A Gd-doped Mg-Al-LDH/Au nanocomposite for CT/MR bimodal imagings and simultaneous drug delivery.

The early diagnosis and simultaneous drug delivery monitored by non-invasive visualization are highly challenging but clinical-relevant for the diagnostics and therapy monitoring of serious diseases such as cancers. Herein, a Gd-doped layered double hydroxide (LDH)/Au nanocomposite has been developed as both a drug carrier and a diagnostic agent. The obtained nanocomposite shows high non-anionic anti-cancer drug DOX loading capacity and an interesting pH-responsive release profile of loaded DOX. The nanocomposite was found to be able to efficiently transport DOX into the cancer cell, release the DOX in the acidic cytoplasm and then cause death of cancer cells. Meanwhile, the nanocomposite demonstrates better in vitro CT and T(1)-weighted MR imaging capabilities than the commercial MRI and CT contrast agents and favorable in vivo CT and T(1)-weighted MR imaging performance. After being modified with heparin, the nanocomposite also demonstrates effective CT and MR imagings of tumors by intravenous administration in tumor-bearing mice. Furthermore, the nanocomposite shows negligible cytotoxicity and no detectable tissue damage on mice after injection of high dosage of nanocomposite. In conclusion, the synthetic nanocomposite is expected to be a potential theranostic agent for bimodal imagings of cancers and anti-cancer drug delivery as well.

[1]  Jong-sang Park,et al.  Cellular uptake behavior of [γ-32P] labeled ATP–LDH nanohybrids , 2001 .

[2]  Wei Feng,et al.  Gd3+ complex-modified NaLuF4-based upconversion nanophosphors for trimodality imaging of NIR-to-NIR upconversion luminescence, X-Ray computed tomography and magnetic resonance. , 2012, Biomaterials.

[3]  Z. X. and,et al.  Hydrothermal Synthesis of Layered Double Hydroxides (LDHs) from Mixed MgO and Al2O3: LDH Formation Mechanism , 2005 .

[4]  Dong Chen,et al.  The shape effect of mesoporous silica nanoparticles on biodistribution, clearance, and biocompatibility in vivo. , 2011, ACS nano.

[5]  I. Tannock,et al.  Acid pH in tumors and its potential for therapeutic exploitation. , 1989, Cancer research.

[6]  Taeghwan Hyeon,et al.  Multifunctional nanostructured materials for multimodal imaging, and simultaneous imaging and therapy. , 2009, Chemical Society reviews.

[7]  K. Brouwer,et al.  Effect of multidrug resistance modulators on the hepatobiliary disposition of doxorubicin in the isolated perfused rat liver. , 1998, Cancer research.

[8]  Julie H. Campbell,et al.  In Vitro Sustained Release of LMWH from MgAl-layered Double Hydroxide Nanohybrids , 2008 .

[9]  Xue Duan,et al.  Nearly monodispersed core-shell structural Fe3O4@DFUR-LDH submicro particles for magnetically controlled drug delivery and release. , 2011, Chemical communications.

[10]  Dongpeng Yan,et al.  Sulforhodamine B intercalated layered double hydroxide thin film with polarized photoluminescence. , 2009, The journal of physical chemistry. B.

[11]  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 .

[12]  Nicholas A Peppas,et al.  Responsive theranostic systems: integration of diagnostic imaging agents and responsive controlled release drug delivery carriers. , 2011, Accounts of chemical research.

[13]  Andrea Protti,et al.  Synthesis of 64CuII–Bis(dithiocarbamatebisphosphonate) and Its Conjugation with Superparamagnetic Iron Oxide Nanoparticles: In Vivo Evaluation as Dual-Modality PET–MRI Agent** , 2011, Angewandte Chemie.

[14]  R. Xu,et al.  Self-assembled Fe3O4-layered double hydroxide colloidal nanohybrids with excellent performance for treatment of organic dyes in water , 2011 .

[15]  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.

[16]  Gang Liu,et al.  A Synergistically Enhanced T1–T2 Dual‐Modal Contrast Agent , 2012, Advanced materials.

[17]  Tymish Y. Ohulchanskyy,et al.  Combined Optical and MR Bioimaging Using Rare Earth Ion Doped NaYF4 Nanocrystals , 2009 .

[18]  Greg M Thurber,et al.  18F labeled nanoparticles for in vivo PET-CT imaging. , 2009, Bioconjugate chemistry.

[19]  Han-Sung Kim,et al.  Tumor-targeting gold particles for dual computed tomography/optical cancer imaging. , 2011, Angewandte Chemie.

[20]  Rong Xu,et al.  Silver Nanoparticles Deposited Layered Double Hydroxide Nanoporous Coatings with Excellent Antimicrobial Activities , 2012 .

[21]  W. Hou,et al.  Synthesis and characterization of 5-fluorocytosine intercalated Zn–Al layered double hydroxide , 2008 .

[22]  Younan Xia,et al.  Gold nanocages: from synthesis to theranostic applications. , 2011, Accounts of chemical research.

[23]  Feng Chen,et al.  Multifunctional Mesoporous Nanoellipsoids for Biological Bimodal Imaging and Magnetically Targeted Delivery of Anticancer Drugs , 2011 .

[24]  J. Choy,et al.  Cellular uptake mechanism of an inorganic nanovehicle and its drug conjugates: Enhanced efficacy due to clathrin-mediated endocytosis. , 2006, Bioconjugate chemistry.

[25]  Taeghwan Hyeon,et al.  Multifunctional mesoporous silica nanocomposite nanoparticles for theranostic applications. , 2011, Accounts of chemical research.

[26]  S. Wise Nanocarriers as an emerging platform for cancer therapy , 2007 .

[27]  D. Astruc,et al.  Applications of vectorized gold nanoparticles to the diagnosis and therapy of cancer. , 2012, Chemical Society reviews.

[28]  Jun Wang,et al.  Magnetic, luminescent Eu-doped Mg-Al layered double hydroxide and its intercalation for ibuprofen. , 2010, Chemistry.

[29]  Ande Bao,et al.  Novel multifunctional theranostic liposome drug delivery system: construction, characterization, and multimodality MR, near-infrared fluorescent, and nuclear imaging. , 2012, Bioconjugate chemistry.

[30]  E. Giannelis,et al.  Nanobiohybrids as delivery vehicles for camptothecin. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[31]  Jin-Ho Choy,et al.  Inorganic–Biomolecular Hybrid Nanomaterials as a Genetic Molecular Code System , 2004 .

[32]  Min Wei,et al.  Preparation of Fe3O4@SiO2@layered double hydroxide core-shell microspheres for magnetic separation of proteins. , 2012, Journal of the American Chemical Society.

[33]  Elena E. Dormidontova,et al.  Doxorubicin and β-Lapachone Release and Interaction with Micellar Core Materials: Experiment and Modeling , 2007 .

[34]  Zhi Ping Xu,et al.  Layered double hydroxide nanoparticles in gene and drug delivery , 2009, Expert opinion on drug delivery.

[35]  Forrest M Kievit,et al.  Surface engineering of iron oxide nanoparticles for targeted cancer therapy. , 2011, Accounts of chemical research.

[36]  Ick Chan Kwon,et al.  Multifunctional nanoparticles for multimodal imaging and theragnosis. , 2012, Chemical Society reviews.

[37]  Sangjin Park,et al.  Antibiofouling polymer-coated gold nanoparticles as a contrast agent for in vivo X-ray computed tomography imaging. , 2007 .

[38]  Jin-Ho Choy,et al.  Anticancer drug encapsulated in inorganic lattice can overcome drug resistance , 2010 .

[39]  G. Lu,et al.  Synthesis of nanorattles with layered double hydroxide core and mesoporous silica shell as delivery vehicles , 2011 .

[40]  Zhanwen Xing,et al.  Gold-nanoshelled microcapsules: a theranostic agent for ultrasound contrast imaging and photothermal therapy. , 2011, Angewandte Chemie.

[41]  Jin-Ho Choy,et al.  Inorganic Layered Double Hydroxides as Nonviral Vectors , 2000 .

[42]  Yu Chen,et al.  Nuclear-targeted drug delivery of TAT peptide-conjugated monodisperse mesoporous silica nanoparticles. , 2012, Journal of the American Chemical Society.

[43]  D. Maysinger,et al.  Micellar Nanocontainers Distribute to Defined Cytoplasmic Organelles , 2003, Science.

[44]  D. Zhao,et al.  Synthesis of well-dispersed layered double hydroxide core@ordered mesoporous silica shell nanostructure (LDH@mSiO₂) and its application in drug delivery. , 2011, Nanoscale.

[45]  M. Osada,et al.  Synthesis, anion exchange, and delamination of Co-Al layered double hydroxide: assembly of the exfoliated nanosheet/polyanion composite films and magneto-optical studies. , 2006, Journal of the American Chemical Society.

[46]  Qianjun He,et al.  Mesoporous carbon@silicon-silica nanotheranostics for synchronous delivery of insoluble drugs and luminescence imaging. , 2012, Biomaterials.

[47]  G. Lu,et al.  Stable suspension of layered double hydroxide nanoparticles in aqueous solution. , 2006, Journal of the American Chemical Society.

[48]  Lin He,et al.  Core-shell Au nanoparticle formation with DNA-polymer hybrid coatings using aqueous ATRP. , 2007, Biomacromolecules.

[49]  David G. Evans,et al.  Preparation of Layered Double-Hydroxide Nanomaterials with a Uniform Crystallite Size Using a New Method Involving Separate Nucleation and Aging Steps , 2002 .

[50]  Sun-ho Han,et al.  Inorganic Drug‐Delivery Nanovehicle Conjugated with Cancer‐Cell‐Specific Ligand , 2009 .

[51]  S. Kawakami,et al.  Designing Dendrimers for Drug Delivery and Imaging: Pharmacokinetic Considerations , 2011, Pharmaceutical Research.

[52]  M. Ulibarri,et al.  Surface-charging behavior of Zn-Cr layered double hydroxide. , 2004, Journal of colloid and interface science.

[53]  G. Lu,et al.  Layered double hydroxide nanomaterials as potential cellular drug delivery agents , 2006 .

[54]  Hui Zhang,et al.  Facile synthesis of hierarchical core-shell Fe3O4@MgAl-LDH@Au as magnetically recyclable catalysts for catalytic oxidation of alcohols. , 2011, Chemical communications.

[55]  Courtney R. Thomas,et al.  Mechanized silica nanoparticles: a new frontier in theranostic nanomedicine. , 2011, Accounts of chemical research.

[56]  Jianlin Shi,et al.  Mesoporous silica nanoparticle based nano drug delivery systems: synthesis, controlled drug release and delivery, pharmacokinetics and biocompatibility , 2011 .

[57]  G. Bond,et al.  Gold on titania catalysts for the oxidation of carbon monoxide: control of pH during preparation with various gold contents , 2005 .

[58]  Taeghwan Hyeon,et al.  Designed Synthesis of Uniformly Sized Iron Oxide Nanoparticles for Efficient Magnetic Resonance Imaging Contrast Agents , 2012 .

[59]  Dar-Bin Shieh,et al.  In vitro and in vivo studies of FePt nanoparticles for dual modal CT/MRI molecular imaging. , 2010, Journal of the American Chemical Society.

[60]  Ralph Weissleder,et al.  Dextran-coated iron oxide nanoparticles: a versatile platform for targeted molecular imaging, molecular diagnostics, and therapy. , 2011, Accounts of chemical research.

[61]  C. Passirani,et al.  Long-circulating nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate). , 1998, Pharmaceutical research.

[62]  Jin Xie,et al.  Nanoparticle-based theranostic agents. , 2010, Advanced drug delivery reviews.