo X-ray computed tomography imaging. , 2007, Journal of the American Chemical Society.

[34]  Feng Gao,et al.  RGD-conjugated dendrimer-modified gold nanorods for in vivo tumor targeting and photothermal therapy. , 2010, Molecular pharmaceutics.

[35]  Mingwu Shen,et al.  Enhanced X-ray attenuation property of dendrimer-entrapped gold nanoparticles complexed with diatrizoic acid , 2011 .

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

[37]  Raoul Kopelman,et al.  Targeted gold nanoparticles enable molecular CT imaging of cancer. , 2008, Nano letters.

[38]  Nengqin Jia,et al.  Gold Nanorods Coated with Multilayer Polyelectrolyte as Intracellular delivery Vector of Antisense Oligonucleotides , 2010 .

[39]  Lisa Brannon-Peppas,et al.  Active targeting schemes for nanoparticle systems in cancer therapeutics. , 2008, Advanced drug delivery reviews.

[40]  Kan Wang,et al.  Optical properties and catalytic activity of bimetallic gold-silver nanoparticles , 2010 .

[41]  F. Guillemin,et al.  Quantum dots en chirurgie oncologique : un rôle d’avenir pour le marquage des berges d’exérèse ? , 2008 .

[42]  Chitta Ranjan Patra,et al.  Noninvasive radiofrequency field-induced hyperthermic cytotoxicity in human cancer cells using cetuximab-targeted gold nanoparticles. , 2008, Journal of experimental therapeutics & oncology.