Gold Nanoclusters‐Based Nanoprobes for Simultaneous Fluorescence Imaging and Targeted Photodynamic Therapy with Superior Penetration and Retention Behavior in Tumors

Gold nanoclusters (GNCs) attract increasing attention due to their potential applications in sensing, catalysis, optoelectronics, and biomedicine. Herein, the formation of highly fluorescent glutathione (GSH)‐capped GNCs is achieved through the delicate control of the reduction kinetics and thermodynamic selection of the Au(I)–SG complexes. Furthermore, the GNCs‐based nanoprobes are developed by the covalent coupling folic acid (FA) and PEG (polyethylene glycol) on the surface of GNCs directly, followed by trapping photosensitizer (chlorin e6, Ce6) within PEG networks and attaching to the GNCs surface. The fabricated nanoprobes (Ce6@GNCs‐PEG2K‐FA) possess a uniform particle size (hydrodynamic diameter ≈6.1 ± 1.2 nm), without affecting the yield of singlet oxygen of the trapped Ce6. In vitro studies show the enhanced cellular uptake and satisfactory photodynamic therapy (PDT) effectiveness toward MGC‐803 cells when compared with free Ce6. The biodistribution and excretion pathway studies of the nanoprobes in MGC‐803 tumor‐bearing nude mice reveal their superior penetration and retention behavior in tumors, while the preserved features of renal clearance and stealthy to reticulo‐endothelial system are mainly attributed to the small hydrodynamic diameters and the FA‐capped PEGylated ligands. The enhanced PDT efficacy and the nontoxicity to mice provide an exciting new nano‐platform with promising clinical translational potential.

[1]  Wolfgang Meier,et al.  Polymeric vesicles: from drug carriers to nanoreactors and artificial organelles. , 2011, Accounts of chemical research.

[2]  Sanjiv S. Gambhir,et al.  Multiplexed imaging of surface enhanced Raman scattering nanotags in living mice using noninvasive Raman spectroscopy , 2009, Proceedings of the National Academy of Sciences.

[3]  Jie Zheng,et al.  Passive tumor targeting of renal-clearable luminescent gold nanoparticles: long tumor retention and fast normal tissue clearance. , 2013, Journal of the American Chemical Society.

[4]  R. Jin,et al.  Quantum sized, thiolate-protected gold nanoclusters. , 2010, Nanoscale.

[5]  B. Bauer,et al.  Dendrimer Templates for the Formation of Gold Nanoclusters , 2000 .

[6]  R. Niu,et al.  Folate-PEG coated cationic modified chitosan--cholesterol liposomes for tumor-targeted drug delivery. , 2010, Biomaterials.

[7]  Sang‐Gun Ahn,et al.  Efficient preparation of highly pure chlorin e6 and its photodynamic anti-cancer activity in a rat tumor model. , 2009, Oncology reports.

[8]  Jianping Xie,et al.  From aggregation-induced emission of Au(I)-thiolate complexes to ultrabright Au(0)@Au(I)-thiolate core-shell nanoclusters. , 2012, Journal of the American Chemical Society.

[9]  J. Karp,et al.  Nanocarriers as an Emerging Platform for Cancer Therapy , 2022 .

[10]  J. Conde,et al.  A promising road with challenges: where are gold nanoparticles in translational research? , 2014, Nanomedicine.

[11]  V. Torchilin.  Recent advances with liposomes as pharmaceutical carriers , 2005, Nature Reviews Drug Discovery.

[12]  Yong-Wei Zhang,et al.  Destabilization of Gold Clusters for Controlled Nanosynthesis: From Clusters to Polyhedra , 2014, Advanced materials.

[13]  H. Park,et al.  Folate-modified–chitosan-coated liposomes for tumor-targeted drug delivery , 2013, Journal of Materials Science.

[14]  Seungpyo Hong,et al.  Prolonged blood circulation and enhanced tumor accumulation of folate-targeted dendrimer-polymer hybrid nanoparticles. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[15]  X. Wu,et al.  Chemotherapy with anticancer drugs encapsulated in solid lipid nanoparticles. , 2007, Advanced drug delivery reviews.

[16]  Jinchao Zhang,et al.  Superior penetration and retention behavior of 50 nm gold nanoparticles in tumors. , 2013, Cancer research.

[17]  Yanglong Hou,et al.  Multifunctional Fe5C2 Nanoparticles: A Targeted Theranostic Platform for Magnetic Resonance Imaging and Photoacoustic Tomography‐Guided Photothermal Therapy , 2014, Advanced materials.

[18]  Jianping Xie,et al.  Ultrasmall Au10−12(SG)10−12 Nanomolecules for High Tumor Specificity and Cancer Radiotherapy , 2014, Advanced materials.

[19]  Vincent M Rotello,et al.  Light-regulated release of DNA and its delivery to nuclei by means of photolabile gold nanoparticles. , 2006, Angewandte Chemie.

[20]  Jie Zheng,et al.  Near-infrared emitting radioactive gold nanoparticles with molecular pharmacokinetics. , 2012, Angewandte Chemie.

[21]  H. Mojzisova,et al.  Cellular uptake and subcellular distribution of chlorin e6 as functions of pH and interactions with membranes and lipoproteins. , 2007, Biochimica et biophysica acta.

[22]  Jianping Xie,et al.  Protein-directed synthesis of highly fluorescent gold nanoclusters. , 2009, Journal of the American Chemical Society.

[23]  Chen Zhou,et al.  Luminescent gold nanoparticles with pH-dependent membrane adsorption. , 2011, Journal of the American Chemical Society.

[24]  Zhe Wang,et al.  Photosensitizer-loaded gold vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy. , 2013, ACS nano.

[25]  Peng Huang,et al.  Enhancement of gastric cell radiation sensitivity by chitosan-modified gold nanoparticles. , 2011, Journal of nanoscience and nanotechnology.

[26]  Premkumar Kumpati,et al.  Acridine orange tethered chitosan reduced gold nanoparticles: a dual functional probe for combined photodynamic and photothermal therapy , 2013 .

[27]  D. A. Russell,et al.  Generation of Cytotoxic Singlet Oxygen via Phthalocyanine-Stabilized Gold Nanoparticles: A Potential Delivery Vehicle for Photodynamic Therapy , 2002 .

[28]  Yueqing Gu,et al.  Thermal responsive micelles for dual tumor-targeting imaging and therapy. , 2013, Nanoscale.

[29]  Malcolm E. Kenney,et al.  Deep penetration of a PDT drug into tumors by noncovalent drug-gold nanoparticle conjugates. , 2011, Journal of the American Chemical Society.

[30]  S. Gambhir,et al.  Quantum Dots for Live Cells, in Vivo Imaging, and Diagnostics , 2005, Science.

[31]  A. Moor,et al.  Signaling pathways in cell death and survival after photodynamic therapy. , 2000, Journal of photochemistry and photobiology. B, Biology.

[32]  Ammu Mathew,et al.  Noble Metal Clusters: Applications in Energy, Environment, and Biology , 2014 .

[33]  Jie Zheng,et al.  Luminescent gold nanoparticles with efficient renal clearance. , 2011, Angewandte Chemie.

[34]  Zhuang Liu,et al.  Drug delivery with carbon nanotubes for in vivo cancer treatment. , 2008, Cancer research.

[35]  Mykhailo V Bondar,et al.  Folate receptor-targeted aggregation-enhanced near-IR emitting silica nanoprobe for one-photon in vivo and two-photon ex vivo fluorescence bioimaging. , 2011, Bioconjugate chemistry.

[36]  Wei Chen,et al.  Fluorescent carbon nanodots conjugated with folic acid for distinguishing folate-receptor-positive cancer cells from normal cells , 2012 .

[37]  Jinatta Jittiwat,et al.  Biodistribution of gold nanoparticles and gene expression changes in the liver and spleen after intravenous administration in rats. , 2010, Biomaterials.

[38]  M. Thanou,et al.  Targeting nanoparticles to cancer. , 2010, Pharmacological research.

[39]  Yingge Zhang,et al.  Insights into the Distinguishing Stress-induced Cytotoxicity of Chiral Gold Nanoclusters and the Relationship with GSTP1 , 2015, Theranostics.

[40]  Jun Li,et al.  Delivery and efficacy of a cancer drug as a function of the bond to the gold nanoparticle surface. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[41]  S. Bagdonas,et al.  Complexes of functionalized quantum dots and chlorin e6 in photodynamic therapy , 2013 .

[42]  Byeong‐Su Kim,et al.  Highly Biocompatible Carbon Nanodots for Simultaneous Bioimaging and Targeted Photodynamic Therapy In Vitro and In Vivo , 2014 .