Nanocarriers as an emerging platform for cancer therapy

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Abstract

Nanotechnology has the potential to revolutionize cancer diagnosis and therapy. Advances in protein engineering and materials science have contributed to novel nanoscale targeting approaches that may bring new hope to cancer patients. Several therapeutic nanocarriers have been approved for clinical use. However, to date, there are only a few clinically approved nanocarriers that incorporate molecules to selectively bind and target cancer cells. This review examines some of the approved formulations and discusses the challenges in translating basic research to the clinic. We detail the arsenal of nanocarriers and molecules available for selective tumour targeting, and emphasize the challenges in cancer treatment.

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Figure 1: Schematic representation of different mechanisms by which nanocarriers can deliver drugs to tumours.
Figure 2: Common targeting agents and ways to improve their affinity and selectivity.
Figure 3: Examples of nanocarriers for targeting cancer.

References

  1. 1

    Stewart, B. W. & Kleihues, P. World Cancer Report (World Health Organization Press, Geneva, 2003).

  2. 2

    Cancer Facts & Figures 2007 (American Cancer Society, Atlanta, 2007).

  3. 3

    Duncan, R. Polymer conjugates as anticancer nanomedicines. Nat. Rev. Cancer 6, 688–701 (2006).

  4. 4

    Ferrari, M. Cancer nanotechnology: opportunities and challenges. Nat. Rev. Cancer 5, 161–171 (2005).

  5. 5

    Couvreur, P. & Vauthier, C. Nanotechnology: Intelligent design to treat complex disease. Pharm. Res. 23, 1417–1450 (2006).

  6. 6

    Alonso, M. J. Nanomedicines for overcoming biological barriers. Biomed. Pharmacother. 58, 168–172 (2004).

  7. 7

    Matsumura, Y. & Maeda, H. A new concept for macromolecular therapeutics in cancer-chemotherapy — Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46, 6387–6392 (1986).

  8. 8

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

  9. 9

    Torchilin, V. P. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov. 4, 145–160 (2005).

  10. 10

    Hobbs, S. K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607–4612 (1998).

  11. 11

    Gottesman, M. M., Fojo, T. & Bates, S. E. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat. Rev. Cancer 2, 48–58 (2002).

  12. 12

    Peer, D. & Margalit, R. Fluoxetine and reversal of multidrug resistance. Cancer Lett. 237, 180–187 (2006).

  13. 13

    Jain, R. K. Barriers to drug-delivery in solid tumors. Sci. Am. 271, 58–65 (1994).

  14. 14

    de Menezes, D. E. L., Pilarski, L. M. & Allen, T. M. In vitro and in vivo targeting of immunoliposomal doxorubicin to human B-cell lymphoma. Cancer Res. 58, 3320–3330 (1998).

  15. 15

    Park, J. W. et al. Anti-HER2 immunoliposomes: enhanced efficacy attributable to targeted delivery. Clin. Cancer Res. 8, 1172–1181 (2002).

  16. 16

    Allen, T. M. Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer 2, 750–763 (2002).

  17. 17

    Pastan, I., Hassan, R., FitzGerald, D. J. & Kreitman, R. J. Immunotoxin therapy of cancer. Nat. Rev. Cancer 6, 559–565 (2006).

  18. 18

    Peer, D., Zhu, P., Carman, C. V., Lieberman, J. & Shimaoka, M. Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1. Proc. Natl Acad. Sci. USA 104, 4095–4100 (2007).

  19. 19

    Sapra, P. & Allen, T. M. Internalizing antibodies are necessary for improved therapeutic efficacy of antibody-targeted liposomal drugs. Cancer Res. 62, 7190–7194 (2002).

  20. 20

    Allen, T. M. Long-circulating (sterically stabilized) liposomes for targeted drug-delivery. Trends Pharmacol. Sci. 15, 215–220 (1994).

  21. 21

    Adams, G. P. et al. High affinity restricts the localization and tumor penetration of single-chain Fv antibody molecules. Cancer Res. 61, 4750–4755 (2001).

  22. 22

    Hong, S. et al. The binding avidity of a nanoparticle-based multivalent targeted drug delivery platform. Chem. Biol. 14, 107–115 (2007).

  23. 23

    Warenius, H. M., Galfre, G., Bleehen, N. M. & Milstein, C. Attempted targeting of A monoclonal-antibody in a human-tumor xenograft system. Eur. J. Cancer Clin. Oncology 17, 1009–1015 (1981).

  24. 24

    von Mehren, A. G., Weiner L. M. Monoclonal antibody therapy for cancer. Annu. Rev. Med. 54, 343–369 (2003).

  25. 25

    Weiner, L. M. & Adams, G. P. New approaches to antibody therapy. Oncogene 19, 6144–6151 (2000).

  26. 26

    Gabizon, A. A. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest. 19, 424–436 (2001).

  27. 27

    James, J. S. & Dubs, G. FDA approves new kind of lymphoma treatment. AIDS Treat. News 284, 2–3 (1997).

  28. 28

    Albanell, J. & Baselga, J. Trastuzumab, a humanized anti-HER2 monoclonal antibody, for the treatment of breast cancer. Drugs Today 35, 931–946 (1999).

  29. 29

    Ferrara, N. VEGF as a therapeutic target in cancer. Oncology 69 (Suppl. 3), 11–16 (2005).

  30. 30

    Carter, P. Improving the efficacy of antibody-based cancer therapies. Nat. Rev. Cancer 1, 118–129 (2001).

  31. 31

    Marks, J. D. Selection of internalizing antibodies for drug delivery. Methods Mol. Biol. 248, 201–208 (2004).

  32. 32

    Marks, J. D. et al. Human-antibody fragments specific for human blood-groups antigens from a phage display library. Bio-Technol. 11, 1145–1149 (1993).

  33. 33

    Liu, B., Conrad, F., Cooperberg, M. R., Kirpotin, D. B. & Marks, J. D. Mapping tumor epitope space by direct selection of single-chain Fv antibody libraries on prostate cancer cells. Cancer Res. 64, 704–710 (2004).

  34. 34

    Arnold, D. M. et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann. Intern. Med. 146, 25–33 (2007).

  35. 35

    Trail, P. A. et al. Cure of xenografted human carcinomas by Br96-doxorubicin immunoconjugates. Science 261, 212–215 (1993).

  36. 36

    Tolcher, A. W. et al. Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J. Clin. Oncology 17, 478–484 (1999).

  37. 37

    Hirsch, L. R. et al. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc. Natl Acad. Sci. USA 100, 13549–13554 (2003).

  38. 38

    Silverman, J. et al. Multivalent avimer proteins evolved by exon shuffling of a family of human receptor domains. Nat. Biotechnol. 23, 1556–1561 (2005).

  39. 39

    Cortez-Retamozo, V. et al. Efficient cancer therapy with a nanobody-based conjugate. Cancer Res. 64, 2853–2857 (2004).

  40. 40

    Nord, K. et al. Binding proteins selected from combinatorial libraries of an alpha-helical bacterial receptor domain. Nat. Biotechnol. 15, 772–777 (1997).

  41. 41

    White, R. R., Sullenger, B. A. & Rusconi, C. P. Developing aptamers into therapeutics. J. Clin. Invest. 106, 929–934 (2000).

  42. 42

    Farokhzad, O. C. et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc. Natl Acad. Sci. USA 103, 6315–6320 (2006).

  43. 43

    Sanfilippo, J. S. et al. Quantitative analyses of epidermal growth factor receptors, HER-2/neu oncoprotein and cathepsin D in nonmalignant and malignant uteri. Cancer 77, 710–716 (1996).

  44. 44

    Antony, A. C. The biological chemistry of folate receptors. Blood 79, 2807–2820 (1992).

  45. 45

    Prost, A. C. et al. Differential transferrin receptor density in human colorectal cancer: A potential probe for diagnosis and therapy. Int. J. Oncol. 13, 871–875 (1998).

  46. 46

    Kukowska-Latallo, J. F. et al. Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer. Cancer Res. 65, 5317–5324 (2005).

  47. 47

    Iinuma, H. et al. Intracellular targeting therapy of cisplatin-encapsulated transferrin-polyethylene glycol liposome on peritoneal dissemination of gastric cancer. Int. J. Cancer 99, 130–137 (2002).

  48. 48

    Ishida, O. et al. Liposomes bearing polyethyleneglycol-coupled transferrin with intracellular targeting property to the solid tumors in vivo. Pharm. Res. 18, 1042–1048 (2001).

  49. 49

    Ekblom, P., Thesleff, I., Lehto, V. P. & Virtanen, I. Distribution of the transferrin receptor in normal human-fibroblasts and fibro-sarcoma cells. Int. J. Cancer 31, 111–117 (1983).

  50. 50

    Li, J. et al. Fusion protein from RGD peptide and Fc fragment of mouse immunoglobulin G inhibits angiogenesis in tumor. Cancer Gene Ther. 11, 363–370 (2004).

  51. 51

    Ruoslahti, E. Cell adhesion and tumor metastasis. Princess Takamatsu Symp. 24, 99–105 (1994).

  52. 52

    Peer, D. & Margalit, R. Tumor-targeted hyaluronan nanoliposomes increase the antitumor activity of liposomal Doxorubicin in syngeneic and human xenograft mouse tumor models. Neoplasia 6, 343–353 (2004).

  53. 53

    Hu, Z., Sun, Y. & Garen, A. Targeting tumor vasculature endothelial cells and tumor cells for immunotherapy of human melanoma in a mouse xenograft model. Proc. Natl Acad. Sci. USA 96, 8161–8166 (1999).

  54. 54

    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).

  55. 55

    Eliaz, R. E. & Szoka, F. C. Jr. Liposome-encapsulated doxorubicin targeted to CD44: a strategy to kill CD44-overexpressing tumor cells. Cancer Res. 61, 2592–2601 (2001).

  56. 56

    LaVan, D. A., McGuire, T. & Langer, R. Small-scale systems for in vivo drug delivery. Nat. Biotechnol. 21, 1184–1191 (2003).

  57. 57

    Arap, W., Pasqualini, R. & Ruoslahti, E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279, 377–380 (1998).

  58. 58

    Schraa, A. J. et al. Targeting of RGD-modified proteins to tumor vasculature: A pharmacokinetic and cellular distribution study. Int. J. Cancer 102, 469–475 (2002).

  59. 59

    Halin, C. et al. Enhancement of the antitumor activity of interleukin-12 by targeted delivery to neovasculature. Nat. Biotechnol. 20, 264–269 (2002).

  60. 60

    Satchi-Fainaro, R. et al. Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nat. Med. 10, 255–261 (2004).

  61. 61

    Satchi-Fainaro, R., Duncan, R. & Barnes, C. M. in Polymer Therapeutics II: Polymers as Drugs, Conjugates and Gene Delivery Systems Vol. 193 (eds Satchi-Fainaro, R. & Duncan, R.) 1–65 (Springer-Verlag, Berlin, 2006).

  62. 62

    Couvreur, P., Kante, B., Roland, M. & Speiser, P. Adsorption of anti-neoplastic drugs to polyalkylcyanoacrylate nanoparticles and their release in calf serum. J. Pharm. Sci. 68, 1521–1524 (1979).

  63. 63

    Couvreur, P. et al. Tissue distribution of anti-tumor drugs associated with polyalkylcyanoacrylate nanoparticles. J. Pharm. Sci. 69, 199–202 (1980).

  64. 64

    Couvreur, P., Kante, B., Grislain, L., Roland, M. & Speiser, P. Toxicity of polyalkylcyanoacrylate nanoparticles II: Doxorubicin-loaded nanoparticles. J. Pharm. Sci. 71, 790–792 (1982).

  65. 65

    Hrkach, J. S., Peracchia, M. T., Domb, A., Lotan, N. & Langer, R. Nanotechnology for biomaterials engineering: Structural characterization of amphiphilic polymeric nanoparticles by H-1 NMR spectroscopy. Biomaterials 18, 27–30 (1997).

  66. 66

    Calvo, P., RemunanLopez, C., VilaJato, J. L. & Alonso, M. J. Chitosan and chitosan ethylene oxide propylene oxide block copolymer nanoparticles as novel carriers for proteins and vaccines. Pharm. Res. 14, 1431–1436 (1997).

  67. 67

    Elsamaligy, M. S. & Rohdewald, P. Reconstituted collagen nanoparticles, a novel drug carrier delivery system. J. Pharm. Pharmacol. 35, 537–539 (1983).

  68. 68

    Moses, M. A., Brem, H. & Langer, R. Advancing the field of drug delivery: taking aim at cancer. Cancer Cell 4, 337–341 (2003).

  69. 69

    Farokhzad, O. C. & Langer, R. Nanomedicine: Developing smarter therapeutic and diagnostic modalities. Adv. Drug Deliv. Rev. 58, 1456–1459 (2006).

  70. 70

    Guo, R. et al. Synthesis of alginic acid-poly[2-(diethylamino)ethyl methacrylate] monodispersed nanoparticles by a polymer-monomer pair reaction system. Biomacromolecules 8, 843–850 (2007).

  71. 71

    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).

  72. 72

    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).

  73. 73

    Ahmed, F. et al. Shrinkage of a rapidly growing tumor by drug-loaded polymersomes: pH-triggered release through copolymer degradation. Mol. Pharm. 3, 340–350 (2006).

  74. 74

    Discher, D. E. & Ahmed, F. Polymersomes. Annu. Rev. Biomed. Eng. 8, 323–341 (2006).

  75. 75

    Matsumura, Y. et al. Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin. Brit. J. Cancer 91, 1775–1781 (2004).

  76. 76

    Kato, K. et al. Phase I study of NK105, a paclitaxel-incorporating micellar nanoparticle, in patients with advanced cancer. J. Clin. Oncol 24 (suppl.), 2018 (2006).

  77. 77

    Torchilin, V. P. Micellar nanocarriers: Pharmaceutical perspectives. Pharm. Res. 24, 1–16 (2007).

  78. 78

    Brigger, I., Dubernet, C. & Couvreur, P. Nanoparticles in cancer therapy and diagnosis. Adv. Drug Deliv. Rev. 54, 631–651 (2002).

  79. 79

    Kreuter, J. & Higuchi, T. Improved delivery of methoxsalen. J. Pharm. Sci. 68, 451–454 (1979).

  80. 80

    Papahadjopoulos, D. et al. Sterically stabilized liposomes - improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc. Natl Acad. Sci. USA 88, 11460–11464 (1991).

  81. 81

    Haran, G., Cohen, R., Bar, L. K. & Barenholz, Y. Transmembrane ammonium-sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim. Biophys. Acta 1151, 201–215 (1993).

  82. 82

    Gabizon, A. A., Shmeeda, H. & Zalipsky, S. Pros and cons of the liposome platform in cancer drug targeting. J. Liposome Res. 16, 175–183 (2006).

  83. 83

    Lorusso, D. et al. Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia ('hand-foot' syndrome). Ann. Oncol. (2007).

  84. 84

    Sengupta, S. et al. Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nature 436, 568–572 (2005).

  85. 85

    Damascelli, B. et al. Intraarterial chemotherapy with polyoxyethylated castor oil free paclitaxel, incorporated in albumin nanoparticles (ABI-007). Cancer 92, 2592–2602 (2001).

  86. 86

    Gillies, E. R. & Frechet, J. M. J. Dendrimers and dendritic polymers in drug delivery. Drug Discov. Today 10, 35–43 (2005).

  87. 87

    Malik, N. et al. Dendrimers: Relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of I-125-labelled polyamidoamine dendrimers in vivo. J. Control. Release 65, 133–148 (2000).

  88. 88

    Morawski, A. M., Lanza, G. A. & Wickline, S. A. Targeted contrast agents for magnetic resonance imaging and ultrasound. Curr. Opin. Biotechnol. 16, 89–92 (2005).

  89. 89

    Loo, C., Lowery, A., Halas, N., West, J., Drezek, R. Immunotargeted nanoshells for integrated cancer imaging and therapy. Nano Lett. 5, 709–711 (2005).

  90. 90

    Chen, J. et al. Gold nanocages: Bioconjugation and their potential use as optical imaging contrast agents. Nano Lett. 5, 473–477 (2005).

  91. 91

    Danson, S. et al. Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP 1049C) in patients with advanced cancer. Brit. J. Cancer 90, 2085–2091 (2004).

  92. 92

    Batrakova, E. V. et al. Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: In vivo evaluation of anti-cancer activity. Brit. J. Cancer 74, 1545–1552 (1996).

  93. 93

    Goren, D. et al. Nuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance efflux pump. Clin. Cancer Res. 6, 1949–1957 (2000).

  94. 94

    Matsuo, H. et al. Possibility of the reversal of multidrug resistance and the avoidance of side effects by liposomes modified with MRK-16, a monoclonal antibody to P-glycoprotein. J. Control. Release 77, 77–86 (2001).

  95. 95

    Duncan, R., Vicent, M. J., Greco, F. & Nicholson, R. I. Polymer-drug conjugates: towards a novel approach for the treatment of endrocine-related cancer. Endocrine-Relat. Cancer 12, S189–S199 (2005).

  96. 96

    Wong, H. L. et al. A new polymer-lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells. Pharm. Res. 23, 1574–1585 (2006).

  97. 97

    Garcion, E. et al. A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats. Mol. Cancer Ther. 5, 1710–1722 (2006).

  98. 98

    Lee, E. S., Na, K. & Bae, Y. H. Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant MCF-7 tumor. J. Control. Release 103, 405–418 (2005).

  99. 99

    Sapra, P. & Allen, T. M. Ligand-targeted liposomal anticancer drugs. Prog. Lipid Res. 42, 439–462 (2003).

  100. 100

    Moghimi, S. M. Recent developments in polymeric nanoparticle engineering and their applications in experimental and clinical oncology. Anticancer Agents Med. Chem. 6, 553–561 (2006).

  101. 101

    Lee, K. S. et al. Multicenter phase II trial of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer. Breast Cancer Res. Treat. (2007).

  102. 102

    Nakanishi, T. et al. Development of the polymer micelle carrier system for doxorubicin. J. Control. Release 74, 295–302 (2001).

  103. 103

    Hirsch, L. R. et al. Metal nanoshells. Ann. Biomed. Engin. 34, 15–22 (2006).

  104. 104

    Sokolov, K. et al. Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanoparticles. Cancer Res. 63, 1999–2004 (2003).

  105. 105

    Chen, J. Y. et al. Facile synthesis of gold-silver nanocages with controllable pores on the surface. J. Am. Chem. Soc. 128, 14776–14777 (2006).

  106. 106

    Kontermann, R. E. Immunolliposomes for cancer therapy. Curr. Opin. Mol. Ther. 8, 39–45 (2006).

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Acknowledgements

We would like to acknowledge Shiladitya Sengupta for critically reviewing the manuscript and Maeve Cullinane for helpful discussions. This work was supported by federal funds NIH/NCI CA119349, NIH/NIBIB EB 003647, and NIH R01-EB000244. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH.

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Correspondence to Robert Langer.

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O.C.F. and R.L. have financial interest in BIND Bioscience. The rest of the authors declare no competing financial interests.

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Peer, D., Karp, J., Hong, S. et al. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotech 2, 751–760 (2007) doi:10.1038/nnano.2007.387

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