title: Tunable ultrasmall visible-to-extended near-infrared emitting silver sulfide quantum dots for integrin-targeted cancer imaging.
abstract: The large size of many near-infrared (NIR) fluorescent nanoparticles prevents rapid extravasation from blood vessels and subsequent diffusion to tumors. This confines in vivo uptake to the peritumoral space and results in high liver retention. In this study, we developed a viscosity modulated approach to synthesize ultrasmall silver sulfide quantum dots (QDs) with distinct tunable light emission from 500 to 1200 nm and a QD core diameter between 1.5 and 9 nm. Conjugation of a tumor-avid cyclic pentapeptide (Arg-Gly-Asp-DPhe-Lys) resulted in monodisperse, water-soluble QDs (hydrodynamic diameter < 10 nm) without loss of the peptide's high binding affinity to tumor-associated integrins (KI = 1.8 nM/peptide). Fluorescence and electron microscopy showed that selective integrin-mediated internalization was observed only in cancer cells treated with the peptide-labeled QDs, demonstrating that the unlabeled hydrophilic nanoparticles exhibit characteristics of negatively charged fluorescent dye molecules, which typically do not internalize in cells. The biodistribution profiles of intravenously administered QDs in different mouse models of cancer reveal an exceptionally high tumor-to-liver uptake ratio, suggesting that the small sized QDs evaded conventional opsonization and subsequent high uptake in the liver and spleen. The seamless tunability of the QDs over a wide spectral range with only a small increase in size, as well as the ease of labeling the bright and noncytotoxic QDs with biomolecules, provides a platform for multiplexing information, tracking the trafficking of single molecules in cells, and selectively targeting disease biomarkers in living organisms without premature QD opsonization in circulating blood.
authors.affiliation: Department of Radiology, Washington University in St. Louis, School of Medicine , St. Louis, Missouri 63110, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Tang
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Xue
authors.forename: Baogang
authors.initials: B
authors.lastname: Xu
authors.forename: Duanwen
authors.initials: D
authors.lastname: Shen
authors.forename: Gail P
authors.initials: GP
authors.lastname: Sudlow
authors.forename: Samuel
authors.initials: S
authors.lastname: Achilefu
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D006801:Humans; D007259:Infrared Rays; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D057054:Molecular Imaging / Q000379:methods*; D055620:Optical Phenomena; D010316:Particle Size; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D045663:Quantum Dots / Q000737:chemistry* / Q000378:metabolism; D018030:Silver Compounds / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D018030:Silver Compounds; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl); D014867:Water; C013251:silver sulfide
keywords: microscopy; near-infrared; optical imaging; silver sulfide; small animal; tumor