Ultra-small BaGdF5-based upconversion nanoparticles as drug carriers and multimodal imaging probes.

A new type of drug-delivery system (DDS) was constructed, in which the anti-cancer drug doxorubicin (DOX) was conjugated to the ultra-small sized (sub-10 nm) BaGdF5:Yb(3+)/Tm(3+) based upconversion nanoparticles (UCNPs). This multifunctional DDS simultaneously possesses drug delivery and optical/magnetic/X-ray computed tomography imaging capabilities. The DOX can be selectively released by cleavage of hydrazone bonds in acidic environment, which shows a pH-triggered drug release behavior. The MTT assay shows these DOX-conjugated UCNPs exhibit obvious cytotoxic effect on HeLa cells. Moreover, to improve the upconversion luminescence intensity, core-shell structured UCNPs were constructed. The in vitro upconversion luminescence images of these UCNPs uptaken by HeLa cells show bright emission with high contrast. In addition, these UCNPs were further explored for T1-weighted magnetic resonance (MR) and X-ray computed tomography (CT) imaging in vitro. Long-term in vivo toxicity studies indicated that mice intravenously injected with 10 mg/kg of UCNPs survived for 40 days without any apparent adverse effects to their health. The results indicate that this multifunctional drug-delivery system with optimized size, excellent optical/MR/CT trimodal imaging capabilities, and pH-triggered drug release property is expected to be a promising platform for simultaneous cancer therapy and bioimaging.

[1]  M. Zignani,et al.  Current status of pH-sensitive liposomes in drug delivery. , 2000, Progress in lipid research.

[2]  Zhuang Liu,et al.  Drug delivery with upconversion nanoparticles for multi-functional targeted cancer cell imaging and therapy. , 2011, Biomaterials.

[3]  Zongxi Li,et al.  Biocompatibility, biodistribution, and drug-delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. , 2010, Small.

[4]  Jun Lin,et al.  Rare earth fluoride nano-/microcrystals: synthesis, surface modification and application , 2010 .

[5]  Taeghwan Hyeon,et al.  Inorganic Nanoparticles for MRI Contrast Agents , 2009 .

[6]  Shouheng Sun,et al.  Recent advances in syntheses and therapeutic applications of multifunctional porous hollow nanoparticles , 2010 .

[7]  Lehui Lu,et al.  A high-performance ytterbium-based nanoparticulate contrast agent for in vivo X-ray computed tomography imaging. , 2012, Angewandte Chemie.

[8]  Zhuang Liu,et al.  Upconversion nanoparticles and their composite nanostructures for biomedical imaging and cancer therapy. , 2013, Nanoscale.

[9]  Taeghwan Hyeon,et al.  Nonblinking and Nonbleaching Upconverting Nanoparticles as an Optical Imaging Nanoprobe and T1 Magnetic Resonance Imaging Contrast Agent , 2009 .

[10]  Thomas J. Meade,et al.  Multimodal MRI contrast agents , 2007, JBIC Journal of Biological Inorganic Chemistry.

[11]  Sophie Laurent,et al.  Contrast agents: magnetic resonance. , 2008, Handbook of experimental pharmacology.

[12]  F. Vetrone,et al.  Near-Infrared-to-Blue Upconversion in Colloidal BaYF5:Tm3+, Yb3+ Nanocrystals , 2009 .

[13]  Kai Yang,et al.  Facile preparation of multifunctional upconversion nanoprobes for multimodal imaging and dual-targeted photothermal therapy. , 2011, Angewandte Chemie.

[14]  Ya-Wen Zhang,et al.  High-quality sodium rare-earth fluoride nanocrystals: controlled synthesis and optical properties. , 2006, Journal of the American Chemical Society.

[15]  Jun Lin,et al.  Up-conversion cell imaging and pH-induced thermally controlled drug release from NaYF4/Yb3+/Er3+@hydrogel core-shell hybrid microspheres. , 2012, ACS nano.

[16]  G. Chow,et al.  Synthesis of Hexagonal‐Phase NaYF4:Yb,Er and NaYF4:Yb,Tm Nanocrystals with Efficient Up‐Conversion Fluorescence , 2006 .

[17]  Deepthy Menon,et al.  Folate receptor targeted, rare-earth oxide nanocrystals for bi-modal fluorescence and magnetic imaging of cancer cells. , 2010, Biomaterials.

[18]  N. Nishiyama,et al.  In vivo antitumor activity of the folate-conjugated pH-sensitive polymeric micelle selectively releasing adriamycin in the intracellular acidic compartments. , 2007, Bioconjugate chemistry.

[19]  Cunhai Dong,et al.  Ln(3+)-doped nanoparticles for upconversion and magnetic resonance imaging: some critical notes on recent progress and some aspects to be considered. , 2012, Nanoscale.

[20]  K. Ulbrich,et al.  Synthesis of HPMA Copolymers Containing Doxorubicin Bound via a Hydrazone Linkage. Effect of Spacer on Drug Release and in vitro Cytotoxicity , 2002 .

[21]  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.

[22]  Yan Zhang,et al.  Tuning sub-10 nm single-phase NaMnF3 nanocrystals as ultrasensitive hosts for pure intense fluorescence and excellent T1 magnetic resonance imaging. , 2012, Chemical communications.

[23]  Tymish Y. Ohulchanskyy,et al.  High contrast in vitro and in vivo photoluminescence bioimaging using near infrared to near infrared up-conversion in Tm3+ and Yb3+ doped fluoride nanophosphors. , 2008, Nano letters.

[24]  Zhi-Jun Zhang,et al.  Synthesis of a novel magnetic drug delivery system composed of doxorubicin-conjugated Fe3O4 nanoparticle cores and a PEG-functionalized porous silica shell. , 2010, Chemical communications.

[25]  Ruimin Xing,et al.  Facile synthesis of fluorescent porous zinc sulfide nanospheres and their application for potential drug delivery and live cell imaging. , 2012, Nanoscale.

[26]  Christopher G. Morgan,et al.  The Active‐Core/Active‐Shell Approach: A Strategy to Enhance the Upconversion Luminescence in Lanthanide‐Doped Nanoparticles , 2009 .

[27]  Hyesung Jeon,et al.  Facile synthesis of monodispersed mesoporous silica nanoparticles with ultralarge pores and their application in gene delivery. , 2011, ACS nano.

[28]  Meng Wang,et al.  Immunolabeling and NIR-excited fluorescent imaging of HeLa cells by using NaYF(4):Yb,Er upconversion nanoparticles. , 2009, ACS nano.

[29]  Jun Lin,et al.  Doxorubicin conjugated NaYF(4):Yb(3+)/Tm(3+) nanoparticles for therapy and sensing of drug delivery by luminescence resonance energy transfer. , 2012, Biomaterials.

[30]  Renfu Li,et al.  Time-resolved FRET biosensor based on amine-functionalized lanthanide-doped NaYF4 nanocrystals. , 2011, Angewandte Chemie.

[31]  Yun Sun,et al.  Dual-modality in vivo imaging using rare-earth nanocrystals with near-infrared to near-infrared (NIR-to-NIR) upconversion luminescence and magnetic resonance properties. , 2010, Biomaterials.

[32]  Jun Lin,et al.  Functionalized mesoporous silica materials for controlled drug delivery. , 2012, Chemical Society reviews.

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

[34]  Fan Zhang,et al.  Mesoporous multifunctional upconversion luminescent and magnetic "nanorattle" materials for targeted chemotherapy. , 2012, Nano letters.

[35]  Chun-Hua Yan,et al.  Bioimaging and toxicity assessments of near-infrared upconversion luminescent NaYF4:Yb,Tm nanocrystals. , 2011, Biomaterials.

[36]  Jun Lin,et al.  Colloidal synthesis and remarkable enhancement of the upconversion luminescence of BaGdF5:Yb3+/Er3+ nanoparticles by active-shell modification , 2011 .

[37]  Xiaogang Liu,et al.  Recent Advances in the Chemistry of Lanthanide‐Doped Upconversion Nanocrystals , 2009 .

[38]  Yun Sun,et al.  Fluorine-18-labeled Gd3+/Yb3+/Er3+ co-doped NaYF4 nanophosphors for multimodality PET/MR/UCL imaging. , 2011, Biomaterials.

[39]  Guanying Chen,et al.  Ultrasmall monodisperse NaYF(4):Yb(3+)/Tm(3+) nanocrystals with enhanced near-infrared to near-infrared upconversion photoluminescence. , 2010, ACS nano.

[40]  Yanqing Hua,et al.  Multifunctional nanoprobes for upconversion fluorescence, MR and CT trimodal imaging. , 2012, Biomaterials.

[41]  Liangping Zhou,et al.  Controlled synthesis of uniform and monodisperse upconversion core/mesoporous silica shell nanocomposites for bimodal imaging. , 2012, Chemistry.

[42]  Helmut Schäfer,et al.  Upconverting nanoparticles. , 2011, Angewandte Chemie.

[43]  Zhi-Gang Chen,et al.  Synthesis, characterization, and in vivo targeted imaging of amine-functionalized rare-earth up-converting nanophosphors. , 2009, Biomaterials.

[44]  Taeghwan Hyeon,et al.  Theranostic Probe Based on Lanthanide‐Doped Nanoparticles for Simultaneous In Vivo Dual‐Modal Imaging and Photodynamic Therapy , 2012, Advanced materials.

[45]  Liang Yan,et al.  Mn2+ Dopant‐Controlled Synthesis of NaYF4:Yb/Er Upconversion Nanoparticles for in vivo Imaging and Drug Delivery , 2012, Advanced materials.

[46]  P. Choyke,et al.  Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. , 2008, Nanomedicine.

[47]  B. Fei,et al.  Dual-modal fluorescent/magnetic bioprobes based on small sized upconversion nanoparticles of amine-functionalized BaGdF5:Yb/Er. , 2012, Nanoscale.

[48]  Greg J. Stanisz,et al.  Size-Tunable, Ultrasmall NaGdF4 Nanoparticles: Insights into Their T1 MRI Contrast Enhancement , 2011 .

[49]  Paras N. Prasad,et al.  Monodisperse NaYbF4:Tm3+/NaGdF4 core/shell nanocrystals with near-infrared to near-infrared upconversion photoluminescence and magnetic resonance properties. , 2011, Nanoscale.

[50]  Jesse V Jokerst,et al.  Nanoparticle PEGylation for imaging and therapy. , 2011, Nanomedicine.

[51]  F. V. van Veggel,et al.  Silica-coated Ln3+-Doped LaF3 nanoparticles as robust down- and upconverting biolabels. , 2006, Chemistry.

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

[53]  Yuliang Zhao,et al.  Size-tunable synthesis of lanthanide-doped Gd2O3 nanoparticles and their applications for optical and magnetic resonance imaging , 2012 .

[54]  Yang Yang,et al.  Long-term in vivo biodistribution imaging and toxicity of polyacrylic acid-coated upconversion nanophosphors. , 2010, Biomaterials.

[55]  Fuyou Li,et al.  High contrast upconversion luminescence targeted imaging in vivo using peptide-labeled nanophosphors. , 2009, Analytical chemistry.

[56]  Jianhua Hao,et al.  Water dispersible ultra-small multifunctional KGdF4:Tm3+, Yb3+ nanoparticles with near-infrared to near-infrared upconversion , 2011 .

[57]  F. Huang,et al.  Lanthanide dopant-induced formation of uniform sub-10 nm active-core/active-shell nanocrystals with near-infrared to near-infrared dual-modal luminescence , 2012 .

[58]  P. Perriat,et al.  Hybrid gadolinium oxide nanoparticles: multimodal contrast agents for in vivo imaging. , 2007, Journal of the American Chemical Society.

[59]  Mingdong Huang,et al.  Amine-functionalized lanthanide-doped KGdF4 nanocrystals as potential optical/magnetic multimodal bioprobes. , 2012, Journal of the American Chemical Society.

[60]  Wei Feng,et al.  Upconversion‐Nanophosphor‐Based Functional Nanocomposites , 2013, Advanced materials.

[61]  C. Mou,et al.  Intracellular pH-responsive mesoporous silica nanoparticles for the controlled release of anticancer chemotherapeutics. , 2010, Angewandte Chemie.

[62]  Hui Guo,et al.  Mesoporous-silica-coated up-conversion fluorescent nanoparticles for photodynamic therapy. , 2009, Small.

[63]  D Artemov,et al.  Combined vascular and extracellular pH imaging of solid tumors , 2002, NMR in biomedicine.