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Adv Funct Mater. Author manuscript; available in PMC 2016 July 18. Published in final edited form as: Adv Funct Mater. 2016 January 13; 26(2): 267–276. doi:10.1002/adfm.201503453.
Tumor-Targeted Multimodal Optical Imaging with Versatile Cadmium-Free Quantum Dots Dr. Xiangyou Liu, Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA
Author Manuscript
Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA Dr. Gary B. Braun, Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA Center for Nanomedicine and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA Prof. Haizheng Zhong, Beijing Key Laboratory of Nanophotonics and Ultrafine Optoelectronic Systems, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing 100081, P. R. China
Author Manuscript
Prof. David J. Hall, Moores Cancer Center, Department of Radiology, University of California, San Diego, La Jolla, CA 92093, USA Dr. Wenlong Han, Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA Mingde Qin, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
Author Manuscript
Chuanzhen Zhao, Beijing Key Laboratory of Nanophotonics and Ultrafine Optoelectronic Systems, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing 100081, P. R. China Dr. Meina Wang, Research Center of Materials Science, Beijing Institute of Technology, Beijing 100081, P. R. China Dr. Zhi-Gang She,
Correspondence to: Kazuki N. Sugahara, [email protected]. Supporting Information Supporting Information is available from the Wiley Online Library or from the author. No potential conflicts of interest were disclosed by the other authors.
Liu et al.
Page 2
Author Manuscript
Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA Dr. Chuanbao Cao, Research Center of Materials Science, Beijing Institute of Technology, Beijing 100081, P. R. China Prof. Michael J. Sailor, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA Prof. William B. Stallcup, Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA
Author Manuscript
Prof. Erkki Ruoslahti, and Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA Center for Nanomedicine and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA Prof. Kazuki N. Sugahara Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA Kazuki N. Sugahara: [email protected]
Author Manuscript
Abstract
Author Manuscript
The rapid development of fluorescence imaging technologies requires concurrent improvements in the performance of fluorescent probes. Quantum dots have been extensively used as an imaging probe in various research areas because of their inherent advantages based on unique optical and electronic properties. However, their clinical translation has been limited by the potential toxicity especially from cadmium. Here, a versatile bioimaging probe is developed by using highly luminescent cadmium-free CuInSe2/ZnS core/shell quantum dots conjugated with CGKRK (Cys– Gly–Lys–Arg–Lys) tumor-targeting peptides. This probe exhibits excellent photostability, reasonably long circulation time, minimal toxicity, and strong tumor-specific homing property. The most important feature of this probe is that it shows distinctive versatility in tumor-targeted multimodal imaging including near-infrared, time-gated, and two-photon imaging in different tumor models. In a glioblastoma mouse model, the targeted probe clearly denotes tumor boundaries and positively labels a population of diffusely infiltrating tumor cells, suggesting its utility in precise tumor detection during surgery. This work lays a foundation for potential clinical translation of the probe.
Adv Funct Mater. Author manuscript; available in PMC 2016 July 18.
Liu et al.
Page 3
Author Manuscript
1. Introduction
Author Manuscript
Fluorescence imaging has become an indispensable technique in cancer research because of the informative molecular, cellular, anatomical, and functional insights it provides.[1] Although the rapid advances in fluorescence imaging owe much to new imaging technologies, further improvements in sensitivity and biological selectivity require higher performance fluorescent probes. Quantum dots (QDs) are one of the most intensively studied bioimaging probes, as they possess many inherent advantages based on their unique optical and electronic properties.[2] QDs have high quantum yields (QYs), exceptional resistance to photobleaching, and high surface area-to-volume ratio that allow efficient functionalization with biomolecular ligands.[3] They can be used in near-infrared (NIR) imaging and even multiplexed imaging owing to their tunable photoluminescence (PL), large Strokes shifts, and narrow emission.[4] For some QDs, large two-photon (TP) excitation cross-sections allow them to be used in multiphoton imaging.[5] Furthermore, QDs can be used in time-gated (TG) imaging because of the relatively long luminescence lifetime (>10 ns).[6,7] These features make it possible to achieve multimodal imaging with a single QD probe, which could combine the advantages of different imaging techniques and ultimately improve both detection sensitivity and accuracy.
Author Manuscript
A major concern for QD-based probes is their potential toxicity.[8] Most QDs used currently are binary II–VI and IV–VI QDs (e.g., CdTe, CdSe, and PbS) and their core/shell nanocomplexes, which contain highly toxic elements, especially cadmium. Any possible release or leaching of the toxic elements may cause considerable safety and environmental concerns, hindering their wider applications.[9] As such, cadmium-free I–III–VI ternary semiconductor nanocrystals, such as CuInS2 (CIS) and CuInSe2 (CISe), have been considered as potential alternatives to replace conventional binary QDs. Generally, the QYs of naked CIS and CISe QDs are relatively low (typically
Adv Funct Mater. Author manuscript; available in PMC 2016 July 18. Published in final edited form as: Adv Funct Mater. 2016 January 13; 26(2): 267–276. doi:10.1002/adfm.201503453.
Tumor-Targeted Multimodal Optical Imaging with Versatile Cadmium-Free Quantum Dots Dr. Xiangyou Liu, Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA
Author Manuscript
Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA Dr. Gary B. Braun, Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA Center for Nanomedicine and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA Prof. Haizheng Zhong, Beijing Key Laboratory of Nanophotonics and Ultrafine Optoelectronic Systems, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing 100081, P. R. China
Author Manuscript
Prof. David J. Hall, Moores Cancer Center, Department of Radiology, University of California, San Diego, La Jolla, CA 92093, USA Dr. Wenlong Han, Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA Mingde Qin, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
Author Manuscript
Chuanzhen Zhao, Beijing Key Laboratory of Nanophotonics and Ultrafine Optoelectronic Systems, School of Materials Science and Engineering, Beijing Institute of Technology, Beijing 100081, P. R. China Dr. Meina Wang, Research Center of Materials Science, Beijing Institute of Technology, Beijing 100081, P. R. China Dr. Zhi-Gang She,
Correspondence to: Kazuki N. Sugahara, [email protected]. Supporting Information Supporting Information is available from the Wiley Online Library or from the author. No potential conflicts of interest were disclosed by the other authors.
Liu et al.
Page 2
Author Manuscript
Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA Dr. Chuanbao Cao, Research Center of Materials Science, Beijing Institute of Technology, Beijing 100081, P. R. China Prof. Michael J. Sailor, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA Prof. William B. Stallcup, Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA
Author Manuscript
Prof. Erkki Ruoslahti, and Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA Center for Nanomedicine and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA Prof. Kazuki N. Sugahara Cancer Research Center, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA 92037, USA Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA Kazuki N. Sugahara: [email protected]
Author Manuscript
Abstract
Author Manuscript
The rapid development of fluorescence imaging technologies requires concurrent improvements in the performance of fluorescent probes. Quantum dots have been extensively used as an imaging probe in various research areas because of their inherent advantages based on unique optical and electronic properties. However, their clinical translation has been limited by the potential toxicity especially from cadmium. Here, a versatile bioimaging probe is developed by using highly luminescent cadmium-free CuInSe2/ZnS core/shell quantum dots conjugated with CGKRK (Cys– Gly–Lys–Arg–Lys) tumor-targeting peptides. This probe exhibits excellent photostability, reasonably long circulation time, minimal toxicity, and strong tumor-specific homing property. The most important feature of this probe is that it shows distinctive versatility in tumor-targeted multimodal imaging including near-infrared, time-gated, and two-photon imaging in different tumor models. In a glioblastoma mouse model, the targeted probe clearly denotes tumor boundaries and positively labels a population of diffusely infiltrating tumor cells, suggesting its utility in precise tumor detection during surgery. This work lays a foundation for potential clinical translation of the probe.
Adv Funct Mater. Author manuscript; available in PMC 2016 July 18.
Liu et al.
Page 3
Author Manuscript
1. Introduction
Author Manuscript
Fluorescence imaging has become an indispensable technique in cancer research because of the informative molecular, cellular, anatomical, and functional insights it provides.[1] Although the rapid advances in fluorescence imaging owe much to new imaging technologies, further improvements in sensitivity and biological selectivity require higher performance fluorescent probes. Quantum dots (QDs) are one of the most intensively studied bioimaging probes, as they possess many inherent advantages based on their unique optical and electronic properties.[2] QDs have high quantum yields (QYs), exceptional resistance to photobleaching, and high surface area-to-volume ratio that allow efficient functionalization with biomolecular ligands.[3] They can be used in near-infrared (NIR) imaging and even multiplexed imaging owing to their tunable photoluminescence (PL), large Strokes shifts, and narrow emission.[4] For some QDs, large two-photon (TP) excitation cross-sections allow them to be used in multiphoton imaging.[5] Furthermore, QDs can be used in time-gated (TG) imaging because of the relatively long luminescence lifetime (>10 ns).[6,7] These features make it possible to achieve multimodal imaging with a single QD probe, which could combine the advantages of different imaging techniques and ultimately improve both detection sensitivity and accuracy.
Author Manuscript
A major concern for QD-based probes is their potential toxicity.[8] Most QDs used currently are binary II–VI and IV–VI QDs (e.g., CdTe, CdSe, and PbS) and their core/shell nanocomplexes, which contain highly toxic elements, especially cadmium. Any possible release or leaching of the toxic elements may cause considerable safety and environmental concerns, hindering their wider applications.[9] As such, cadmium-free I–III–VI ternary semiconductor nanocrystals, such as CuInS2 (CIS) and CuInSe2 (CISe), have been considered as potential alternatives to replace conventional binary QDs. Generally, the QYs of naked CIS and CISe QDs are relatively low (typically
