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In vivo cancer targeting and imaging with semiconductor quantum dots

Abstract

We describe the development of multifunctional nanoparticle probes based on semiconductor quantum dots (QDs) for cancer targeting and imaging in living animals. The structural design involves encapsulating luminescent QDs with an ABC triblock copolymer and linking this amphiphilic polymer to tumor-targeting ligands and drug-delivery functionalities. In vivo targeting studies of human prostate cancer growing in nude mice indicate that the QD probes accumulate at tumors both by the enhanced permeability and retention of tumor sites and by antibody binding to cancer-specific cell surface biomarkers. Using both subcutaneous injection of QD-tagged cancer cells and systemic injection of multifunctional QD probes, we have achieved sensitive and multicolor fluorescence imaging of cancer cells under in vivo conditions. We have also integrated a whole-body macro-illumination system with wavelength-resolved spectral imaging for efficient background removal and precise delineation of weak spectral signatures. These results raise new possibilities for ultrasensitive and multiplexed imaging of molecular targets in vivo.

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Figure 1: Schematic illustration of biconjugated QDs for in vivo cancer targeting and imaging.
Figure 2: Immunocytochemical studies of QD-PSMA Ab binding activity in cultured prostate cancer cells.
Figure 3: Histological examination of QD uptake, retention and distribution in six different normal host organs and in C4-2 tumor xenografts maintained in athymic nude mice.
Figure 4: Spectral imaging of QD-PSMA Ab conjugates in live animals harboring C4-2 tumor xenografts.
Figure 5: In vivo fluorescence images of tumor-bearing mice using QD probes with three different surface modifications: carboxylic acid groups (left), PEG groups (middle) and PEG-PSMA Ab conjugates (right).
Figure 6: Sensitivity and multicolor capability of QD imaging in live animals.

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References

  1. Chan, W.C.W. et al. Luminescent QDs for multiplexed biological detection and imaging. Curr. Opin. Biotechnol. 13, 40–46 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Bruchez, M., Jr, Moronne, M., Gin, P., Weiss, S. & Alivisatos, A.P. Semiconductor nanocrystals as fluorescent biological labels. Science 281, 2013–2015 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Chan, W.C.W. & Nie, S.M. Quantum dot bioconjugates for ultrasensitive nonisotopic detection. Science 281, 2016–2018 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Mattoussi, H. et al. Self-assembly of CdSe-ZnS quantum dot bioconjugates using an engineered recombinant protein. J. Am. Chem. Soc. 122, 12142–12150 (2000).

    Article  CAS  Google Scholar 

  5. Akerman, M.E., Chan, W.C.W., Laakkonen, P., Bhatia, S.N. & Ruoslahti, E. Nanocrystal targeting in vivo. Proc. Natl. Acad. Sci. USA 99, 12617–12621 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dubertret, B. et al. In vivo imaging of QDs encapsulated in phospholipid micelles. Science 298, 1759–1762 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Wu, X.Y. et al. Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor QDs. Nat. Biotechnol. 21, 41–46 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Jaiswal, J.K., Mattoussi, H., Mauro, J.M. & Simon, S.M. Long-term multiple color imaging of live cells using quantum dot bioconjugates. Nat. Biotechnol. 21, 47–51 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Larson, D.R. et al. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science 300, 1434–1436 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Ishii, D. et al. Chaperonin-mediated stabilization and ATP-triggered release of semiconductor nanoparticles. Nature 423, 628–632 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Medintz, I.L. et al. Self-assembled nanoscale biosensors based on quantum dot FRET donors. Nat. Mater. 2, 630–639 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Dahan, M. et al. Diffusion dynamics of glycine receptors revealed by single–quantum dot tracking. Science 302, 442–445 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Rosenthal, S.J. et al. Targeting cell surface receptors with ligand-conjugated nanocrystals. J. Am. Chem. Soc. 124, 4586–4594 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Niemeyer, C.M. Nanoparticles, proteins, and nucleic acids: biotechnology meets materials science. Angew. Chem. Int. Ed. Engl. 40, 4128–4158 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Alivisatos, A.P. Semiconductor clusters, nanocrystals, and quantum dots. Science 271, 933–937 (1996).

    Article  CAS  Google Scholar 

  16. Han, M.Y., Gao, X.H., Su, J.Z. & Nie, S.M. Quantum dot-tagged microbeads for multiplexed optical coding of biomolecules. Nat. Biotechnol. 19, 631–635 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Gao, X.H. & Nie, S.M. Doping mesoporous materials with multicolor quantum dots. J. Phys. Chem. B. 107, 11575–11578 (2003).

    Article  CAS  Google Scholar 

  18. Gao, X.H. & Nie, S.M. Quantum dot-encoded mesoporous beads with high brightness and uniformity: rapid readout using flow cytometry. Anal. Chem. 76, 2406–2410 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Josephson, L., Kircher, M.F., Mahmood, U., Tang, Y. & Weissleder, R. Near-infrared fluorescent nanoparticles as combined MR/optical imaging probes. Bioconjug. Chem. 13, 554–560 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Gao, X.H. & Nie, S.M. Molecular profiling of single cells and tissue specimens with quantum dots. Trends Biotechnol. 21, 371–373 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Jovin, T.M. Quantum dots finally come of age. Nat. Biotechnol. 21, 32–33 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Lim, Y.T. et al. Selection of quantum dot wavelengths for biomedical assays and imaging. Mol. Imaging 2, 50–64 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Ballou, B., Lagerholm, B.C., Ernst, L.A., Bruchez, M.P. & Waggoner, A.S. Noninvasive imaging of quantum dots in mice. Bioconjug. Chem. 15, 79–86 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Kim, S. et al. Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat. Biotechnol. 22, 93–95 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Lidke, D.S. et al. Quantum dot ligands provide new insights into erbB/HER receptor–mediated signal transduction. Nat. Biotechnol. 22, 198–203 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Savic, R., Luo, L.B., Eisenberg, A. & Maysinger, D. Micellar nanocontainers distribute to defined cytoplasmic organelles. Science 300, 615–618 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Allen, C., Maysinger, D. & Eisenberg, A. Nano-engineering block copolymer aggregates for drug delivery. Colloids Surf. B Biointerfaces 16, 3–27 (1999).

    Article  CAS  Google Scholar 

  28. Ludwigs, S. et al. Self-assembly of functional nanostructures from ABC triblock copolymers. Nat. Mater. 2, 744–747 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Ness, J.M., Akhtar, R.S., Latham, C.B. & Roth, K.A. Combined tyramide signal amplification and quantum dots for sensitive and photostable immunofluorescence detection. J. Histochem. Cytochem. 51, 981–987 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Nirmal, M. et al. Fluorescence intermittency in single cadmium selenide nanocrystals Nature 383, 802–804 (1996).

    Article  CAS  Google Scholar 

  31. Empedocles, S.A. & Bawendi, M.G. Quantum-confined stark effect in single CdSe nanocrystallite quantum dots. Science 278, 2114–2117 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Kirpotin, D. et al. Sterically stabilized anti-HER2 immunoliposomes: design and targeting to human breast cancer cell in vitro. Biochemistry 36, 66–75 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Duncan, R. The dawning era of polymer therapeutics. Nat. Rev. Drug Discov. 2, 347–360 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Jain, R.K. Transport of molecules, particles, and cells in solid tumors. Ann. Rev. Biomed. Eng. 1, 241–263 (1999).

    Article  CAS  Google Scholar 

  35. Jain, R.K. Delivery of molecular medicine to solid tumors: lessons from in vivo imaging of gene expression and function. J. Control. Release 74, 7–25 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Chang, S.S., Reuter, V.E., Heston, W.D.W. & Gaudin, P.B. Metastatic renal cell carcinoma neovasculature expresses prostate-specific membrane antigen. Urology 57, 801–805 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Schulke, N. et al. The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy. Proc. Natl. Acad. Sci. USA 100, 12590–12595 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bander, N.H. et al. Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate specific membrane antigen. J. Urol. 170, 1717–1721 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Wunderbaldinger, P., Josephson, L. & Weissleder, R. Tat peptide directs enhanced clearance and hepatic permeability of magnetic nanoparticles. Bioconjug. Chem. 13, 264–268 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Campbell, R.B. et al. Cationic Charge Determines the Distribution of Liposomes between the Vascular and Extravascular Compartments of Tumors. Cancer Res. 62, 6831–6836 (2002).

    CAS  PubMed  Google Scholar 

  41. Levenson, R.M. Spectral imaging and pathology: seeing more. Lab. Med. 35, 244–251 (2004).

    Article  Google Scholar 

  42. Yang, M. et al. Direct external imaging of nascent cancer, tumor progression, angiogenesis, and metastasis on internal organs in the fluorescent orthotopic model. Proc. Natl. Acad. Sci. USA 99, 3824–3829 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lewin, M. et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat. Biotechnol 18, 410–414 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Randolph, G.J., Inaba, K., Robbiani, D.F., Steinman, R.M. & Muller, W.A. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11, 753–761 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Hess, B.C. et al. Surface transformation and photoinduced recovery in CdSe nanocrystals. Phys. Rev. Lett. 86, 3132–3135 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Manna, L., Scher, E.C., Li, L.-S. & Alivisatos, A.P. Epitaxial growth and photochemical annealing of graded CdS/ZnS shells on colloidal CdSe nanorods. J. Am. Chem. Soc. 124, 7136–7145 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Mammen, M., Choi, S.K. & Whitesides, G.M. Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew. Chem. Int. Edn Engl. 37, 2754–2794 (1998).

    Article  Google Scholar 

  48. Jin, R., Wu, G., Li, Z. & Mirkin, C.A. & Schatz, G.C. What controls the melting properties of DNA-linked gold nanoparticle assemblies. J. Am. Chem. Soc. 125, 1643–1654 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Cheong, W.F., Prahl, S.A. & Welch, A.J. A review of the optical properties of biological tissues. IEEE J. Quantum Electron. 26, 2166–2185 (1990).

    Article  Google Scholar 

  50. Ntziachristos, V., Bremer, C. & Weissleder, R. Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imaging. Eur. Radiol. 13, 195–208 (2003).

    PubMed  Google Scholar 

  51. Bailey, R.E. & Nie, S.M. Alloyed semiconductor QDs: tuning the optical properties without changing the particle size. J. Am. Chem. Soc. 125, 7100–7106 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Kim, S., Fisher, B., Eisler, H.J. & Bawendi, M.G. Type-II quantum dots: CdTe/CdSe (core/shell) and CdSe/ZnTe (core/shell) heterostructures. J. Am. Chem. Soc. 125, 11466–11467 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Derfus, A.M., Chan, W.C.W. & Bhatia, S.N. Probing the cytotoxicity of semiconductor quantum dots. Nano Lett. 4, 11–18 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Peng, Z.A. & Peng, X. Formation of high-quality CdTe, CdSe, and CdS nanocrystals using CdO as precursor. J. Am. Chem. Soc. 123, 183–184 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Qu, L.H., Peng, Z.A. & Peng, X. Alternative routes toward high quality CdSe nanocrystals. Nano Lett. 1, 333–337 (2001).

    Article  CAS  Google Scholar 

  56. Hsieh, C.L. et al. Improved gene-expression by a modified bicistronic retroviral vector. Biochem. Bioph. Res. Commun. 214, 910–917 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants to S.N. and L.W.K.C. from the National Institutes of Health (R01 GM60562 to S.N. and P01 CA098912 to L.W.K.C.), the Georgia Cancer Coalition (Distinguished Cancer Scholar Awards), the Coulter Translational Research Program at Georgia Tech and Emory University and the Department of Defense (17-03-2-0033 to L.W.K.C.). We acknowledge Lily Yang and Binfei Zhou for technical help, and Fray F. Marshall, John A. Petros, Hyunsuk Shim and Jonathan W. Simons for stimulating discussions. We are also grateful to Millennium Pharmaceuticals for providing the PSMA monoclonal antibody (J591).

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Correspondence to Leland W K Chung or Shuming Nie.

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Supplementary Fig. 1

Comparison of red-emitting QDs and red organic dyes for in vivo optical imaging. (PDF 54 kb)

Supplementary Fig. 2

Comparison of mouse skin and QD emission spectra. (PDF 159 kb)

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Gao, X., Cui, Y., Levenson, R. et al. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 22, 969–976 (2004). https://doi.org/10.1038/nbt994

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