Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Treating metastatic cancer with nanotechnology

Key Points

  • In most patients, by the time cancer is detected, metastasis has already occurred. More than 80% of patients diagnosed with lung cancer, for example, present with metastatic disease.

  • Nanotechnology is not alien to the clinic; more than 40 nanotherapeutics have reached patients, including anticancer drugs and imaging agents.

  • Many current therapies are not reaching the sites of metastases. Nanomaterials have the potential to combine multiple therapeutic functions into a single platform, can be targeted to specific tissues and can reach particular subcellular compartments.

  • Primary targeting is the act of steering nanoparticles to the specific organ or organs in which the metastases reside.

  • Secondary targeting is the direction of these delivered materials to the cancer cells and potentially to a specific subcellular location within the cancer cell.

  • Many solid tumours exhibit the enhanced permeation and retention (EPR) effect through which nanomaterials may accumulate and be retained in the tumour. However, this effect is limited to tumours larger than 4.6 mm in diameter, hindering its use for targeting small, unvascularized metastases.

  • To treat the complex problem of metastatic cancer, we must combine the expertise of engineers, biologists and clinicians.

Abstract

Metastasis accounts for the vast majority of cancer deaths. The unique challenges for treating metastases include their small size, high multiplicity and dispersion to diverse organ environments. Nanoparticles have many potential benefits for diagnosing and treating metastatic cancer, including the ability to transport complex molecular cargoes to the major sites of metastasis, such as the lungs, liver and lymph nodes, as well as targeting to specific cell populations within these organs. This Review highlights the research, opportunities and challenges for integrating engineering sciences with cancer biology and medicine to develop nanotechnology-based tools for treating metastatic disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The steps of metastasis and opportunities for therapeutic intervention.
Figure 2: Nanomaterial strategies from the point-of-view of the cell.
Figure 3: Metastatic spread to different organs.
Figure 4: The enhanced permeation and retention (EPR) effect.

Similar content being viewed by others

References

  1. Howlader, N. et al. SEER cancer statistics review 1975–2008. National Cancer Institute [online] (2011).

    Google Scholar 

  2. Steeg, P. S. Tumor metastasis: mechanistic insights and clinical challenges. Nature Med. 12, 895–904 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Sharp, P. A. & Langer, R. Research agenda. Promoting convergence in biomedical science. Science 333, 527 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Safra, T. et al. Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann. Oncol. 11, 1029–1033 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Tomao, S,. Miele, E,. Spinelli, G. P,. Miele, E. & Tomao, F. Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer. Int. J. Nanomedicine 4, 99–105 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Harisinghani, M. G. et al. A pilot study of lymphotrophic nanoparticle-enhanced magnetic resonance imaging technique in early stage testicular cancer: a new method for noninvasive lymph node evaluation. Urology 66, 1066–1071 (2005).

    Article  PubMed  Google Scholar 

  7. Shih, H. A. et al. Mapping of nodal disease in locally advanced prostate cancer: rethinking the clinical target volume for pelvic nodal irradiation based on vascular rather than bony anatomy. Int. J. Radiat. Oncol. Biol. Phys. 63, 1262–1269 (2005).

    Article  PubMed  Google Scholar 

  8. Duncan, R. & Gaspar, R. Nanomedicine(s) under the microscope. Mol. Pharm. 5 Oct 2011 (doi:10.1021/mp200394t).

  9. Wang, J,. Tian, S,. Petros, R. A,. Napier, M. E. & Desimone, J. M. The complex role of multivalency in nanoparticles targeting the transferrin receptor for cancer therapies. J. Am. Chem. Soc. 132, 11306–11313 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li, Z. et al. Nanoparticle delivery of anti-metastatic NM23-H1 gene improves chemotherapy in a mouse tumor model. Cancer Gene Ther. 16, 423–429 (2009).

    Article  PubMed  CAS  Google Scholar 

  11. Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010). This paper describes the first therapeutic siRNA knockdown in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li, S. D,. Chono, S. & Huang, L. Efficient oncogene silencing and metastasis inhibition via systemic delivery of siRNA. Mol. Ther. 16, 942–946 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Ma, L. et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nature Cell Biol. 12, 247–256 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Ma, L,. Teruya-Feldstein, J. & Weinberg, R. A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Ma, L. et al. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model. Nature Biotech. 28, 341–347 (2010).

    Article  CAS  Google Scholar 

  16. Gupta, R. A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pecot, C. V,. Calin, G. A,. Coleman, R. L,. Lopez-Berestein, G. & Sood, A. K. RNA interference in the clinic: challenges and future directions. Nature Rev. Cancer 11, 59–67 (2011).

    Article  CAS  Google Scholar 

  18. Zamora-Avila, D. E. et al. WT1 gene silencing by aerosol delivery of PEI-RNAi complexes inhibits B16-F10 lung metastases growth. Cancer Gene Ther. 16, 892–899 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Park, J. H. et al. Cooperative nanoparticles for tumor detection and photothermally triggered drug delivery. Adv. Mater. 22, 880–885 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. von Maltzahn, G. et al. SERS-coded gold nanorods as a multifunctional platform for densely multiplexed near-infrared imaging and photothermal heating. Adv. Mater. 21, 3175–3180 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gabizon, A,. Shmeeda, H. & Barenholz, Y. Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies. Clin. Pharmacokinet. 42, 419–436 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Lee, J. et al. Nucleic acid-binding polymers as anti-inflammatory agents. Proc. Natl Acad. Sci. USA 108, 14055–14060 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hood, J. D. et al. Tumor regression by targeted gene delivery to the neovasculature. Science 296, 2404–2407 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Murphy, E. A. et al. Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proc. Natl Acad. Sci. USA 105, 9343–9348 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138, 645–659 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Aboody, K. S. et al. Development of a tumor-selective approach to treat metastatic cancer. PLoS ONE 1, e23 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Peer, D. & Margalit, R. Loading mitomycin C inside long circulating hyaluronan targeted nano-liposomes increases its antitumor activity in three mice tumor models. Int. J. Cancer 108, 780–789 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Poon, Z. et al. Ligand-clustered “patchy” nanoparticles for modulated cellular uptake and in vivo tumor targeting. Angew. Chem. Int. Ed. Engl. 49, 7266–7270 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ali, O. A,. Emerich, D,. Dranoff, G. & Mooney, D. J. In situ regulation of DC Subsets and T cells mediates tumor regression in mice. Sci. Transl. Med. 1, 8–19 (2009).

    Article  CAS  Google Scholar 

  31. Timko, B. P,. Dvir, T. & Kohane, D. S. Remotely triggerable drug delivery systems. Adv. Mater. 22, 4925–4943 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Fischel-Ghodsian, F,. Brown, L,. Mathiowitz, E,. Brandenburg, D. & Langer, R. Enzymatically controlled drug delivery. Proc. Natl Acad. Sci. USA 85, 2403–2406 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schroeder, A. et al. Controlling liposomal drug release with low frequency ultrasound: mechanism and feasibility. Langmuir 23, 4019–4025 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Dromi, S. et al. Pulsed-high intensity focused ultrasound and low temperature sensitive liposomes for enhanced targeted drug delivery and antitumor effect. Clin. Cancer Res. 13, 2722–2727 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Burks, S. R. et al. Investigation of cellular and molecular responses to pulsed focused ultrasound in a mouse model. PLoS ONE 6, e24730 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lu, J,. Choi, E,. Tamanoi, F. & Zink, J. I. Light-activated nanoimpeller-controlled drug release in cancer cells. Small 4, 421–426 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kuruppuarachchi, M,. Savoie, H,. Lowry, A,. Alonso, C. & Boyle, R. W. Polyacrylamide nanoparticles as a delivery system in photodynamic therapy. Mol. Pharm. 8, 920–931 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Wu, G. et al. Remotely triggered liposome release by near-infrared light absorption via hollow gold nanoshells. J. Am. Chem. Soc. 130, 8175–8177 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Derfus, A. M. et al. Remotely triggered release from magnetic nanoparticles. Adv. Mater. 19, 3932–3936 (2007).

    Article  CAS  Google Scholar 

  40. Hoare, T. et al. Magnetically triggered nanocomposite membranes: a versatile platform for triggered drug release. Nano Lett. 11, 1395–1400 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lal, S,. Clare, S. E. & Halas, N. J. Nanoshell-enabled photothermal cancer therapy: impending clinical impact. Acc. Chem. Res. 41, 1842–1851 (2008). The interaction between tissue-transparent near-infrared light and gold nanomaterials results in the rapid heating of the nanoparticle, which can kill nearby tumour cells.

    Article  CAS  PubMed  Google Scholar 

  42. Yang, W. et al. Do liposomal apoptotic enhancers increase tumor coagulation and end-point survival in percutaneous radiofrequency ablation of tumors in a rat tumor model? Radiology 257, 685–696 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Baker, I,. Zeng, Q,. Li, W. D. & Sullivan, C. R. Heat deposition in iron oxide and iron nanoparticles for localized hyperthermia. J. Appl. Phys. 99, 08H106 (2006).

    Article  CAS  Google Scholar 

  44. Ivkov, R. et al. Application of high amplitude alternating magnetic fields for heat induction of nanoparticles localized in cancer. Clin. Cancer Res. 11, 7093s–7103s (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Young, J. H,. Wang, M. T. & Brezovich, I. A. Frequency-depth-penetration considerations in hyperthermia by magnetically induced currents. Electron. Lett. 16, 358–359 (1980).

    Article  Google Scholar 

  46. Kennedy, J. E. High-intensity focused ultrasound in the treatment of solid tumours. Nature Rev. Cancer 5, 321–327 (2005).

    Article  CAS  Google Scholar 

  47. Ziegelberger, G. ICNIRP statement on far infrared radiation exposure. Health Phys. 91, 630–645 (2006).

    Article  CAS  Google Scholar 

  48. Curley, S. A. et al. Noninvasive radiofrequency field-induced hyperthermic cytotoxicity in human cancer cells using cetuximab-targeted gold nanoparticles. J. Exp. Ther. Oncol. 7, 313–326 (2008).

    CAS  PubMed  Google Scholar 

  49. Moghimi, S. M,. Hunter, A. C. & Murray, J. C. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev. 53, 283–318 (2001).

    CAS  PubMed  Google Scholar 

  50. Eichler, A. F. et al. The biology of brain metastases-translation to new therapies. Nature Rev. Clin. Oncol. 8, 344–356 (2011).

    Article  CAS  Google Scholar 

  51. Lesniak, M. S. & Brem, H. Targeted therapy for brain tumours. Nature Rev. Drug Discov. 3, 499–508 (2004).

    Article  CAS  Google Scholar 

  52. Minagar, A. & Alexander, J. S. Blood-brain barrier disruption in multiple sclerosis. Mult. Scler. 9, 540–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Kizelsztein, P,. Ovadia, H,. Garbuzenko, O,. Sigal, A. & Barenholz, Y. Pegylated nanoliposomes remote-loaded with the antioxidant tempamine ameliorate experimental autoimmune encephalomyelitis. J. Neuroimmunol. 213, 20–25 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Jain, R. K. Physiological barriers to delivery of monoclonal-antibodies and other macromolecules in tumors. Cancer Res. 50, S814–S819 (1990).

    Google Scholar 

  55. Enochs, W. S,. Harsh, G,. Hochberg, F. & Weissleder, R. Improved delineation of human brain tumors on MR images using a long-circulating, superparamagnetic iron oxide agent. J. Magn. Reson. Imaging 9, 228–232 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Veiseh, O. et al. Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood-brain barrier. Cancer Res. 69, 6200–6207 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Calvo, P. et al. Long-circulating PEGylated polycyanoacrylate nanoparticles as new drug carrier for brain delivery. Pharm. Res. 18, 1157–1166 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Kreuter, J,. Alyautdin, R. N,. Kharkevich, D. A. & Ivanov, A. A. Passage of peptides through the blood-brain-barrier with colloidal polymer particles (nanoparticles). Brain Res. 674, 171–174 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Lockman, P. R,. Koziara, J. M,. Mumper, R. J. & Allen, D. D. Nanoparticle surface charges alter blood-brain barrier integrity and permeability. J. Drug Target. 12, 635–641 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Rousselle, C. et al. New advances in the transport of doxorubicin through the blood-brain barrier by a peptide vector-mediated strategy. Mol. Pharmacol. 57, 679–686 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Bisgaier, C. L,. Siebenkas, M. V. & Williams, K. J. Effects of apolipoproteins A-IV and A-I on the uptake of phospholipid liposomes by hepatocytes. J. Biol. Chem. 264, 862–866 (1989).

    CAS  PubMed  Google Scholar 

  62. Akinc, A. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kreuter, J. et al. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J. Drug Target. 10, 317–325 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Michaelis, K. et al. Covalent linkage of apolipoprotein E to albumin nanoparticles strongly enhances drug transport into the brain. J. Pharmacol. Exp. Ther. 317, 1246–1253 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Mahley, R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240, 622–630 (1988).

    Article  CAS  PubMed  Google Scholar 

  66. Yan, X. et al. The role of apolipoprotein E in the elimination of liposomes from blood by hepatocytes in the mouse. Biochem. Biophys. Res. Commun. 328, 57–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Huwyler, J,. Wu, D. F. & Pardridge, W. M. Brain drug delivery of small molecules using immunoliposomes. Proc. Natl Acad. Sci. USA 93, 14164–14169 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. van Kasteren, S. I. et al. Glyconanoparticles allow pre-symptomatic in vivo imaging of brain disease. Proc. Natl Acad. Sci. USA 106, 18–23 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Pollard, J. W. Macrophages define the invasive microenvironment in breast cancer. J. Leukoc. Biol. 84, 623–630 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. DeNardo, D. G,. Johansson, M. & Coussens, L. M. Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev. 27, 11–18 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Afergan, E. et al. Delivery of serotonin to the brain by monocytes following phagocytosis of liposomes. J. Control. Release 132, 84–90 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Wu, Y. J. et al. In vivo leukocyte labeling with intravenous ferumoxides/protamine sulfate complex and in vitro characterization for cellular magnetic resonance imaging. Am. J. Physiol. Cell Physiol. 293, C1698–C1708 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Cheng, H. et al. Nanoparticulate cellular patches for cell-mediated tumoritropic delivery. ACS Nano 4, 625–631 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Stephan, M. T,. Moon, J. J,. Um, S. H,. Bershteyn, A. & Irvine, D. J. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nature Med. 16, 1035–1041 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Moore, A,. Sergeyev, N,. Bredow, S. & Weissleder, R. A model system to quantitate tumor burden in locoregional lymph nodes during cancer spread. Invasion Metastasis 18, 192–197 (1998).

    Article  PubMed  Google Scholar 

  76. Raz, A,. Bucana, C,. Fogler, W. E,. Poste, G. & Fidler, I. J. Biochemical, morphological, and ultrastructural studies on the uptake of liposomes by murine macrophages. Cancer Res. 41, 487–494 (1981).

    CAS  PubMed  Google Scholar 

  77. Hsu, M. J. & Juliano, R. L. Interactions of liposomes with the reticuloendothelial system. II: nonspecific and receptor-mediated uptake of liposomes by mouse peritoneal macrophages. Biochim. Biophys. Acta 720, 411–419 (1982).

    Article  CAS  PubMed  Google Scholar 

  78. Tassa, C,. Shaw, S. Y. & Weissleder, R. Dextran-coated iron oxide nanoparticles: a versatile platform for targeted molecular imaging, molecular diagnostics, and therapy. Acc. Chem. Res. 44, 842–852 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nahrendorf, M. et al. Detection of macrophages in aortic aneurysms by nanoparticle positron emission tomography-computed tomography. Arterioscler. Thromb. Vasc. Biol. 31, 750–757 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Harisinghani, M. G. et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N. Engl. J. Med. 348, 2491–2499 (2003). Iron oxide nanoparticles have evolved over time into effective tools for imaging the spread of metastatic cancer.

    Article  PubMed  Google Scholar 

  81. Finkelstein, M. C,. Kuhn, S. H,. Schieren, H,. Weissmann, G. & Hoffstein, S. Liposome uptake by human-leukocytes - enhancement of entry mediated by human-serum and aggregated immunoglobulins. Biochim. Biophys. Acta 673, 286–302 (1981).

    Article  CAS  PubMed  Google Scholar 

  82. Torchilin, V. P. & Papisov, M. I. Why do polyethylene glycol-coated liposomes circulate so long? J. Liposome Res. 4, 725–739 (1994).

    Article  Google Scholar 

  83. Gref, R. et al. Biodegradable long-circulating polymeric nanospheres. Science 263, 1600–1603 (1994). The clinical benefits of using materials such as PEG to add 'stealth' properties to nanoparticles for systemic administration.

    Article  CAS  PubMed  Google Scholar 

  84. Gabizon, A. A. Stealth liposomes and tumor targeting: one step further in the quest for the magic bullet. Clin. Cancer Res. 7, 223–225 (2001).

    CAS  PubMed  Google Scholar 

  85. Choi, H. S. et al. Rapid translocation of nanoparticles from the lung airspaces to the body. Nature Biotech. 28, 1300–1303 (2010). The biodistribution of nanomaterials is greatly affected by the route of administration.

    Article  CAS  Google Scholar 

  86. Allen, T. M,. Hansen, C. B. & Guo, L. S. Subcutaneous administration of liposomes: a comparison with the intravenous and intraperitoneal routes of injection. Biochim. Biophys. Acta 1150, 9–16 (1993).

    Article  CAS  PubMed  Google Scholar 

  87. Reddy, S. T. et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nature Biotech. 25, 1159–1164 (2007).

    Article  CAS  Google Scholar 

  88. Akinc, A. et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nature Biotech. 26, 561–569 (2008).

    Article  CAS  Google Scholar 

  89. Sadauskas, E. et al. Kupffer cells are central in the removal of nanoparticles from the organism. Part. Fibre Toxicol. 4, 10 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Baenziger, J. U. & Fiete, D. Galactose and N-acetylgalactosamine-specific endocytosis of glycopeptides by isolated rat hepatocytes. Cell 22, 611–620 (1980).

    Article  CAS  PubMed  Google Scholar 

  91. Cervantes, A. et al. Phase I dose-escalation study of ALN-VSP02, a novel RNAi therapeutic for solid tumors with liver involvement. J. Clin. Oncol. Abstr. 29 3025 (2011).

    Article  Google Scholar 

  92. Maeda, H. & Matsumura, Y. EPR effect based drug design and clinical outlook for enhanced cancer chemotherapy Preface. Adv. Drug Deliv. Rev. 63, 129–130 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Yuan, F. et al. Vascular-permeability in a human tumor xenograft - molecular-size dependence and cutoff size. Cancer Res. 55, 3752–3756 (1995).

    CAS  PubMed  Google Scholar 

  95. Braet, F. & Wisse, E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp. Hepatol 1, 1 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Torchilin, V. Tumor delivery of macromolecular drugs based on the EPR effect. Adv. Drug Deliv. Rev. 63, 131–135 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Adiseshaiah, P. P,. Hall, J. B. & McNeil, S. E. Nanomaterial standards for efficacy and toxicity assessment. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2, 99–112 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Edwards, D. A. et al. Large porous particles for pulmonary drug delivery. Science 276, 1868–1871 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Azarmi, S,. Roa, W. H. & Lobenberg, R. Targeted delivery of nanoparticles for the treatment of lung diseases. Adv. Drug Deliv. Rev. 60, 863–875 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Ilium, L. et al. Blood clearance and organ deposition of intravenously administered colloidal particles. The effects of particle size, nature and shape. Int. J. Pharm. 12, 135–146 (1982).

    Article  Google Scholar 

  101. Pinkerton, N. M. et al. Lung targeting with triggered release using gel microparticles with encapsulated nanoparticles. AICHE annual meeting Abstr. 524F (2011).

  102. Ekrami, H,. Kennedy, A. R. & Shen, W. C. Disposition of positively charged bowman-birk protease inhibitor conjugates in mice - influence of protein conjugate charge-density and size on lung targeting. J. Pharm. Sci. 84, 456–461 (1995).

    Article  CAS  PubMed  Google Scholar 

  103. Ma, Z. et al. Redirecting adenovirus to pulmonary endothelium by cationic liposomes. Gene Ther. 9, 176–182 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Polach, K. J. et al. Delivery of siRNA to the mouse lung via a functionalized lipopolyamine. Mol. Ther. 11 Oct 2011 (doi:10.1038/mt.2011.210).

  105. Sakurai, F,. Nishioka, T,. Yamashita, F,. Takakura, Y. & Hashida, M. Effects of erythrocytes and serum proteins on lung accumulation of lipoplexes containing cholesterol or DOPE as a helper lipid in the single-pass rat lung perfusion system. Eur. J. Pharm. Biopharm. 52, 165–172 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Senior, J. H,. Trimble, K. R. & Maskiewicz, R. Interaction of positively-charged liposomes with blood: implications for their application in vivo. Biochim. Biophys. Acta 1070, 173–179 (1991).

    Article  CAS  PubMed  Google Scholar 

  107. Sarfati, G,. Dvir, T,. Elkabets, M,. Apte, R. N. & Cohen, S. Targeting of polymeric nanoparticles to lung metastases by surface-attachment of YIGSR peptide from laminin. Biomaterials 32, 152–161 (2010).

    Article  PubMed  CAS  Google Scholar 

  108. Hess, K. R. et al. Metastatic patterns in adenocarcinoma. Cancer 106, 1624–1633 (2006).

    Article  PubMed  Google Scholar 

  109. Roodman, G. D. Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655–1664 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Wang, D,. Miller, S. C,. Kopeckova, P. & Kopecek, J. Bone-targeting macromolecular therapeutics. Adv. Drug Deliv. Rev. 57, 1049–1076 (2005). This paper highlights the need to develop new modalities for targeting bone metastasis.

    Article  CAS  PubMed  Google Scholar 

  111. Roodman, G. D. Mechanisms of bone metastasis. Discov. Med. 4, 144–148 (2004).

    PubMed  Google Scholar 

  112. Hengst, V,. Oussoren, C,. Kissel, T. & Storm, G. Bone targeting potential of bisphosphonate-targeted liposomes. Preparation, characterization and hydroxyapatite binding in vitro. Int. J. Pharm. 331, 224–227 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Steeg, P. S. Metastasis suppressors alter the signal transduction of cancer cells. Nature Rev. Cancer 3, 55–63 (2003).

    Article  CAS  Google Scholar 

  114. Chertok, B,. David, A. E. & Yang, V. C. Brain tumor targeting of magnetic nanoparticles for potential drug delivery: effect of administration route and magnetic field topography. J. Control. Release 155, 393–399 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chertok, B,. David, A. E,. Huang, Y. & Yang, V. C. Glioma selectivity of magnetically targeted nanoparticles: a role of abnormal tumor hydrodynamics. J. Control. Release 122, 315–323 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lum, A. F. et al. Ultrasound radiation force enables targeted deposition of model drug carriers loaded on microbubbles. J. Control. Release 111, 128–134 (2006).

    Article  CAS  PubMed  Google Scholar 

  117. von Maltzahn G. Fau - Park, J.-H. et al. Nanoparticles that communicate in vivo to amplify tumour targeting. Nature Mater. 10, 545–552 (2011). Two-part nanoparticle system, where one nanoparticle recruits a second therapeutic nanoparticle to a disease site.

    Article  CAS  Google Scholar 

  118. Ebbens, S. J. & Howse, J. R. In pursuit of propulsion at the nanoscale. Soft Matter 6, 726–738 (2010).

    Article  CAS  Google Scholar 

  119. Mallouk, T. E. & Sen, A. Powering nanorobots. Sci. Am. 300, 72–77 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Balzar, M,. Winter, M. J,. de Boer, C. J. & Litvinov, S. V. The biology of the 17–11A antigen (Ep-CAM). J. Mol. Med. 77, 699–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. Kaminski, M. S. et al. I-131-tositumomab therapy as initial treatment for follicular lymphoma. N. Engl. J. Med. 352, 441–449 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Cheever, M. A. et al. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin. Cancer Res. 15, 5323–5337 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Jain, R. K. et al. Phase I oncology studies: evidence that in the era of targeted therapies patients on lower doses do not fare worse. Clin. Cancer Res. 16, 1289–1297 (2010). This study suggests that targeted drugs show better efficacy than untargeted ones, this may be due to higher accumulation in disease sites.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Torchilin, V. P,. Lukyanov, A. N,. Gao, Z. & Papahadjopoulos-Sternberg, B. Immunomicelles: targeted pharmaceutical carriers for poorly soluble drugs. Proc. Natl Acad. Sci. USA 100, 6039–6044 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Brannon-Peppas, L. & Blanchette, J. O. Nanoparticle and targeted systems for cancer therapy. Adv. Drug Deliv. Rev. 56, 1649–1659 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Kirpotin, D. B. et al. Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res. 66, 6732–6740 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Yang, W. et al. TMTP1, a novel tumor-homing peptide specifically targeting metastasis. Clin. Cancer Res. 14, 5494–5502 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Chen, K. et al. Triblock copolymer coated iron oxide nanoparticle conjugate for tumor integrin targeting. Biomaterials 30, 6912–6919 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Desgrosellier, J. S. & Cheresh, D. A. Integrins in cancer: biological implications and therapeutic opportunities. Nature Rev. Cancer 10, 9–22 (2010).

    Article  CAS  Google Scholar 

  130. Hanes, J,. Jermutus, L. & Plückthun, A. Selecting and evolving functional proteins in vitro by ribosome display. Methods Enzymol. 328, 404–430 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Farokhzad, O. C. et al. Nanopartide-aptamer bioconjugates: a new approach for targeting prostate cancer cells. Cancer Res. 64, 7668–7672 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Shigdar, S. et al. RNA aptamer against a cancer stem cell marker epithelial cell adhesion molecule. Cancer Sci. 102, 991–998 (2011).

    Article  CAS  PubMed  Google Scholar 

  133. Gragoudas, E. S,. Adamis, A. P,. Cunningham, E. T. Jr, Feinsod, M. & Guyer, D. R. Pegaptanib for neovascular age-related macular degeneration. N. Engl. J. Med. 351, 2805–2816 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Hanvey, J. C. et al. Antisense and antigene properties of peptide nucleic-acids. Science 258, 1481–1485 (1992).

    Article  CAS  PubMed  Google Scholar 

  135. Zannetti, A. et al. Inhibition of Sp1 activity by a decoy PNA-DNA chimera prevents urokinase receptor expression and migration of breast cancer cells. Biochem. Pharmacol. 70, 1277–1287 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Yamada, A. et al. Design of folate-linked liposomal doxorubicin to its antitumor effect in mice. Clin. Cancer Res. 14, 8161–8168 (2008).

    Article  CAS  PubMed  Google Scholar 

  137. Hartmann, L. C. et al. Folate receptor overexpression is associated with poor outcome in breast cancer. Int. J. Cancer 121, 938–942 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Wang, X. et al. A folate receptor-targeting nanoparticle minimizes drug resistance in a human cancer model. ACS Nano 5, 6184–6194 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. D'Angelica, M. et al. Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance. Mod. Pathol. 24, 1221–1228 (2011).

    Article  PubMed  Google Scholar 

  140. Garin, J. et al. The phagosome proteome: insight into phagosome functions. J. Cell Biol. 152, 165–180 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Rajendran, L,. Knolker, H. J. & Simons, K. Subcellular targeting strategies for drug design and delivery. Nature Rev. Drug Discov. 9, 29–42 (2010).

    Article  CAS  Google Scholar 

  142. Verma, A. et al. Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles. Nature Mater. 7, 588–595 (2008).

    Article  CAS  Google Scholar 

  143. Kabanov, A. V,. Sahay, G. & Alakhova, D. Y. Endocytosis of nanomedicines. J. Control. Release 145, 182–195 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Bareford, L. A. & Swaan, P. W. Endocytic mechanisms for targeted drug delivery. Adv. Drug Deliv. Reviews 59, 748–758 (2007).

    Article  CAS  Google Scholar 

  145. Schroeder, A,. Levins, C. G,. Cortez, C,. Langer, R. & Anderson, D. G. Lipid-based nanotherapeutics for siRNA delivery. J. Internal Med. 267, 9–21 (2010).

    Article  CAS  PubMed  Google Scholar 

  146. Goldberg, M,. Langer, R. & Jia, X. Nanostructured materials for applications in drug delivery and tissue engineering. J. Biomater Sci. Polym. Ed. 18, 241–268 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Torchilin, V. P. Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery. Biopolymers 90, 604–610 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. Love, K. T. et al. Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl Acad. Sci. USA 107, 1864–1869 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Andersen, E. S. et al. Self-assembly of a nanoscale DNA box with a controllable lid. Nature 459, 73–76 (2009). Sophisticated structures made of nucleic acids can be logically controlled to carry out delivery-related tasks.

    Article  CAS  PubMed  Google Scholar 

  150. Zhang, W. et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin. Cancer Res. 16, 3420–3430 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Scarberry, K. E,. Dickerson, E. B,. Zhang, Z. J,. Benigno, B. B. & McDonald, J. F. Selective removal of ovarian cancer cells from human ascites fluid using magnetic nanoparticles. Nanomedicine 6, 399–408 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Galanzha, E. I. et al. In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells. Nature Nanotechnol. 4, 855–860 (2009).

    Article  CAS  Google Scholar 

  153. Coffey, D. S,. Getzenberg, R. H. & DeWeese, T. L. Hyperthermic biology and cancer therapies: a hypothesis for the “Lance Armstrong effect”. JAMA 296, 445–448 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Ruggiero, A. et al. Paradoxical glomerular filtration of carbon nanotubes. Proc. Natl Acad. Sci. USA 107, 12369–12374 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Geng, Y. et al. Shape effects of filaments versus spherical particles in flow and drug delivery. Nature Nanotechnol. 2, 249–255 (2007). The mechanical properties and shape of the particle have great effects on the circulation time and on the ability to penetrate disease sites.

    Article  CAS  Google Scholar 

  156. Slowing, I.I., Trewyn, B. G. & Lin, V. S. Mesoporous silica nanoparticles for intracellular delivery of membrane-impermeable proteins. J. Am. Chem. Soc. 129, 8845–8849 (2007).

    Article  CAS  PubMed  Google Scholar 

  157. Gratton, S. E. et al. The effect of particle design on cellular internalization pathways. Proc. Natl Acad. Sci. USA 105, 11613–11618 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Wiltschke, C. et al. A phase I study to evaluate safety, immunogenicity and antitumor activity of a HER2 multi-peptide virosome vaccine in patients with metastatic breast cancer. J. Clin. Oncol. Abstr. 26, 3055 (2008).

    Article  Google Scholar 

  159. Brunel, F. M. et al. Hydrazone ligation strategy to assemble multifunctional viral nanoparticles for cell imaging and tumor targeting. Nano Lett. 10, 1093–1097 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Chow, E. K. et al. Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment. Sci. Transl. Med. 3, 73ra21 (2011).

    Article  PubMed  Google Scholar 

  161. Alexis, F,. Pridgen, E,. Molnar, L. K. & Farokhzad, O. C. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol. Pharm. 5, 505–515 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Cortez, C. et al. Influence of size, surface, cell line, and kinetic properties on the specific binding of A33 antigen-targeted multilayered particles and capsules to colorectal cancer cells. ACS Nano 1, 93–102 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Astete, C. E. & Sabliov, C. M. Synthesis and characterization of PLGA nanoparticles. J. Biomater. Sci. Polym. Ed. 17, 247–289 (2006).

    Article  CAS  PubMed  Google Scholar 

  164. Murphy, E. A. et al. Targeted nanogels: a versatile platform for drug delivery to tumors. Mol. Cancer Ther. 10, 972–982 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Schroeder, A,. Kost, J. & Barenholz, Y. Ultrasound, liposomes, and drug delivery: principles for using ultrasound to control the release of drugs from liposomes. Chem. Phys. Lipids 162, 1–16 (2009).

    Article  CAS  PubMed  Google Scholar 

  166. Liu, X. Q,. Song, W. J,. Sun, T. M,. Zhang, P. Z. & Wang, J. Targeted delivery of antisense inhibitor of miRNA for antiangiogenesis therapy using cRGD-functionalized nanoparticles. Mol. Pharm. 8, 250–259 (2011).

    Article  CAS  PubMed  Google Scholar 

  167. Tannock, I. F. & Rotin, D. Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res. 49, 4373–4384 (1989).

    CAS  PubMed  Google Scholar 

  168. Lee, E. S,. Gao, Z. & Bae, Y. H. Recent progress in tumor pH targeting nanotechnology. J. Control. Release 132, 164–170 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Park, J. H. et al. Cooperative nanomaterial system to sensitize, target, and treat tumors. Proc. Natl Acad. Sci. USA 107, 981–986 (2010).

    Article  CAS  PubMed  Google Scholar 

  170. Libutti, S. K. et al. Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. Clin. Cancer Res. 16, 6139–6149 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Dai, H. J,. Kam, N. W. S. & Liu, Z. Functionalization of carbon nanotubes via cleavable disulfide bonds for efficient intracellular delivery of siRNA and potent gene silencing. J. Am. Chem. Soc. 127, 12492–12493 (2005).

    Article  PubMed  CAS  Google Scholar 

  172. Kedmi, R,. Ben-Arie, N. & Peer, D. The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation. Biomaterials 26, 6867–6875 (2010).

    Article  CAS  Google Scholar 

  173. Chonn, A,. Cullis, P. R. & Devine, D. V. The role of surface charge in the activation of the classical and alternative pathways of complement by liposomes. J. Immunol. 146, 4234–4241 (1991).

    CAS  PubMed  Google Scholar 

  174. Reddy, J. A. et al. Preclinical evaluation of EC145, a folate-vinca alkaloid conjugate. Cancer Res. 67, 4434–4442 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Hamad, I. et al. Distinct polymer architecture mediates switching of complement activation pathways at the nanosphere-serum interface: implications for stealth nanoparticle engineering. ACS Nano 4, 6629–6638 (2010).

    Article  CAS  PubMed  Google Scholar 

  176. Harashima, H,. Sakata, K,. Funato, K. & Kiwada, H. Enhanced hepatic uptake of liposomes through complement activation depending on the size of liposomes. Pharm. Res. 11, 402–406 (1994).

    Article  CAS  PubMed  Google Scholar 

  177. Chanan-Khan, A. et al. Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions. Ann. Oncol. 14, 1430–1437 (2003).

    Article  CAS  PubMed  Google Scholar 

  178. Grimaldi, S,. Lisi, A,. Pozzi, D. & Santoro, N. Attempts to use liposomes and RBC ghosts as vectors in drug and antisense therapy of virus infection. Res. Virol. 148, 177–180 (1997).

    Article  CAS  PubMed  Google Scholar 

  179. Pierige, F,. Serafini, S,. Rossi, L. & Magnani, M. Cell-based drug delivery. Adv. Drug Deliv. Rev. 60, 286–295 (2008).

    Article  CAS  PubMed  Google Scholar 

  180. Hu, C. M,. Zhang, L,. Aryal, S,. Cheung, C. & Fang, R. H. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc. Natl Acad. Sci. USA 108, 10980–10985 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Updike, S. J,. Wakamiya, R. T. & Lightfoot, E. N. Jr. Asparaginase entrapped in red blood cells: action and survival. Science 193, 681–683 (1976).

    Article  CAS  PubMed  Google Scholar 

  182. Kruse, C. A,. Tin, G. W. & Baldeschwieler, J. D. Stability of erythrocyte ghosts: a γ-ray perturbed angular correlation study. Proc. Natl Acad. Sci. USA 80, 1212–1216 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Yang, F. et al. Genetic engineering of human stem cells for enhanced angiogenesis using biodegradable polymeric nanoparticles. Proc. Natl Acad. Sci. USA 107, 3317–3322 (2010).

    Article  CAS  PubMed  Google Scholar 

  184. Rachakatla, R. S. et al. Attenuation of mouse melanoma by A/C magnetic field after delivery of bi-magnetic nanoparticles by neural progenitor cells. ACS Nano 4, 7093–7104 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Bronshtein, T,. Toledano, N,. Danino, D,. Pollack, S. & Machluf, M. Cell derived liposomes expressing CCR5 as a new targeted drug-delivery system for HIV infected cells. J. Control. Release 151, 139–148 (2011).

    Article  CAS  PubMed  Google Scholar 

  186. Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotech. 29, 341–345 (2011).

    Article  CAS  Google Scholar 

  187. Hardman, R. A toxicologic review of quantum dots: toxicity depends on physicochemical and environmental factors. Environ. Health Perspect. 114, 165–172 (2006).

    Article  PubMed  Google Scholar 

  188. Lytton-Jean, A. K. R,. Langer, R. & Anderson, D. G. Five years of siRNA delivery: spotlight on gold nanoparticles. Small 7, 1932–1937 (2011).

    Article  CAS  PubMed  Google Scholar 

  189. Zhang, C. et al. Specific targeting of tumor angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner. Cancer Res. 67, 1555–1562 (2007).

    Article  CAS  PubMed  Google Scholar 

  190. Bolskar, R. D. et al. First soluble M@C60 derivatives provide enhanced access to metallofullerenes and permit in vivo evaluation of Gd@C60[C(COOH)2]10 as a MRI contrast agent. J. Am. Chem. Soc. 125, 5471–5478 (2003).

    Article  CAS  PubMed  Google Scholar 

  191. Yu, X. et al. High-resolution MRI characterization of human thrombus using a novel fibrin-targeted paramagnetic nanoparticle contrast agent. Magn. Reson. Med. 44, 867–872 (2000).

    Article  CAS  PubMed  Google Scholar 

  192. Benezra, M. et al. Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma. J. Clin. Invest. 121, 2768–2780 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Jennings, L. E. & Long, N. J. 'Two is better than one'-probes for dual-modality molecular imaging. Chem. Commun. 28, 3511–3524 (2009).

    Article  CAS  Google Scholar 

  194. Lee, H. Y. et al. PET/MRI dual-modality tumor imaging using arginine-glycine-aspartic (RGD) - conjugated radiolabeled iron oxide nanoparticles. J. Nucl. Med. 49, 1371–1379 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  196. Rabin, O,. Perez, J. M,. Grimm, J,. Wojtkiewicz, G. & Weissleder, R. An X-ray computed tomography imaging agent based on long-circulating bismuth sulphide nanoparticles. Nature Mater. 5, 118–122 (2006).

    Article  CAS  Google Scholar 

  197. Hu, G. et al. Imaging of Vx-2 rabbit tumors with ανβ3-integrin-targeted 111In nanoparticles. Int. J. Cancer 120, 1951–1957 (2007).

    Article  CAS  PubMed  Google Scholar 

  198. Choi, J. H. et al. Multimodal biomedical imaging with asymmetric single-walled carbon nanotube/iron oxide nanoparticle complexes. Nano Lett. 7, 861–867 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Kim, C. S. et al. Enhanced detection of early-stage oral cancer in vivo by optical coherence tomography using multimodal delivery of gold nanoparticles. J. Biomed. Opt. 14, 034008 (2009).

    Article  PubMed  CAS  Google Scholar 

  200. Nguyen, Q. T. et al. Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival. Proc. Natl Acad. Sci. USA 107, 4317–4322 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Voura, E. B,. Jaiswal, J. K,. Mattoussi, H. & Simon, S. M. Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy. Nature Med. 10, 993–998 (2004).

    Article  CAS  PubMed  Google Scholar 

  202. Stroh, M. et al. Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo. Nature Med. 11, 678–682 (2005).

    Article  CAS  PubMed  Google Scholar 

  203. Heller, D. A. et al. Multimodal optical sensing and analyte specificity using single-walled carbon nanotubes. Nature Nanotechnol. 4, 114–120 (2009).

    Article  CAS  Google Scholar 

  204. Haes, A. J. & Van Duyne, R. P. A nanoscale optical blosensor: sensitivity and selectivity of an approach based on the localized surface plasmon resonance spectroscopy of triangular silver nanoparticles. J. Am. Chem. Soc. 124, 10596–10604 (2002). Molecules in the vicinity of gold or silver nanoparticles can be detected down to the single-molecule level, allowing sensitive analyte detection.

    Article  CAS  PubMed  Google Scholar 

  205. Zheng, G. F,. Patolsky, F,. Cui, Y,. Wang, W. U. & Lieber, C. M. Multiplexed electrical detection of cancer markers with nanowire sensor arrays. Nature Biotech. 23, 1294–1301 (2005).

    Article  CAS  Google Scholar 

  206. Bajaj, A. et al. Detection and differentiation of normal, cancerous, and metastatic cells using nanoparticle-polymer sensor arrays. Proc. Natl Acad. Sci. USA 106, 10912–10916 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Cheng, H. Y. et al. Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis. PLoS ONE 6, e17745 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Chinnaiyan, A. M. et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910–914 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Heath, J. R. et al. Integrated barcode chips for rapid, multiplexed analysis of proteins in microliter quantities of blood. Nature Biotech. 26, 1373–1378 (2008).

    Article  CAS  Google Scholar 

  210. Pouyssegur, J,. Dayan, F. & Mazure, N. M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437–443 (2006).

    Article  CAS  PubMed  Google Scholar 

  211. Denko, N. C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nature Rev. Cancer 8, 705–713 (2008).

    Article  CAS  Google Scholar 

  212. Lopez-Otin, C. & Matrisian, L. M. Emerging roles of proteases in tumour suppression. Nature Rev. Cancer 7, 800–808 (2007).

    Article  CAS  Google Scholar 

  213. Cavallaro, U. & Christofori, G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nature Rev. Cancer 4, 118–132 (2004).

    Article  CAS  Google Scholar 

  214. Lin, R. Z. et al. Tumor-induced endothelial cell apoptosis: roles of NAD(P)H oxidase-derived reactive oxygen species. J. Cell. Physiol. 226, 1750–1762 (2011).

    Article  CAS  PubMed  Google Scholar 

  215. Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Chiang, A. C. & Massague, J. Molecular basis of metastasis. N. Engl. J. Med. 359, 2814–2823 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Nguyen, D. X. & Massague, J. Genetic determinants of cancer metastasis. Nature Rev. Genet. 8, 341–352 (2007).

    Article  CAS  PubMed  Google Scholar 

  218. Brown, D. M. & Ruoslahti, E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5, 365–374 (2004).

    Article  CAS  PubMed  Google Scholar 

  219. Miles, F. L,. Pruitt, F. L,. van Golen, K. L. & Cooper, C. R. Stepping out of the flow: capillary extravasation in cancer metastasis. Clin. Exp. Metastasis 25, 305–324 (2008).

    Article  CAS  PubMed  Google Scholar 

  220. Gay, L. J. & Felding-Habermann, B. Contribution of platelets to tumour metastasis. Nature Rev. Cancer 11, 123–134 (2011).

    Article  CAS  Google Scholar 

  221. Meng, S. et al. Circulating tumor cells in patients with breast cancer dormancy. Clin. Cancer Res. 10, 8152–8162 (2004).

    Article  PubMed  Google Scholar 

  222. Gupta, G. P. et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765–770 (2007).

    Article  CAS  PubMed  Google Scholar 

  223. Weis, S,. Cui, J,. Barnes, L. & Cheresh, D. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J. Cell Biol. 167, 223–229 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nature Rev. Cancer 9, 239–252 (2009).

    Article  CAS  Google Scholar 

  225. Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nature Rev. Cancer 9, 285–293 (2009).

    Article  CAS  Google Scholar 

  226. Christian, D. A. et al. Flexible filaments for in vivo imaging and delivery: persistent circulation of filomicelles opens the dosage window for sustained tumor shrinkage. Mol. Pharm. 6, 1343–1352 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank R. Weinberg, R. Weissleder, J. Kolodny, C. A. Alabi, B. Chertok, V. Frenkel and D. Siegwart for helpful discussions. A.S. thanks the Misrock Foundation and D.A.H. thanks the Damon Runyon Cancer Research Foundation for postdoctoral support. M.M.W. thanks the US National Institutes of Health (NIH; grant K99-CA151968). J.D. thanks the National Defense Science and Engineering Graduate fellowship, National Science Foundation and MIT Presidential Fellowships for support as well as A. Bell and J. Haught for motivation. The authors thank the MIT-Harvard Center of Cancer Nanotechnology Excellence (CCNE) for NIH grants U54CA151884 and EB000244.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Robert Langer, Tyler Jacks or Daniel G. Anderson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Glossary

Shear rates

The velocity gradient that is the relative velocity at which one layer of the fluid flows over an adjacent layer of the fluid.

Kupffer cells

A type of macrophage that lines the sinusoid walls of the liver and that removes toxins present in blood coming from the digestive tract. Involved in the breakdown and recycling of red blood cells and haemoglobin.

Phage display

A selection technique in which a library of peptide or protein variants is expressed on the outer membrane of virus-infected bacteria (phage virion) and then screened for binding affinity using a process called panning.

Ribosome display

A selection technique in which diverse gene sequences encoding functional proteins are produced by ribosomes and then screened for their affinity to bioactive targets using a process called panning.

Aptamers

Oligonucleotides with high binding affinity to proteins or other molecules.

Peptide nucleic acids

Artificial polymers that mimic the DNA or RNA base structure, but that replace the negatively charged deoxyribose and ribose sugar backbone with N-(2-aminoethyl)-glycine units linked by peptide bonds.

DNA origami cages

The specificity between complementary DNA base pairs enables constructing nanoscale architectures using a combination of predesigned long and short DNA strands.

Filomicelles

Worm-like micelles that are composed mainly of biodegradable materials that can reach up to several microns in length and that can remain in circulation for long periods of time after intravenous administration.

Tunable imaging agents

The emission wavelength of quantum dots can be modulated by changing their size.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schroeder, A., Heller, D., Winslow, M. et al. Treating metastatic cancer with nanotechnology. Nat Rev Cancer 12, 39–50 (2012). https://doi.org/10.1038/nrc3180

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3180

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer