Development and haematotoxicological evaluation of doped hydroxyapatite based multimodal nanocontrast agent for near-infrared, magnetic resonance and X-ray contrast imaging

Abstract Multimodal molecular imaging provides both anatomical and molecular information, aiding early stage detection and better treatment planning of diseased conditions. Here, we report development and nanotoxicity evaluation of a novel hydroxyapatite nanoparticle (nHAp) based multimodal contrast agent for combined near-infrared (NIR), MR and X-ray imaging. Under optimised wet-chemical conditions, we achieved simultaneous doping of nHAp (size ∼50 nm) with indocyanine green and Gd3+ contributing to NIR contrast (∼750–850 nm), paramagnetic behaviour and X-ray absorption suitable for NIR, MR and X-ray contrast imaging, respectively. Haematocompatibility studies using stem cell viability, haemolysis, platelet activation, platelet aggregation and coagulation time analysis indicated excellent compatibility of doped nHAp (D-nHAp). Further, the immunogenic function studies using human lymphocytes (in vitro) showed that D-nHAp caused no adverse effects. Collectively, our studies suggest that D-nHAp with excellent biocompatibility and multifunctional properties is a promising nanocontrast agent for combined NIR, MR and X-ray imaging applications.

[1]  Ralph Weissleder,et al.  Optical and Multimodality Molecular Imaging: Insights Into Atherosclerosis , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[2]  V. Grassian,et al.  Inflammatory response of mice following inhalation exposure to iron and copper nanoparticles , 2008 .

[3]  Weili Lin,et al.  Self-assembled hybrid nanoparticles for cancer-specific multimodal imaging. , 2007, Journal of the American Chemical Society.

[4]  Frank J Rybicki,et al.  Biochemical safety profiles of gadolinium‐based extracellular contrast agents and nephrogenic systemic fibrosis , 2007, Journal of magnetic resonance imaging : JMRI.

[5]  Jung Ho Yu,et al.  Designed Fabrication of a Multifunctional Polymer Nanomedical Platform for Simultaneous Cancer‐ Targeted Imaging and Magnetically Guided Drug Delivery , 2008 .

[6]  Douglas L. Vizard,et al.  Analytical radiography for planar radiographic images implemented with a multi-modal system , 2010, Comput. Methods Programs Biomed..

[7]  Ruth Duncan,et al.  Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation , 2004, Nature Biotechnology.

[8]  Dhermendra K. Tiwari,et al.  Dose-dependent in-vivo toxicity assessment of silver nanoparticle in Wistar rats , 2011, Toxicology mechanisms and methods.

[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]  J. Quinn,et al.  Effect of different classes of gadolinium-based contrast agents on control and nephrogenic systemic fibrosis-derived fibroblast proliferation. , 2010, Radiology.

[11]  Mohammad A. Yaseen,et al.  Synthesis of Near-Infrared-Absorbing Nanoparticle-Assembled Capsules , 2007 .

[12]  S. Nair,et al.  A molecular receptor targeted, hydroxyapatite nanocrystal based multi-modal contrast agent. , 2010, Biomaterials.

[13]  Weihong Tan,et al.  Synthesis and Characterization of Fluorescent, Radio‐Opaque, and Paramagnetic Silica Nanoparticles for Multimodal Bioimaging Applications , 2005 .

[14]  James H. Adair,et al.  Bioconjugation of calcium phosphosilicate composite nanoparticles for selective targeting of human breast and pancreatic cancers in vivo. , 2010, ACS nano.

[15]  Klaas Nicolay,et al.  Quantum dots with a paramagnetic coating as a bimodal molecular imaging probe. , 2006, Nano letters.

[16]  N. McKeown,et al.  The influence of surface modification on the cytotoxicity of PAMAM dendrimers. , 2003, International journal of pharmaceutics.

[17]  T. Albrecht,et al.  Gadolinium-DTPA as X-ray contrast medium in clinical studies. , 2000, The British journal of radiology.

[18]  S. Mordon,et al.  A Preliminary Study of the In Vivo Behaviour of an Emulsion Formulation of Indocyanine Green , 1998, Lasers in Medical Science.

[19]  Anna Moore,et al.  In Vivo Targeting of Underglycosylated MUC-1 Tumor Antigen Using a Multimodal Imaging Probe , 2004, Cancer Research.

[20]  James H. Adair,et al.  Calcium phosphate nanocomposite particles for in vitro imaging and encapsulated chemotherapeutic drug delivery to cancer cells. , 2008, Nano letters.

[21]  Tzu-Wei Wang,et al.  A novel biomagnetic nanoparticle based on hydroxyapatite , 2007 .

[22]  James H. Adair,et al.  Encapsulation of organic molecules in calcium phosphate nanocomposite particles for intracellular imaging and drug delivery. , 2008, Nano letters.

[23]  R. Heumann,et al.  Effective transfection of cells with multi-shell calcium phosphate-DNA nanoparticles. , 2006, Biomaterials.

[24]  Huibi Xu,et al.  Protective effect of PEGylation against poly(amidoamine) dendrimer-induced hemolysis of human red blood cells. , 2010, Journal of biomedical materials research. Part B, Applied biomaterials.

[25]  M. Dobrovolskaia,et al.  Immunological properties of engineered nanomaterials , 2007, Nature Nanotechnology.

[26]  M. Morandi,et al.  Nanoparticle‐induced platelet aggregation and vascular thrombosis , 2005, British journal of pharmacology.

[27]  J. Kos,et al.  Procoagulant properties of bare and highly PEGylated vinyl-modified silica nanoparticles. , 2010, Nanomedicine.

[28]  M. Epple,et al.  Lanthanide-doped calcium phosphate nanoparticles with high internal crystallinity and with a shell of DNA as fluorescent probes in cell experiments , 2007 .

[29]  Z. Bhujwalla,et al.  Image-Guided Enzyme/Prodrug Cancer Therapy , 2008, Clinical Cancer Research.

[30]  Matthias Epple,et al.  Functionalisation of calcium phosphate nanoparticles by oligonucleotides and their application for gene silencing , 2007 .

[31]  J. Remy,et al.  Multi-detector row CT angiography of pulmonary circulation with gadolinium-based contrast agents: prospective evaluation in 60 patients. , 2006, Radiology.

[32]  D. Sinha,et al.  Role of calcium ions and the heavy chain of factor XIa in the activation of human coagulation factor IX. , 1987, Biochemistry.

[33]  M. Gelderman,et al.  Carbon nanotubes activate blood platelets by inducing extracellular Ca2+ influx sensitive to calcium entry inhibitors. , 2009, Nano letters.

[34]  John C. Rutledge,et al.  Induction of Inflammation in Vascular Endothelial Cells by Metal Oxide Nanoparticles: Effect of Particle Composition , 2006, Environmental health perspectives.

[35]  Ignacy Gryczynski,et al.  Metal-enhanced emission from indocyanine green: a new approach to in vivo imaging. , 2003, Journal of biomedical optics.

[36]  V. Patravale,et al.  Immunological effects and membrane interactions of chitosan nanoparticles. , 2009, Molecular pharmaceutics.

[37]  J. Lieske,et al.  Biologic nanoparticles and platelet reactivity. , 2009, Nanomedicine.

[38]  Christoph Abels,et al.  Absorption and Fluorescence Spectroscopic Investigation of Indocyanine Green , 1996 .

[39]  R. Weissleder,et al.  Cell-specific targeting of nanoparticles by multivalent attachment of small molecules , 2005, Nature Biotechnology.

[40]  R. Herfkens,et al.  Nephrogenic Systemic Fibrosis in Patients With Chronic Kidney Disease Who Received Gadopentetate Dimeglumine , 2009, Investigative radiology.

[41]  Weili Lin,et al.  Hybrid silica nanoparticles for multimodal imaging. , 2007, Angewandte Chemie.

[42]  Ralph Weissleder,et al.  A multimodal nanoparticle for preoperative magnetic resonance imaging and intraoperative optical brain tumor delineation. , 2003, Cancer research.

[43]  B. Nemery,et al.  Acute Toxicity and Prothrombotic Effects of Quantum Dots: Impact of Surface Charge , 2008, Environmental health perspectives.

[44]  G M Bydder,et al.  Gadolinium-DTPA as a contrast agent in MRI: initial clinical experience in 20 patients. , 1984, AJR. American journal of roentgenology.

[45]  G. Spenlehauer,et al.  Interactions of poly(lactic acid) and poly(lactic acid-co-ethylene oxide) nanoparticles with the plasma factors of the coagulation system. , 1997, Biomaterials.

[46]  S. Bhatia,et al.  Probing the Cytotoxicity Of Semiconductor Quantum Dots. , 2004, Nano letters.

[47]  J. Nagy,et al.  Discovery of a potent nanoparticle P‐selectin antagonist with anti‐inflammatory effects in allergic airway disease , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  Parag Aggarwal,et al.  Preclinical studies to understand nanoparticle interaction with the immune system and its potential effects on nanoparticle biodistribution. , 2008, Molecular pharmaceutics.

[49]  Eleonore Fröhlich,et al.  The role of nanoparticle size in hemocompatibility. , 2009, Toxicology.

[50]  K. Nicolay,et al.  Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis , 2010, Angiogenesis.

[51]  Jinwoo Cheon,et al.  Dual-mode nanoparticle probes for high-performance magnetic resonance and fluorescence imaging of neuroblastoma. , 2006, Angewandte Chemie.

[52]  M. Harboe,et al.  A method for determination of hemoglobin in plasma by near-ultraviolet spectrophotometry. , 1959, Scandinavian journal of clinical and laboratory investigation.

[53]  James H. Adair,et al.  Near-infrared emitting fluorophore-doped calcium phosphate nanoparticles for in vivo imaging of human breast cancer. , 2008, ACS nano.

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

[55]  Amy J Wagoner Johnson,et al.  The mechanical properties and osteoconductivity of hydroxyapatite bone scaffolds with multi-scale porosity. , 2007, Biomaterials.

[56]  Jinwoo Cheon,et al.  Biocompatible heterostructured nanoparticles for multimodal biological detection. , 2006, Journal of the American Chemical Society.