Functionalization of Gadolinium Chelates Silica Nanoparticle through Silane Chemistry for Simultaneous MRI/64Cu PET Imaging

Multimodal nanoprobes are highly demanded for biomedical imaging applications to enhance the reliability of the diagnostic results. Among different types of nano-objects, ultrasmall silica gadolinium nanoparticle (SiGdNP) appears as a safe, effective, and versatile platform for this purpose. In this study, a new method to functionalize SiGdNP based on silane chemistry has been reported. Two types of chelating silanes (APTES-DOTAGA and APTES-NODAGA) have been synthesized and grafted on SiGdNP by a simple one-step protocol. This functionalization strategy requires no other reactants or catalyzers and does not compromise the ultrasmall size of the particles. NODAGA-functionalized particle has been labeled with 64Cu isotope and injected intravenously to mice bearing TS/A carcinoma tumor for biodistribution study to demonstrate its potential as a bimodal MRI/PET imaging agent. A fully integrated MRI/PET system was used to simultaneously monitor the distribution of the particle. The results showed that the functionalized particle maintained properties of a renal clearable NP which could rapidly escape through kidneys and had low retention in other organs, especially liver, even though its accumulation in the tumor was modest.

[1]  J. Howl.  Peptide Synthesis and Applications , 2005, Methods in Molecular Biology™.

[2]  A. Bevilacqua,et al.  Equilibrium and thermodynamic study of the aqueous complexation of 1,4,7-triazacyclononane-N,N',N''-triacetic acid with protons, alkaline-earth-metal cations, and copper(II) , 1987 .

[3]  O. Tillement,et al.  Synthesis and Characterization of (89)Zr-Labeled Ultrasmall Nanoparticles. , 2016, Molecular pharmaceutics.

[4]  Andrew S Torres,et al.  Preclinical assessment of a zwitterionic tantalum oxide nanoparticle X-ray contrast agent. , 2012, ACS nano.

[5]  R Berbeco,et al.  The use of theranostic gadolinium-based nanoprobes to improve radiotherapy efficacy , 2014, The British journal of radiology.

[6]  Olivier Tillement,et al.  Long-term in vivo clearance of gadolinium-based AGuIX nanoparticles and their biocompatibility after systemic injection. , 2015, ACS nano.

[7]  Cédric Louis,et al.  A top-down synthesis route to ultrasmall multifunctional Gd-based silica nanoparticles for theranostic applications. , 2013, Chemistry.

[8]  C. Orvig,et al.  The Chemistry of Inorganic Nuclides (86Y, 68Ga, 64Cu, 89Zr, 124I) , 2014 .

[9]  S. Figueroa,et al.  [64Cu-NOTA-8-Aoc-BBN(7-14)NH2] targeting vector for positron-emission tomography imaging of gastrin-releasing peptide receptor-expressing tissues , 2007, Proceedings of the National Academy of Sciences.

[10]  Jean-Luc Coll,et al.  Ultrasmall rigid particles as multimodal probes for medical applications. , 2011, Angewandte Chemie.

[11]  A. Almutairi,et al.  Nanogels from Metal-Chelating Crosslinkers as Versatile Platforms Applied to Copper-64 PET Imaging of Tumors and Metastases , 2015, Theranostics.

[12]  P. Perriat,et al.  Functionalization of small rigid platforms with cyclic RGD peptides for targeting tumors overexpressing αvβ3-integrins. , 2013, Bioconjugate chemistry.

[13]  F. Kiessling,et al.  Noninvasive Imaging of Nanomedicines and Nanotheranostics: Principles, Progress, and Prospects. , 2015, Chemical reviews.

[14]  68Ga-radiolabeled AGuIX nanoparticles as dual-modality imaging agents for PET/MRI-guided radiation therapy. , 2017, Nanomedicine.

[15]  O. Tillement,et al.  Small rigid platforms functionalization with quaternary ammonium: targeting extracellular matrix of chondrosarcoma. , 2014, Nanomedicine : nanotechnology, biology, and medicine.

[16]  Ross Berbeco,et al.  Ultrasmall Silica-Based Bismuth Gadolinium Nanoparticles for Dual Magnetic Resonance-Computed Tomography Image Guided Radiation Therapy. , 2017, Nano letters.

[17]  Gang Zheng,et al.  Tailoring nanoparticle designs to target cancer based on tumor pathophysiology , 2016, Proceedings of the National Academy of Sciences.

[18]  Jean Martínez,et al.  Unambiguous and Controlled One-Pot Synthesis of Multifunctional Silica Nanoparticles , 2016 .

[19]  P. Perriat,et al.  Ultrasmall particles for Gd-MRI and (68) Ga-PET dual imaging. , 2015, Contrast media & molecular imaging.

[20]  M. Bawendi,et al.  Renal clearance of quantum dots , 2007, Nature Biotechnology.

[21]  E. Sevick-Muraca,et al.  Comparison of DOTA and NODAGA as chelators for (64)Cu-labeled immunoconjugates. , 2015, Nuclear medicine and biology.

[22]  Yin Zhang,et al.  Positron Emission Tomography Imaging of CD105 Expression with a 64Cu-Labeled Monoclonal Antibody: NOTA Is Superior to DOTA , 2011, PloS one.

[23]  B. Rosen,et al.  PET and MR Imaging: The Odd Couple or a Match Made in Heaven? , 2013, The Journal of Nuclear Medicine.

[24]  Liping Chen,et al.  Eu3+ chelate with phenanthroline derivative gives selective emission responses to Cu(II) ions , 2011 .

[25]  Ross Berbeco,et al.  Gadolinium-Based Nanoparticles and Radiation Therapy for Multiple Brain Melanoma Metastases: Proof of Concept before Phase I Trial , 2016, Theranostics.