Targeting Drugs to Cancer: A Tough Journey to the Tumor Cell

  • Shiran Ferber
  • Galia Tiram
  • Ronit Satchi-Fainaro


Chemotherapeutic agents continue to represent the preferred therapeutic option for most malignancies. Despite major therapeutic potential, their use is limited due to severe side-effects and inefficient delivery to the tumor site. In the last four decades, researchers investigated the use of nano-sized drug delivery systems (i.e., nanomedicines) for targeting of anticancer agents. Using a nano-sized macromolecule as scaffold for drug delivery to tumors is an efficient approach to improve the delivery of drugs by ameliorating biodistribution, reducing toxicity, preventing degradation, and enhancing cellular uptake. Nevertheless, in some cases, nonselective targeting is insufficient and the incorporation of a ligand moiety is required for improved accumulation of the drug in the tumor cell. This chapter discusses the different targeting strategies used for delivery of nanomedicines to cancer cells.


Epidermal Growth Factor Receptor Glioblastoma Cell HPMA Copolymer Mononuclear Phagocytic System Central Nervous System Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The Satchi-Fainaro research laboratory is partially supported by The Association for International Cancer Research (AICR), German-Israel Foundation (GIF), The Marguerite Stolz Research Fund for outstanding faculty, Rimonim Consortium and the MAGNET Program of the Office of the Chief Scientist of the Israel Ministry of Industry, Trade & Labor, THE ISRAEL SCIENCE FOUNDATION (Grant No. 1309/10), the United States-Israel Binational Science Foundation (Grant No. 2007347), Swiss Bridge Award, and by grants from the Israeli National Nanotechnology Initiative (INNI), Focal Technology Area (FTA) program: Nanomedicine for Personalized Theranostics, and by The Leona M. and Harry B. Helmsley Nanotechnology Research Fund.


  1. 1.
    Godwin A, Bolina K, Clochard M, Dinand E, Rankin S, Simic S, Brocchini S (2001) New strategies for polymer development in pharmaceutical science – a short review. J Pharm Pharmacol 53(9):1175–1184PubMedGoogle Scholar
  2. 2.
    Rihova B (2002) Immunomodulating activities of soluble synthetic polymer-bound drugs. Adv Drug Deliv Rev 54(5):653–674, S0169409X02000431PubMedGoogle Scholar
  3. 3.
    Duncan R, Ringsdorf H, Satchi-Fainaro R (2006) Polymer therapeutics–polymers as drugs, drug and protein conjugates and gene delivery systems: past, present and future opportunities. J Drug Target 14(6):337–341. doi: 10.1080/10611860600833856, [pii] X8184PVV71724172PubMedGoogle Scholar
  4. 4.
    Segal E, Pan H, Ofek P, Udagawa T, Kopeckova P, Kopecek J, Satchi-Fainaro R (2009) Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics. PLoS One 4(4):e5233. doi: 10.1371/journal.pone.0005233 PubMedCentralPubMedGoogle Scholar
  5. 5.
    Miller K, Eldar-Boock A, Polyak D, Segal E, Benayoun L, Shaked Y, Satchi-Fainaro R (2011) Antiangiogenic antitumor activity of hpma copolymer-paclitaxel-alendronate conjugate on breast cancer bone metastasis mouse model. Mol Pharm 8(4):1052–1062. doi: 10.1021/mp200083n PubMedGoogle Scholar
  6. 6.
    Miller K, Clementi C, Polyak D, Eldar-Boock A, Benayoun L, Barshack I, Shaked Y, Pasut G, S-F R (2013) Poly(ethylene glycol)-paclitaxel-alendronate self-assembled micelles for the targeted treatment of breast cancer bone metastases. Biomaterials 34(15):3795–3806PubMedGoogle Scholar
  7. 7.
    Ringsdorf H (1975) Structure and properties of pharmacologically active polymers. J Polymer Sci 51:135–153Google Scholar
  8. 8.
    Allen TM, Martin FJ (2004) Advantages of liposomal delivery systems for anthracyclines. Semin Oncol 31(6 Suppl 13):5–15PubMedGoogle Scholar
  9. 9.
    Mayer LD, Bally MB, Loughrey H, Masin D, Cullis PR (1990) Liposomal vincristine preparations which exhibit decreased drug toxicity and increased activity against murine l1210 and p388 tumors. Cancer Res 50(3):575–579PubMedGoogle Scholar
  10. 10.
    Gabizon A, Shmeeda H, Barenholz Y (2003) Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin Pharmacokinet 42(5):419–436, pii: 4252PubMedGoogle Scholar
  11. 11.
    Gabizon A, Meshorer A, Barenholz Y (1986) Comparative long-term study of the toxicities of free and liposome-associated doxorubicin in mice after intravenous administration. J Natl Cancer Inst 77(2):459–469PubMedGoogle Scholar
  12. 12.
    Klibanov AL, Maruyama K, Torchilin VP, Huang L (1990) Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 268(1):235–237, 0014-5793(90)81016-HPubMedGoogle Scholar
  13. 13.
    Allen TM, Hansen C (1991) Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim Biophys Acta 1068(2):133–141, doi:0005-2736(91)90201-I [pii]PubMedGoogle Scholar
  14. 14.
    Rinella ES, Threadgill DW (2012) Efficacy of egfr inhibition is modulated by model, sex, genetic background and diet: implications for preclinical cancer prevention and therapy trials. PLoS One 7(6):e39552. doi: 10.1371/journal.pone.0039552, [pii] PONE-D-10-03043PubMedCentralPubMedGoogle Scholar
  15. 15.
    Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46(12 Pt 1):6387–6392PubMedGoogle Scholar
  16. 16.
    Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5):1029–1039PubMedGoogle Scholar
  17. 17.
    Jain RK (1987) Transport of molecules in the tumor interstitium: a review. Cancer Res 47(12):3039–3051PubMedGoogle Scholar
  18. 18.
    Maeda H, Matsumura Y (1989) Tumoritropic and lymphotropic principles of macromolecular drugs. Crit Rev Ther Drug Carrier Syst 6(3):193–210PubMedGoogle Scholar
  19. 19.
    Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the epr effect in macromolecular therapeutics: a review. J Control Release 65(1–2):271–284, S0168-3659(99)00248-5PubMedGoogle Scholar
  20. 20.
    Jang SH, Wientjes MG, Lu D, Au JL (2003) Drug delivery and transport to solid tumors. Pharm Res 20(9):1337–1350PubMedGoogle Scholar
  21. 21.
    Fang J, Nakamura H, Maeda H (2011) The epr effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 63(3):136–151. doi: 10.1016/j.addr.2010.04.009, [pii]: S0169-409X(10)00090-6PubMedGoogle Scholar
  22. 22.
    Torchilin V (2011) Tumor delivery of macromolecular drugs based on the epr effect. Adv Drug Deliv Rev 63(3):131–135. doi: 10.1016/j.addr.2010.03.011, [pii] S0169-409X(10)00080-3PubMedGoogle Scholar
  23. 23.
    Duncan R (2007) Designing polymer conjugates as lysosomotropic nanomedicines. Biochem Soc Trans 35(Pt 1):56–60. doi: 10.1042/BST0350056, [pii] BST0350056PubMedGoogle Scholar
  24. 24.
    Caliceti P, Veronese FM (2003) Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 55(10):1261–1277, S0169409X0300108XPubMedGoogle Scholar
  25. 25.
    Bottaro DP, Liotta LA (2003) Cancer: out of air is not out of action. Nature 423(6940):593–595. doi: 10.1038/423593a 423593a PubMedGoogle Scholar
  26. 26.
    Maeda H, Akaike T, Wu J, Noguchi Y, Sakata Y (1996) Bradykinin and nitric oxide in infectious disease and cancer. Immunopharmacology 33(1–3):222–230PubMedGoogle Scholar
  27. 27.
    Maeda H (2001) The enhanced permeability and retention (epr) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 41:189–207, S0065257100000133PubMedGoogle Scholar
  28. 28.
    Fang J, Sawa T, Maeda H (2003) Factors and mechanism of “epr” effect and the enhanced antitumor effects of macromolecular drugs including smancs. Adv Exp Med Biol 519:29–49. doi: 10.1007/0-306-47932-X_2 PubMedGoogle Scholar
  29. 29.
    Iyer AK, Khaled G, Fang J, Maeda H (2006) Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today 11(17–18):812–818. doi: 10.1016/j.drudis.2006.07.005, [pii] S1359-6446(06)00271-6PubMedGoogle Scholar
  30. 30.
    Maeda H, Bharate GY, Daruwalla J (2009) Polymeric drugs for efficient tumor-targeted drug delivery based on epr-effect. Eur J Pharm Biopharm 71(3):409–419. doi: 10.1016/j.ejpb.2008.11.010, [pii] S0939-6411(08)00450-5PubMedGoogle Scholar
  31. 31.
    Maeda H, Fang J, Inutsuka T, Kitamoto Y (2003) Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications. Int Immunopharmacol 3(3):319–328. doi: 10.1016/S1567-5769(02)00271-0, [pii] S1567-5769(02)00271-0PubMedGoogle Scholar
  32. 32.
    Kuniyasu H, Yasui W, Pettaway CA, Yano S, Oue N, Tahara E, Fidler IJ (2001) Interferon-alpha prevents selection of doxorubicin-resistant undifferentiated-androgen-insensitive metastatic human prostate cancer cells. Prostate 49(1):19–29. doi: 10.1002/pros.1114 PubMedGoogle Scholar
  33. 33.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62. doi: 10.1126/science.1104819, [pii]: 307/5706/58PubMedGoogle Scholar
  34. 34.
    Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64(11):3731–3736. doi: 10.1158/0008-5472, [pii] CAN-04-0074 64/11/3731PubMedGoogle Scholar
  35. 35.
    Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438(7070):967–974. doi: 10.1038/nature04483, [pii] nature04483PubMedGoogle Scholar
  36. 36.
    Beecken WD, Engl T, Blaheta R, Bentas W, Achilles EG, Jonas D, Shing Y, Camphausen K (2004) Angiogenesis inhibition by angiostatin, endostatin and tnp-470 prevents cyclophosphamide induced cystitis. Angiogenesis 7(1):69–73. doi: 10.1023/B:AGEN.0000037334.70257.d2, Pii 5268128PubMedGoogle Scholar
  37. 37.
    Satchi-Fainaro R, Mamluk R, Wang L, Short SM, Nagy JA, Feng D, Dvorak AM, Dvorak HF, Puder M, Mukhopadhyay D, Folkman J (2005) Inhibition of vessel permeability by tnp-470 and its polymer conjugate, caplostatin. Cancer Cell 7(3):251–261. doi: 10.1016/j.ccr.2005.02.007, [pii] S1535-6108(05)00060-7PubMedGoogle Scholar
  38. 38.
    Nagamitsu A, Greish K, Maeda H (2009) Elevating blood pressure as a strategy to increase tumor-targeted delivery of macromolecular drug smancs: cases of advanced solid tumors. Jpn J Clin Oncol 39(11):756–766. doi: 10.1093/jjco/hyp074, [pii] hyp074PubMedGoogle Scholar
  39. 39.
    Monsky WL, Fukumura D, Gohongi T, Ancukiewcz M, Weich HA, Torchilin VP, Yuan F, Jain RK (1999) Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res 59(16):4129–4135PubMedGoogle Scholar
  40. 40.
    Kano MR, Bae Y, Iwata C, Morishita Y, Yashiro M, Oka M, Fujii T, Komuro A, Kiyono K, Kaminishi M, Hirakawa K, Ouchi Y, Nishiyama N, Kataoka K, Miyazono K (2007) Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of tgf-beta signaling. Proc Natl Acad Sci USA 104(9):3460–3465. doi: 10.1073/pnas.0611660104, [pii] 0611660104PubMedGoogle Scholar
  41. 41.
    Scherphof GL, Dijkstra J, Spanjer HH, Derksen JT, Roerdink FH (1985) Uptake and intracellular processing of targeted and nontargeted liposomes by rat kupffer cells in vivo and in vitro. Ann N Y Acad Sci 446:368–384PubMedGoogle Scholar
  42. 42.
    Hatakeyama H, Akita H, Harashima H (2011) A multifunctional envelope type nano device (mend) for gene delivery to tumours based on the epr effect: a strategy for overcoming the peg dilemma. Adv Drug Deliv Rev 63(3):152–160. doi: 10.1016/j.addr.2010.09.001, [pii] S0169-409X(10)00179-1PubMedGoogle Scholar
  43. 43.
    Mishra S, Webster P, Davis ME (2004) Pegylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur J Cell Biol 83(3):97–111PubMedGoogle Scholar
  44. 44.
    Ishida T, Ichihara M, Wang X, Yamamoto K, Kimura J, Majima E, Kiwada H (2006) Injection of pegylated liposomes in rats elicits peg-specific igm, which is responsible for rapid elimination of a second dose of pegylated liposomes. J Control Release 112(1):15–25. doi: 10.1016/j.jconrel.2006.01.005, [pii]: S0168-3659(06)00037-XPubMedGoogle Scholar
  45. 45.
    Ishida T, Kiwada H (2008) accelerated blood clearance (abc) phenomenon induced by administration of pegylated liposome. Yakugaku Zasshi 128(2):233–243, pii JST.JSTAGE/yakushi/128.233PubMedGoogle Scholar
  46. 46.
    Shiraishi K, Hamano M, Ma H, Kawano K, Maitani Y, Aoshi T, Ishii KJ, Yokoyama M (2013) Hydrophobic blocks of peg-conjugates play a significant role in the accelerated blood clearance (abc) phenomenon. J Control Release 165(3):183–190. doi: 10.1016/j.jconrel.2012.11.016, [pii] S0168-3659(12)00813-9PubMedGoogle Scholar
  47. 47.
    Eldar-Boock A, Miller K, Sanchis J, Lupu R, Vicent MJ, Satchi-Fainaro R (2011) Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel. Biomaterials 32(15):3862–3874. doi: 10.1016/j.biomaterials.2011.01.073, [pii]:S0142-9612(11)00119-0PubMedGoogle Scholar
  48. 48.
    Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314(5797):268–274. doi: 10.1126/science.1133427, [pii] 1133427PubMedGoogle Scholar
  49. 49.
    Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B (2007) The genomic landscapes of human breast and colorectal cancers. Science 318(5853):1108–1113. doi: 10.1126/science.1145720, 1145720PubMedGoogle Scholar
  50. 50.
    Sellers WR (2011) A blueprint for advancing genetics-based cancer therapy. Cell 147(1):26–31. doi: 10.1016/j.cell.2011.09.016, [pii] S0092-8674(11)01074-9PubMedGoogle Scholar
  51. 51.
    Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC (2008) Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther 83(5):761–769. doi: 10.1038/sj.clpt.6100400, [pii]: 6100400PubMedGoogle Scholar
  52. 52.
    Gaspar R, Duncan R (2009) Polymeric carriers: preclinical safety and the regulatory implications for design and development of polymer therapeutics. Adv Drug Deliv Rev 61(13):1220–1231. doi: 10.1016/j.addr.2009.06.003, [pii]: S0169-409X(09)00243-9PubMedGoogle Scholar
  53. 53.
    Sanchis J, Canal F, Lucas R, Vicent MJ (2010) Polymer-drug conjugates for novel molecular targets. Nanomedicine (Lond) 5(6):915–935. doi: 10.2217/nnm.10.71 Google Scholar
  54. 54.
    Begley DJ (2004) Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol Ther 104(1):29–45. doi: 10.1016/j.pharmthera.2004.08.001, [pii]: S0163-7258(04)00105-6PubMedGoogle Scholar
  55. 55.
    Lampson LA (2009) Targeted therapy for neuro-oncology: reviewing the menu. Drug Discov Today 14(3–4):185–191. doi: 10.1016/j.drudis.2008.11.003, [pii]: S1359-6446(08)00401-7PubMedGoogle Scholar
  56. 56.
    Chekhonin VP, Baklaushev VP, Yusubalieva GM, Belorusova AE, Gulyaev MV, Tsitrin EB, Grinenko NF, Gurina OI, Pirogov YA (2012) Targeted delivery of liposomal nanocontainers to the peritumoral zone of glioma by means of monoclonal antibodies against gfap and the extracellular loop of cx43. Nanomedicine 8(1):63–70. doi: 10.1016/j.nano.2011.05.011, [pii]: S1549-9634(11)00183-3PubMedGoogle Scholar
  57. 57.
    Sharpe MA, Marcano DC, Berlin JM, Widmayer MA, Baskin DS, Tour JM (2012) Antibody-targeted nanovectors for the treatment of brain cancers. ACS Nano 6(4):3114–3120. doi: 10.1021/nn2048679 PubMedGoogle Scholar
  58. 58.
    Yan H, Wang L, Wang J, Weng X, Lei H, Wang X, Jiang L, Zhu J, Lu W, Wei X, Li C (2012) Two-order targeted brain tumor imaging by using an optical/paramagnetic nanoprobe across the blood brain barrier. ACS Nano 6(1):410–420. doi: 10.1021/nn203749v PubMedGoogle Scholar
  59. 59.
    Huynh GH, Deen DF, Szoka FC Jr (2006) Barriers to carrier mediated drug and gene delivery to brain tumors. J Control Release 110(2):236–259. doi: 10.1016/j.jconrel.2005.09.053, [pii]: S0168-3659(05)00527-4PubMedGoogle Scholar
  60. 60.
    Thorne RG, Nicholson C (2006) In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci USA 103(14):5567–5572. doi: 10.1073/pnas.0509425103, 0509425103PubMedGoogle Scholar
  61. 61.
    Ong BY, Ranganath SH, Lee LY, Lu F, Lee HS, Sahinidis NV, Wang CH (2009) Paclitaxel delivery from plga foams for controlled release in post-surgical chemotherapy against glioblastoma multiforme. Biomaterials 30(18):3189–3196. doi: 10.1016/j.biomaterials.2009.02.030, [pii]: S0142-9612(09)00226-9PubMedGoogle Scholar
  62. 62.
    Pardridge WM (2007) Drug targeting to the brain. Pharm Res 24(9):1733–1744. doi: 10.1007/s11095-007-9324-2 PubMedGoogle Scholar
  63. 63.
    Pardridge WM (2010) Biopharmaceutical drug targeting to the brain. J Drug Target 18(3):157–167. doi: 10.3109/10611860903548354 PubMedGoogle Scholar
  64. 64.
    Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068, Collaborators (231)Google Scholar
  65. 65.
    Du J, Bernasconi P, Clauser KR, Mani DR, Finn SP, Beroukhim R, Burns M, Julian B, Peng XP, Hieronymus H, Maglathlin RL, Lewis TA, Liau LM, Nghiemphu P, Mellinghoff IK, Louis DN, Loda M, Carr SA, Kung AL, Golub TR (2009) Bead-based profiling of tyrosine kinase phosphorylation identifies src as a potential target for glioblastoma therapy. Nat Biotechnol 27(1):77–83. doi: 10.1038/nbt.1513, [pii]: nbt.1513PubMedCentralPubMedGoogle Scholar
  66. 66.
    Frederick L, Wang XY, Eley G, James CD (2000) Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 60(5):1383–1387PubMedGoogle Scholar
  67. 67.
    Kleihues P, Ohgaki H (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro Oncol 1(1):44–51PubMedCentralPubMedGoogle Scholar
  68. 68.
    Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, Huang HJ (1994) A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci USA 91(16):7727–7731PubMedGoogle Scholar
  69. 69.
    Li B, Yuan M, Kim IA, Chang CM, Bernhard EJ, Shu HK (2004) Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/akt pathway and promotes radioresistance in cells of astrocytic origin. Oncogene 23(26):4594–4602. doi: 10.1038/sj.onc.1207602, [pii]1207602PubMedGoogle Scholar
  70. 70.
    Weissenberger J, Steinbach JP, Malin G, Spada S, Rulicke T, Aguzzi A (1997) Development and malignant progression of astrocytomas in gfap-v-src transgenic mice. Oncogene 14(17):2005–2013. doi: 10.1038/sj.onc.1201168 PubMedGoogle Scholar
  71. 71.
    Ozawa T, Brennan CW, Wang L, Squatrito M, Sasayama T, Nakada M, Huse JT, Pedraza A, Utsuki S, Yasui Y, Tandon A, Fomchenko EI, Oka H, Levine RL, Fujii K, Ladanyi M, Holland EC (2010) Pdgfra gene rearrangements are frequent genetic events in pdgfra-amplified glioblastomas. Genes Dev 24(19):2205–2218. doi: 10.1101/gad.1972310, [pii] 24/19/2205PubMedGoogle Scholar
  72. 72.
    Lustig R (2006) Long term responses with cetuximab therapy in glioblastoma multiforme. Cancer Biol Ther 5(9):1242–1243. doi:3420 [pii]Google Scholar
  73. 73.
    Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to egfr kinase inhibitors. N Engl J Med 353(19):2012–2024. doi: 10.1056/NEJMoa051918, [pii]: 353/19/2012PubMedGoogle Scholar
  74. 74.
    Neyns B, Sadones J, Joosens E, Bouttens F, Verbeke L, Baurain JF, D'Hondt L, Strauven T, Chaskis C, In't Veld P, Michotte A, De Greve J (2009) Stratified phase ii trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol 20(9):1596–1603. doi: 10.1093/annonc/mdp032, [pii]: mdp032PubMedGoogle Scholar
  75. 75.
    Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LA, Das J, Doweyko AM, Fairchild C, Hunt JT, Inigo I, Johnston K, Kamath A, Kan D, Klei H, Marathe P, Pang S, Peterson R, Pitt S, Schieven GL, Schmidt RJ, Tokarski J, Wen ML, Wityak J, Borzilleri RM (2004) Discovery of n-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (bms-354825), a dual src/abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47(27):6658–6661. doi: 10.1021/jm049486a PubMedGoogle Scholar
  76. 76.
    Xin H, Sha X, Jiang X, Zhang W, Chen L, Fang X (2012) Anti-glioblastoma efficacy and safety of paclitaxel-loading angiopep-conjugated dual targeting peg-pcl nanoparticles. Biomaterials 33(32):8167–8176. doi: 10.1016/j.biomaterials.2012.07.046, [pii] S0142-9612 (12)00841-1PubMedGoogle Scholar
  77. 77.
    Huang S, Li J, Han L, Liu S, Ma H, Huang R, Jiang C (2011) Dual targeting effect of angiopep-2-modified, DNA-loaded nanoparticles for glioma. Biomaterials 32(28):6832–6838. doi: 10.1016/j.biomaterials.2011.05.064, [pii]: S0142-9612(11)00635-1PubMedGoogle Scholar
  78. 78.
    Ren J, Shen S, Wang D, Xi Z, Guo L, Pang Z, Qian Y, Sun X, Jiang X (2012) The targeted delivery of anticancer drugs to brain glioma by pegylated oxidized multi-walled carbon nanotubes modified with angiopep-2. Biomaterials 33(11):3324–3333. doi: 10.1016/j.biomaterials.2012.01.025, [pii]: S0142-9612(12)00044-0PubMedGoogle Scholar
  79. 79.
    Lopes MB, Bogaev CA, Gonias SL, VandenBerg SR (1994) Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein is increased in reactive and neoplastic glial cells. FEBS Lett 338(3):301–305. doi:0014-5793(94)80288-2 [pii]Google Scholar
  80. 80.
    Demeule M, Currie JC, Bertrand Y, Che C, Nguyen T, Regina A, Gabathuler R, Castaigne JP, Beliveau R (2008) Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem 106(4):1534–1544. doi: 10.1111/j.1471-4159.2008.05492.x, [pii]: JNC5492PubMedGoogle Scholar
  81. 81.
    Ke W, Shao K, Huang R, Han L, Liu Y, Li J, Kuang Y, Ye L, Lou J, Jiang C (2009) Gene delivery targeted to the brain using an angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer. Biomaterials 30(36):6976–6985. doi: 10.1016/j.biomaterials.2009.08.049, [pii]: S0142-9612(09)00912-0PubMedGoogle Scholar
  82. 82.
    Desai A, Vyas T, Amiji M (2008) Cytotoxicity and apoptosis enhancement in brain tumor cells upon coadministration of paclitaxel and ceramide in nanoemulsion formulations. J Pharm Sci 97(7):2745–2756. doi: 10.1002/jps.21182 PubMedGoogle Scholar
  83. 83.
    Postma TJ, Heimans JJ, Luykx SA, van Groeningen CJ, Beenen LF, Hoekstra OS, Taphoorn MJ, Zonnenberg BA, Klein M, Vermorken JB (2000) A phase ii study of paclitaxel in chemonaive patients with recurrent high-grade glioma. Ann Oncol 11(4):409–413PubMedGoogle Scholar
  84. 84.
    Keane MM, Ettenberg SA, Nau MM, Russell EK, Lipkowitz S (1999) Chemotherapy augments trail-induced apoptosis in breast cell lines. Cancer Res 59(3):734–741PubMedGoogle Scholar
  85. 85.
    Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM (1997) An antagonist decoy receptor and a death domain-containing receptor for trail. Science 277(5327):815–818PubMedGoogle Scholar
  86. 86.
    Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z, Schwall RH (1999) Safety and antitumor activity of recombinant soluble apo2 ligand. J Clin Invest 104(2):155–162. doi: 10.1172/JCI6926 PubMedCentralPubMedGoogle Scholar
  87. 87.
    Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC, Lynch DH (1999) Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 5(2):157–163. doi: 10.1038/5517 PubMedGoogle Scholar
  88. 88.
    Prochnow N, Dermietzel R (2008) Connexons and cell adhesion: a romantic phase. Histochem Cell Biol 130(1):71–77. doi: 10.1007/s00418-008-0434-7 PubMedCentralPubMedGoogle Scholar
  89. 89.
    Oliveira R, Christov C, Guillamo JS, de Bouard S, Palfi S, Venance L, Tardy M, Peschanski M (2005) Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas. BMC Cell Biol 6(1):7. doi: 10.1186/1471-2121-6-7, [pii]: 1471-2121-6-7PubMedCentralPubMedGoogle Scholar
  90. 90.
    Chekhonin VP, Baklaushev VP, Yusubalieva GM, Gurina OI (2009) Targeted transport of 125i-labeled antibody to gfap and amvb1 in an experimental rat model of c6 glioma. J Neuroimmune Pharmacol 4(1):28–34. doi: 10.1007/s11481-008-9123-5 PubMedGoogle Scholar
  91. 91.
    Bates DC, Sin WC, Aftab Q, Naus CC (2007) Connexin43 enhances glioma invasion by a mechanism involving the carboxy terminus. Glia 55(15):1554–1564. doi: 10.1002/glia.20569 PubMedGoogle Scholar
  92. 92.
    Zhang XX, Eden HS, Chen X (2012) Peptides in cancer nanomedicine: drug carriers, targeting ligands and protease substrates. J Control Release 159(1):2–13. doi: 10.1016/j.jconrel.2011.10.023, [pii]: S0168-3659(11)00995-3PubMedCentralPubMedGoogle Scholar
  93. 93.
    Gu G, Xia H, Hu Q, Liu Z, Jiang M, Kang T, Miao D, Tu Y, Pang Z, Song Q, Yao L, Chen H, Gao X, Chen J (2013) Peg-co-pcl nanoparticles modified with mmp-2/9 activatable low molecular weight protamine for enhanced targeted glioblastoma therapy. Biomaterials 34(1):196–208, 10.1016/j.biomaterials.2012.09.044 S0142-9612(12)01052-6 [pii]PubMedGoogle Scholar
  94. 94.
    Forsyth PA, Wong H, Laing TD, Rewcastle NB, Morris DG, Muzik H, Leco KJ, Johnston RN, Brasher PM, Sutherland G, Edwards DR (1999) Gelatinase-a (mmp-2), gelatinase-b (mmp-9) and membrane type matrix metalloproteinase-1 (mt1-mmp) are involved in different aspects of the pathophysiology of malignant gliomas. Br J Cancer 79(11–12):1828–1835. doi: 10.1038/sj.bjc.6690291 PubMedCentralPubMedGoogle Scholar
  95. 95.
    Wang M, Wang T, Liu S, Yoshida D, Teramoto A (2003) The expression of matrix metalloproteinase-2 and -9 in human gliomas of different pathological grades. Brain Tumor Pathol 20(2):65–72PubMedGoogle Scholar
  96. 96.
    Kager L, Zoubek A, Potschger U, Kastner U, Flege S, Kempf-Bielack B, Branscheid D, Kotz R, Salzer-Kuntschik M, Winkelmann W, Jundt G, Kabisch H, Reichardt P, Jurgens H, Gadner H, Bielack SS (2003) Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 21(10):2011–2018. doi: 10.1200/JCO.2003.08.132, [pii] JCO.2003.08.132PubMedGoogle Scholar
  97. 97.
    Low SA, Kopecek J (2012) Targeting polymer therapeutics to bone. Adv Drug Deliv Rev 64(12):1189–1204. doi: 10.1016/j.addr.2012.01.012, [pii]: S0169-409X(12)00015-4PubMedCentralPubMedGoogle Scholar
  98. 98.
    Saad F, Lipton A (2010) Src kinase inhibition: targeting bone metastases and tumor growth in prostate and breast cancer. Cancer Treat Rev 36(2):177–184. doi: 10.1016/j.ctrv.2009.11.005, [pii]: S0305-7372(09)00179-0PubMedGoogle Scholar
  99. 99.
    Lawson MA, Xia Z, Barnett BL, Triffitt JT, Phipps RJ, Dunford JE, Locklin RM, Ebetino FH, Russell RG (2010) Differences between bisphosphonates in binding affinities for hydroxyapatite. J Biomed Mater Res B Appl Biomater 92(1):149–155. doi: 10.1002/jbm.b.31500 PubMedGoogle Scholar
  100. 100.
    Jahnke W, Henry C (2010) An in vitro assay to measure targeted drug delivery to bone mineral. ChemMedChem 5(5):770–776. doi: 10.1002/cmdc.201000016 PubMedGoogle Scholar
  101. 101.
    Ziebart T, Pabst A, Klein MO, Kammerer P, Gauss L, Brullmann D, Al-Nawas B, Walter C (2011) Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro. Clin Oral Investig 15(1):105–111. doi: 10.1007/s00784-009-0365-2 PubMedGoogle Scholar
  102. 102.
    Marx RE, Sawatari Y, Fortin M, Broumand V (2005) Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63(11):1567–1575. doi: 10.1016/j.joms.2005.07.010, [pii] S0278-2391(05)01187-0PubMedGoogle Scholar
  103. 103.
    Miller K, Erez R, Segal E, Shabat D, Satchi-Fainaro R (2009) Targeting bone metastases with a bispecific anticancer and antiangiogenic polymer-alendronate-taxane conjugate. Angew Chem Int Ed Engl 48(16):2949–2954. doi: 10.1002/anie.200805133 PubMedGoogle Scholar
  104. 104.
    Segal E, Pan H, Benayoun L, Kopeckova P, Shaked Y, Kopecek J, Satchi-Fainaro R (2011) Enhanced anti-tumor activity and safety profile of targeted nano-scaled hpma copolymer-alendronate-tnp-470 conjugate in the treatment of bone malignances. Biomaterials 32(19):4450–4463. doi: 10.1016/j.biomaterials.2011.02.059, [pii] S0142-9612(11)00236-5PubMedGoogle Scholar
  105. 105.
    Bhargava P, Marshall JL, Rizvi N, Dahut W, Yoe J, Figuera M, Phipps K, Ong VS, Kato A, Hawkins MJ (1999) A phase i and pharmacokinetic study of tnp-470 administered weekly to patients with advanced cancer. Clin Cancer Res 5(8):1989–1995PubMedGoogle Scholar
  106. 106.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93(2):165–176, S0092-8674(00)81569-XPubMedGoogle Scholar
  107. 107.
    Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to trance/rankl. Proc Natl Acad Sci USA 95(7):3597–3602PubMedGoogle Scholar
  108. 108.
    Tsutsumi R, Xie C, Wei X, Zhang M, Zhang X, Flick LM, Schwarz EM, O'Keefe RJ (2009) Pge2 signaling through the ep4 receptor on fibroblasts upregulates rankl and stimulates osteolysis. J Bone Miner Res 24(10):1753–1762. doi: 10.1359/jbmr.090412 PubMedGoogle Scholar
  109. 109.
    Tsai HY, Lin HY, Fong YC, Wu JB, Chen YF, Tsuzuki M, Tang CH (2008) Paeonol inhibits rankl-induced osteoclastogenesis by inhibiting erk, p38 and nf-kappab pathway. Eur J Pharmacol 588(1):124–133. doi: 10.1016/j.ejphar.2008.04.024, [pii] S0014-2999(08)00442-1PubMedGoogle Scholar
  110. 110.
    Mayahara K, Yamaguchi A, Takenouchi H, Kariya T, Taguchi H, Shimizu N (2012) Osteoblasts stimulate osteoclastogenesis via rankl expression more strongly than periodontal ligament cells do in response to pge(2). Arch Oral Biol 57(10):1377–1384. doi: 10.1016/j.archoralbio.2012.07.009, [pii] S0003-9969(12)00251-8PubMedGoogle Scholar
  111. 111.
    Minamizaki T, Yoshiko Y, Kozai K, Aubin JE, Maeda N (2009) Ep2 and ep4 receptors differentially mediate mapk pathways underlying anabolic actions of prostaglandin e2 on bone formation in rat calvaria cell cultures. Bone 44(6):1177–1185. doi: 10.1016/j.bone.2009.02.010, [pii] S8756-3282(09)00450-5PubMedGoogle Scholar
  112. 112.
    Li M, Ke HZ, Qi H, Healy DR, Li Y, Crawford DT, Paralkar VM, Owen TA, Cameron KO, Lefker BA, Brown TA, Thompson DD (2003) A novel, non-prostanoid ep2 receptor-selective prostaglandin e2 agonist stimulates local bone formation and enhances fracture healing. J Bone Miner Res 18(11):2033–2042. doi: 10.1359/jbmr.2003.18.11.2033 PubMedGoogle Scholar
  113. 113.
    Gil L, Han Y, Opas EE, Rodan GA, Ruel R, Seedor JG, Tyler PC, Young RN (1999) Prostaglandin e2-bisphosphonate conjugates: potential agents for treatment of osteoporosis. Bioorg Med Chem 7(5):901–919, S0968-0896(99)00045-0 [pii]PubMedGoogle Scholar
  114. 114.
    Kamolratanakul P, Hayata T, Ezura Y, Kawamata A, Hayashi C, Yamamoto Y, Hemmi H, Nagao M, Hanyu R, Notomi T, Nakamoto T, Amagasa T, Akiyoshi K, Noda M (2011) Nanogel-based scaffold delivery of prostaglandin e(2) receptor-specific agonist in combination with a low dose of growth factor heals critical-size bone defects in mice. Arthritis Rheum 63(4):1021–1033. doi: 10.1002/art.30151 PubMedGoogle Scholar
  115. 115.
    Miller SC, Pan H, Wang D, Bowman BM, Kopeckova P, Kopecek J (2008) Feasibility of using a bone-targeted, macromolecular delivery system coupled with prostaglandin e(1) to promote bone formation in aged, estrogen-deficient rats. Pharm Res 25(12):2889–2895. doi: 10.1007/s11095-008-9706-0 PubMedCentralPubMedGoogle Scholar
  116. 116.
    Bellido T, Ali AA, Plotkin LI, Fu Q, Gubrij I, Roberson PK, Weinstein RS, O'Brien CA, Manolagas SC, Jilka RL (2003) Proteasomal degradation of runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J Biol Chem 278(50):50259–50272. doi: 10.1074/jbc.M307444200, [pii] M307444200PubMedGoogle Scholar
  117. 117.
    Jilka RL (2007) Molecular and cellular mechanisms of the anabolic effect of intermittent pth. Bone 40(6):1434–1446. doi: 10.1016/j.bone.2007.03.017, [pii] S8756-3282(07)00173-1PubMedCentralPubMedGoogle Scholar
  118. 118.
    Snedecor SJ, Carter JA, Kaura S, Botteman MF (2012) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a cost-effectiveness analysis. J Med Econ. doi: 10.3111/13696998.2012.719054 PubMedGoogle Scholar
  119. 119.
    Snedecor SJ, Carter JA, Kaura S, Botteman MF (2012) Cost-effectiveness of denosumab versus zoledronic acid in the management of skeletal metastases secondary to breast cancer. Clin Ther 34(6):1334–1349. doi: 10.1016/j.clinthera.2012.04.008, [pii] S0149-2918(12)00266-4PubMedGoogle Scholar
  120. 120.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108. doi:55/2/74 [pii]Google Scholar
  121. 121.
    Larsen JE, Cascone T, Gerber DE, Heymach JV, Minna JD (2011) Targeted therapies for lung cancer: clinical experience and novel agents. Cancer J 17(6):512–527. doi: 10.1097/PPO.0b013e31823e701a, [pii] 00130404-201111000-00014PubMedCentralPubMedGoogle Scholar
  122. 122.
    Rusch V, Baselga J, Cordon-Cardo C, Orazem J, Zaman M, Hoda S, McIntosh J, Kurie J, Dmitrovsky E (1993) Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 53(10 Suppl):2379–2385PubMedGoogle Scholar
  123. 123.
    Dutu T, Michiels S, Fouret P, Penault-Llorca F, Validire P, Benhamou S, Taranchon E, Morat L, Grunenwald D, Le Chevalier T, Sabatier L, Soria JC (2005) Differential expression of biomarkers in lung adenocarcinoma: a comparative study between smokers and never-smokers. Ann Oncol 16(12):1906–1914. doi: 10.1093/annonc/mdi408, [pii] mdi408PubMedGoogle Scholar
  124. 124.
    Hirsch FR, Varella-Garcia M, Bunn PA Jr, Di Maria MV, Veve R, Bremmes RM, Baron AE, Zeng C, Franklin WA (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21(20):3798–3807. doi: 10.1200/JCO.2003.11.069, [pii] JCO.2003.11.069PubMedGoogle Scholar
  125. 125.
    Nicholson RI, Gee JM, Harper ME (2001) Egfr and cancer prognosis. Eur J Cancer 37(Suppl 4):S9–S15. doi:S0959804901002313 [pii]Google Scholar
  126. 126.
    Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, Massuti B, Gonzalez-Larriba JL, Paz-Ares L, Bover I, Garcia-Campelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero R, Sanchez JM, Bastus R, Mayo C, Bertran-Alamillo J, Molina MA, Sanchez JJ, Taron M (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361(10):958–967. doi: 10.1056/NEJMoa0904554, [pii]: NEJMoa0904554PubMedGoogle Scholar
  127. 127.
    Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129–2139. doi:10.1056/NEJMoa040938 [pii] NEJMoa040938PubMedGoogle Scholar
  128. 128.
    Lim EH, Zhang SL, Li JL, Yap WS, Howe TC, Tan BP, Lee YS, Wong D, Khoo KL, Seto KY, Tan L, Agasthian T, Koong HN, Tam J, Tan C, Caleb M, Chang A, Ng A, Tan P (2009) Using whole genome amplification (wga) of low-volume biopsies to assess the prognostic role of egfr, kras, p53, and cmet mutations in advanced-stage non-small cell lung cancer (nsclc). J Thorac Oncol 4(1):12–21. doi: 10.1097/JTO.0b013e3181913e28, [pii]01243894-200901000-00003PubMedGoogle Scholar
  129. 129.
    Sordella R, Bell DW, Haber DA, Settleman J (2004) Gefitinib-sensitizing egfr mutations in lung cancer activate anti-apoptotic pathways. Science 305(5687):1163–1167. doi: 10.1126/science.1101637, [pii] 1101637PubMedGoogle Scholar
  130. 130.
    Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, Eck MJ (2007) Structures of lung cancer-derived egfr mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11(3):217–227. doi: 10.1016/j.ccr.2006.12.017, [pii]: S1535-6108(07)00028-1PubMedCentralPubMedGoogle Scholar
  131. 131.
    Gomez-Roca C, Raynaud CM, Penault-Llorca F, Mercier O, Commo F, Morat L, Sabatier L, Dartevelle P, Taranchon E, Besse B, Validire P, Italiano A, Soria JC (2009) Differential expression of biomarkers in primary non-small cell lung cancer and metastatic sites. J Thorac Oncol 4(10):1212–1220. doi: 10.1097/JTO.0b013e3181b44321 PubMedGoogle Scholar
  132. 132.
    Gong Y, Yao E, Shen R, Goel A, Arcila M, Teruya-Feldstein J, Zakowski MF, Frankel S, Peifer M, Thomas RK, Ladanyi M, Pao W (2009) High expression levels of total igf-1r and sensitivity of nsclc cells in vitro to an anti-igf-1r antibody (r1507). PLoS One 4(10):e7273. doi: 10.1371/journal.pone.0007273 PubMedCentralPubMedGoogle Scholar
  133. 133.
    Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ (2006) Mechanisms of disease: understanding resistance to her2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 3(5):269–280. doi: 10.1038/ncponc0509, [pii]: ncponc0509PubMedGoogle Scholar
  134. 134.
    Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY (2007) Implication of the insulin-like growth factor-ir pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res 13(9):2795–2803. doi: 10.1158/1078-0432.CCR-06-2077, [pii]: 13/9/2795PubMedGoogle Scholar
  135. 135.
    Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X (1999) Plasma levels of insulin-like growth factor-i and lung cancer risk: a case-control analysis. J Natl Cancer Inst 91(2):151–156PubMedGoogle Scholar
  136. 136.
    Han JY, Choi BG, Choi JY, Lee SY, Ju SY (2006) The prognostic significance of pretreatment plasma levels of insulin-like growth factor (igf)-1, igf-2, and igf binding protein-3 in patients with advanced non-small cell lung cancer. Lung Cancer 54(2):227–234. doi: 10.1016/j.lungcan.2006.07.014, [pii]: S0169-5002(06)00364-3PubMedGoogle Scholar
  137. 137.
    Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, Le Bon T, Kathuria S, Chen E et al (1986) Insulin-like growth factor i receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J 5(10):2503–2512PubMedGoogle Scholar
  138. 138.
    Tsuta K, Kozu Y, Mimae T, Yoshida A, Kohno T, Sekine I, Tamura T, Asamura H, Furuta K, Tsuda H (2012) C-met/phospho-met protein expression and met gene copy number in non-small cell lung carcinomas. J Thorac Oncol 7(2):331–339. doi: 10.1097/JTO.0b013e318241655f PubMedGoogle Scholar
  139. 139.
    Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, Stevens C, O'Meara S, Smith R, Parker A, Barthorpe A, Blow M, Brackenbury L, Butler A, Clarke O, Cole J, Dicks E, Dike A, Drozd A, Edwards K, Forbes S, Foster R, Gray K, Greenman C, Halliday K, Hills K, Kosmidou V, Lugg R, Menzies A, Perry J, Petty R, Raine K, Ratford L, Shepherd R, Small A, Stephens Y, Tofts C, Varian J, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Knowles M, Leung SY, Louis DN, Looijenga LH, Malkowicz B, Pierotti MA, Teh B, Chenevix-Trench G, Weber BL, Yuen ST, Harris G, Goldstraw P, Nicholson AG, Futreal PA, Wooster R, Stratton MR (2004) Lung cancer: intragenic erbb2 kinase mutations in tumours. Nature 431(7008):525–526. doi: 10.1038/431525b, [pii] 431525bPubMedGoogle Scholar
  140. 140.
    Wang SE, Narasanna A, Perez-Torres M, Xiang B, Wu FY, Yang S, Carpenter G, Gazdar AF, Muthuswamy SK, Arteaga CL (2006) Her2 kinase domain mutation results in constitutive phosphorylation and activation of her2 and egfr and resistance to egfr tyrosine kinase inhibitors. Cancer Cell 10(1):25–38. doi: 10.1016/j.ccr.2006.05.023, [pii]: S1535-6108(06)00179-6PubMedGoogle Scholar
  141. 141.
    Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, Iafrate AJ (2012) Ros1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30(8):863–870. doi: 10.1200/JCO.2011.35.6345, [pii] JCO.2011.35.6345PubMedGoogle Scholar
  142. 142.
    Baker CH, Kedar D, McCarty MF, Tsan R, Weber KL, Bucana CD, Fidler IJ (2002) Blockade of epidermal growth factor receptor signaling on tumor cells and tumor-associated endothelial cells for therapy of human carcinomas. Am J Pathol 161(3):929–938. doi: 10.1016/S0002-9440(10)64253-8, [pii]: S0002-9440(10)64253-8PubMedGoogle Scholar
  143. 143.
    DeGrendele H (2003) Epidermal growth factor receptor inhibitors, gefitinib and erlotinib (tarceva, osi-774), in the treatment of bronchioloalveolar carcinoma. Clin Lung Cancer 5(2):83–85. doi: 10.1016/S1525-7304(11)70324-2, [pii]: S1525-7304(11)70324-2PubMedGoogle Scholar
  144. 144.
    Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) Egfr mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497–1500. doi: 10.1126/science.1099314, [pii] 1099314PubMedGoogle Scholar
  145. 145.
    Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, Haney J, Witta S, Danenberg K, Domenichini I, Ludovini V, Magrini E, Gregorc V, Doglioni C, Sidoni A, Tonato M, Franklin WA, Crino L, Bunn PA Jr, Varella-Garcia M (2005) Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97(9):643–655. doi:97/9/643 [pii] 10.1093/jnci/dji112Google Scholar
  146. 146.
    Pao W, Miller VA (2005) Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 23(11):2556–2568. doi: 10.1200/JCO.2005.07.799, [pii]: JCO.2005.07.799PubMedGoogle Scholar
  147. 147.
    Kim IY, Kang YS, Lee DS, Park HJ, Choi EK, Oh YK, Son HJ, Kim JS (2009) Antitumor activity of egfr targeted ph-sensitive immunoliposomes encapsulating gemcitabine in a549 xenograft nude mice. J Control Release 140(1):55–60. doi: 10.1016/j.jconrel.2009.07.005, [pii]: S0168-3659(09)00479-9PubMedGoogle Scholar
  148. 148.
    Molina JR, Adjei AA, Jett JR (2006) Advances in chemotherapy of non-small cell lung cancer. Chest 130(4):1211–1219, 130/4/1211 [pii] 10.1378/chest.130.4.1211PubMedGoogle Scholar
  149. 149.
    Wang LR, Huang MZ, Xu N, Shentu JZ, Liu J, Cai J (2005) Pharmacokinetics of gemcitabine in Chinese patients with non-small-cell lung cancer. J Zhejiang Univ Sci B 6(5):446–450. doi: 10.1631/jzus.2005.B0446 PubMedCentralPubMedGoogle Scholar
  150. 150.
    Liu J, Chu L, Wang Y, Duan Y, Feng L, Yang C, Wang L, Kong D (2011) Novel peptide-dendrimer conjugates as drug carriers for targeting nonsmall cell lung cancer. Int J Nanomedicine 6:59–69. doi: 10.2147/IJN.S14601 PubMedCentralGoogle Scholar
  151. 151.
    Pasqualini R, Ruoslahti E (1996) Organ targeting in vivo using phage display peptide libraries. Nature 380(6572):364–366. doi: 10.1038/380364a0 PubMedGoogle Scholar
  152. 152.
    Barry MA, Dower WJ, Johnston SA (1996) Toward cell-targeting gene therapy vectors: selection of cell-binding peptides from random peptide-presenting phage libraries. Nat Med 2(3):299–305PubMedGoogle Scholar
  153. 153.
    Christianson DR, Ozawa MG, Pasqualini R, Arap W (2007) Techniques to decipher molecular diversity by phage display. Methods Mol Biol 357:385–406. doi: 10.1385/1-59745-214-9:385, [pii]: 1-59745-214-9:385PubMedGoogle Scholar
  154. 154.
    Deutscher SL (2010) Phage display in molecular imaging and diagnosis of cancer. Chem Rev 110(5):3196–3211. doi: 10.1021/cr900317f PubMedCentralPubMedGoogle Scholar
  155. 155.
    Li ZJ, Cho CH (2010) Development of peptides as potential drugs for cancer therapy. Curr Pharm Des 16(10):1180–1189, BSP/CPD/E-Pub/00037PubMedGoogle Scholar
  156. 156.
    Blanco E, Bey EA, Khemtong C, Yang SG, Setti-Guthi J, Chen H, Kessinger CW, Carnevale KA, Bornmann WG, Boothman DA, Gao J (2010) Beta-lapachone micellar nanotherapeutics for non-small cell lung cancer therapy. Cancer Res 70(10):3896–3904. doi: 10.1158/0008-5472.CAN-09-3995, [pii]: 0008-5472.CAN-09-3995PubMedCentralPubMedGoogle Scholar
  157. 157.
    Belinsky M, Jaiswal AK (1993) Nad(p)h:Quinone oxidoreductase1 (dt-diaphorase) expression in normal and tumor tissues. Cancer Metastasis Rev 12(2):103–117PubMedGoogle Scholar
  158. 158.
    Bey EA, Bentle MS, Reinicke KE, Dong Y, Yang CR, Girard L, Minna JD, Bornmann WG, Gao J, Boothman DA (2007) An nqo1- and parp-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc Natl Acad Sci USA 104(28): 11832–11837. doi: 10.1073/pnas.0702176104, [pii] 0702176104PubMedGoogle Scholar
  159. 159.
    Bentle MS, Bey EA, Dong Y, Reinicke KE, Boothman DA (2006) New tricks for old drugs: the anticarcinogenic potential of DNA repair inhibitors. J Mol Histol 37(5–7):203–218. doi: 10.1007/s10735-006-9043-8 PubMedGoogle Scholar
  160. 160.
    Wiseman BS, Werb Z (2002) Stromal effects on mammary gland development and breast cancer. Science 296(5570):1046–1049. doi: 10.1126/science.1067431, [pii] 296/5570/1046PubMedCentralPubMedGoogle Scholar
  161. 161.
    Prat A, Perou CM (2009) Mammary development meets cancer genomics. Nat Med 15(8):842–844. doi: 10.1038/nm0809-842, [pii]: nm0809-842PubMedGoogle Scholar
  162. 162.
    Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94. doi: 10.1038/nature09807, [pii]: nature09807PubMedGoogle Scholar
  163. 163.
    Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW, Harris CC, McLellan MD, Fulton RS, Fulton LL, Abbott RM, Hoog J, Dooling DJ, Koboldt DC, Schmidt H, Kalicki J, Zhang Q, Chen L, Lin L, Wendl MC, McMichael JF, Magrini VJ, Cook L, McGrath SD, Vickery TL, Appelbaum E, Deschryver K, Davies S, Guintoli T, Crowder R, Tao Y, Snider JE, Smith SM, Dukes AF, Sanderson GE, Pohl CS, Delehaunty KD, Fronick CC, Pape KA, Reed JS, Robinson JS, Hodges JS, Schierding W, Dees ND, Shen D, Locke DP, Wiechert ME, Eldred JM, Peck JB, Oberkfell BJ, Lolofie JT, Du F, Hawkins AE, O'Laughlin MD, Bernard KE, Cunningham M, Elliott G, Mason MD, Thompson DM Jr, Ivanovich JL, Goodfellow PJ, Perou CM, Weinstock GM, Aft R, Watson M, Ley TJ, Wilson RK, Mardis ER (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464(7291):999–1005. doi: 10.1038/nature08989, [pii]: nature08989PubMedCentralPubMedGoogle Scholar
  164. 164.
    Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, Sahin A, Liu S, Barrera JA, Burgues O, Lluch AM, Chen H, Hortobagyi GN, Mills GB, Meric-Bernstam F (2011) Pi3k pathway mutations and pten levels in primary and metastatic breast cancer. Mol Cancer Ther 10(6):1093–1101. doi: 10.1158/1535-7163.MCT-10-1089, [pii]: 1535-7163.MCT-10-1089PubMedCentralPubMedGoogle Scholar
  165. 165.
    Dupont Jensen J, Laenkholm AV, Knoop A, Ewertz M, Bandaru R, Liu W, Hackl W, Barrett JC, Gardner H (2011) Pik3ca mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res 17(4):667–677. doi: 10.1158/1078-0432.CCR-10-1133, [pii]: 1078-0432.CCR-10-1133PubMedGoogle Scholar
  166. 166.
    Subik K, Lee JF, Baxter L, Strzepek T, Costello D, Crowley P, Xing L, Hung MC, Bonfiglio T, Hicks DG, Tang P (2010) The expression patterns of er, pr, her2, ck5/6, egfr, ki-67 and ar by immunohistochemical analysis in breast cancer cell lines. Breast Cancer (Auckl) 4:35–41PubMedCentralGoogle Scholar
  167. 167.
    Macdonald RG, Byrd JC (2003) The insulin-like growth factor ii/mannose 6-phosphate receptor: implications for igf action in breast cancer. Breast Dis 17:61–72PubMedGoogle Scholar
  168. 168.
    Koda M, Kanczuga-Koda L, Sulkowska M, Surmacz E, Sulkowski S (2010) Relationships between hypoxia markers and the leptin system, estrogen receptors in human primary and metastatic breast cancer: effects of preoperative chemotherapy. BMC Cancer 10:320. doi: 10.1186/1471-2407-10-320, [pii]: 1471-2407-10-320PubMedCentralPubMedGoogle Scholar
  169. 169.
    Safra T, Muggia F, Jeffers S, Tsao-Wei DD, Groshen S, Lyass O, Henderson R, Berry G, Gabizon A (2000) Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 11(8):1029–1033PubMedGoogle Scholar
  170. 170.
    Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, Brufman G, Gabizon A (2000) Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (doxil) in metastatic breast carcinoma. Cancer 89(5):1037–1047. doi:10.1002/1097-0142 (20000901)89:5<1037:AID-CNCR13>3.0.CO;2-Z [pii]Google Scholar
  171. 171.
    Perez AT, Domenech GH, Frankel C, Vogel CL (2002) Pegylated liposomal doxorubicin (doxil) for metastatic breast cancer: the cancer research network, inc., experience. Cancer Invest 20(Suppl 2):22–29PubMedGoogle Scholar
  172. 172.
    Harbeck N, Pegram MD, Ruschoff J, Mobus V (2010) Targeted therapy in metastatic breast cancer: the her2/neu oncogene. Breast Care (Basel) 5(s1):3–7. doi: 10.1159/000285714, [pii] 285714Google Scholar
  173. 173.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the her-2/neu oncogene. Science 235(4785):177–182PubMedGoogle Scholar
  174. 174.
    Colombo M, Corsi F, Foschi D, Mazzantini E, Mazzucchelli S, Morasso C, Occhipinti E, Polito L, Prosperi D, Ronchi S, Verderio P (2010) Her2 targeting as a two-sided strategy for breast cancer diagnosis and treatment: outlook and recent implications in nanomedical approaches. Pharmacol Res 62(2):150–165. doi: 10.1016/j.phrs.2010.01.013, [pii] S1043-6618(10)00027-7PubMedGoogle Scholar
  175. 175.
    Inoue S, Ding H, Portilla-Arias J, Hu J, Konda B, Fujita M, Espinoza A, Suhane S, Riley M, Gates M, Patil R, Penichet ML, Ljubimov AV, Black KL, Holler E, Ljubimova JY (2011) Polymalic acid-based nanobiopolymer provides efficient systemic breast cancer treatment by inhibiting both her2/neu receptor synthesis and activity. Cancer Res 71(4):1454–1464. doi: 10.1158/0008-5472.CAN-10-3093, [pii] 0008-5472.CAN-10-3093PubMedCentralPubMedGoogle Scholar
  176. 176.
    Kumar M, Yigit M, Dai G, Moore A, Medarova Z (2010) Image-guided breast tumor therapy using a small interfering rna nanodrug. Cancer Res 70(19):7553–7561. doi: 10.1158/0008-5472.CAN-10-2070, [pii]: 0008-5472.CAN-10-2070PubMedCentralPubMedGoogle Scholar
  177. 177.
    Perey L, Hayes DF, Maimonis P, Abe M, O'Hara C, Kufe DW (1992) Tumor selective reactivity of a monoclonal antibody prepared against a recombinant peptide derived from the df3 human breast carcinoma-associated antigen. Cancer Res 52(9):2563–2568PubMedGoogle Scholar
  178. 178.
    Osborne CK (1998) Steroid hormone receptors in breast cancer management. Breast Cancer Res Treat 51(3):227–238PubMedGoogle Scholar
  179. 179.
    Rai S, Paliwal R, Vaidya B, Gupta PN, Mahor S, Khatri K, Goyal AK, Rawat A, Vyas SP (2007) Estrogen(s) and analogs as a non-immunogenic endogenous ligand in targeted drug/DNA delivery. Curr Med Chem 14(19):2095–2109PubMedGoogle Scholar
  180. 180.
    Paliwal SR, Paliwal R, Mishra N, Mehta A, Vyas SP (2010) A novel cancer targeting approach based on estrone anchored stealth liposome for site-specific breast cancer therapy. Curr Cancer Drug Targets 10(3):343–353, [pii]: EPub-Abstract-CCDT-32PubMedGoogle Scholar
  181. 181.
    Paliwal SR, Paliwal R, Pal HC, Saxena AK, Sharma PR, Gupta PN, Agrawal GP, Vyas SP (2012) Estrogen-anchored ph-sensitive liposomes as nanomodule designed for site-specific delivery of doxorubicin in breast cancer therapy. Mol Pharm 9(1):176–186. doi: 10.1021/mp200439z PubMedGoogle Scholar
  182. 182.
    Hadjipanayis CG, Machaidze R, Kaluzova M, Wang L, Schuette AJ, Chen H, Wu X, Mao H (2010) Egfrviii antibody-conjugated iron oxide nanoparticles for magnetic resonance imaging-guided convection-enhanced delivery and targeted therapy of glioblastoma. Cancer Res 70(15):6303–6312. doi: 10.1158/0008-5472.CAN-10-1022, [pii] 0008-5472.CAN-10-1022PubMedCentralPubMedGoogle Scholar
  183. 183.
    Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91(6):2076–2080PubMedGoogle Scholar
  184. 184.
    Hadjipanayis CG, Fellows-Mayle W, Deluca NA (2008) Therapeutic efficacy of a herpes simplex virus with radiation or temozolomide for intracranial glioblastoma after convection-enhanced delivery. Mol Ther 16(11):1783–1788. doi: 10.1038/mt.2008.185, [pii]: mt2008185PubMedCentralPubMedGoogle Scholar
  185. 185.
    Bulte JW, Kraitchman DL (2004) Iron oxide mr contrast agents for molecular and cellular imaging. NMR Biomed 17(7):484–499. doi: 10.1002/nbm.924 PubMedGoogle Scholar
  186. 186.
    Moore A, Weissleder R, Bogdanov A Jr (1997) Uptake of dextran-coated monocrystalline iron oxides in tumor cells and macrophages. J Magn Reson Imaging 7(6):1140–1145PubMedGoogle Scholar
  187. 187.
    Gao X, Cui Y, Levenson RM, Chung LW, Nie S (2004) In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 22(8):969–976. doi: 10.1038/nbt994, [pii]: nbt994PubMedGoogle Scholar
  188. 188.
    Moore A, Marecos E, Bogdanov A Jr, Weissleder R (2000) Tumoral distribution of long-circulating dextran-coated iron oxide nanoparticles in a rodent model. Radiology 214(2):568–574PubMedGoogle Scholar
  189. 189.
    Zimmer C, Weissleder R, Poss K, Bogdanova A, Wright SC Jr, Enochs WS (1995) Mr imaging of phagocytosis in experimental gliomas. Radiology 197(2):533–538PubMedGoogle Scholar
  190. 190.
    Villanueva A, Canete M, Roca AG, Calero M, Veintemillas-Verdaguer S, Serna CJ, Morales Mdel P, Miranda R (2009) The influence of surface functionalization on the enhanced internalization of magnetic nanoparticles in cancer cells. Nanotechnology 20(11):115103. doi: 10.1088/0957-4484/20/11/115103, [pii]: S0957-4484(09)98457-4PubMedGoogle Scholar
  191. 191.
    Guthi JS, Yang SG, Huang G, Li S, Khemtong C, Kessinger CW, Peyton M, Minna JD, Brown KC, Gao J (2010) Mri-visible micellar nanomedicine for targeted drug delivery to lung cancer cells. Mol Pharm 7(1):32–40. doi: 10.1021/mp9001393 PubMedCentralPubMedGoogle Scholar
  192. 192.
    Guan H, McGuire MJ, Li S, Brown KC (2008) Peptide-targeted polyglutamic acid doxorubicin conjugates for the treatment of alpha(v)beta(6)-positive cancers. Bioconjug Chem 19(9):1813–1821. doi: 10.1021/bc800154f PubMedGoogle Scholar
  193. 193.
    Elayadi AN, Samli KN, Prudkin L, Liu YH, Bian A, Xie XJ, Wistuba II, Roth JA, McGuire MJ, Brown KC (2007) A peptide selected by biopanning identifies the integrin alphavbeta6 as a prognostic biomarker for nonsmall cell lung cancer. Cancer Res 67(12):5889–5895. doi: 10.1158/0008-5472.CAN-07-0245, [pii]: 67/12/5889PubMedGoogle Scholar
  194. 194.
    Ahmed N, Riley C, Rice GE, Quinn MA, Baker MS (2002) Alpha(v)beta(6) integrin-a marker for the malignant potential of epithelial ovarian cancer. J Histochem Cytochem 50(10):1371–1380PubMedGoogle Scholar
  195. 195.
    Arihiro K, Kaneko M, Fujii S, Inai K, Yokosaki Y (2000) Significance of alpha 9 beta 1 and alpha v beta 6 integrin expression in breast carcinoma. Breast Cancer 7(1):19–26PubMedGoogle Scholar
  196. 196.
    Hazelbag S, Kenter GG, Gorter A, Dreef EJ, Koopman LA, Violette SM, Weinreb PH, Fleuren GJ (2007) Overexpression of the alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival. J Pathol 212(3):316–324. doi: 10.1002/path.2168 PubMedGoogle Scholar
  197. 197.
    Jones J, Watt FM, Speight PM (1997) Changes in the expression of alpha v integrins in oral squamous cell carcinomas. J Oral Pathol Med 26(2):63–68PubMedGoogle Scholar
  198. 198.
    Kawashima A, Tsugawa S, Boku A, Kobayashi M, Minamoto T, Nakanishi I, Oda Y (2003) Expression of alphav integrin family in gastric carcinomas: increased alphavbeta6 is associated with lymph node metastasis. Pathol Res Pract 199(2):57–64PubMedGoogle Scholar
  199. 199.
    Nasongkla N, Bey E, Ren J, Ai H, Khemtong C, Guthi JS, Chin SF, Sherry AD, Boothman DA, Gao J (2006) Multifunctional polymeric micelles as cancer-targeted, mri-ultrasensitive drug delivery systems. Nano Lett 6(11):2427–2430. doi: 10.1021/nl061412u PubMedGoogle Scholar
  200. 200.
    Fu A, Wilson RJ, Smith BR, Mullenix J, Earhart C, Akin D, Guccione S, Wang SX, Gambhir SS (2012) Fluorescent magnetic nanoparticles for magnetically enhanced cancer imaging and targeting in living subjects. ACS Nano 6(8):6862–6869. doi: 10.1021/nn301670a PubMedCentralPubMedGoogle Scholar
  201. 201.
    Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA (1994) Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79(7):1157–1164. doi: 10.1016/0092-8674(94)90007-8 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Shiran Ferber
    • 1
  • Galia Tiram
    • 1
  • Ronit Satchi-Fainaro
    • 1
  1. 1.Department of Physiology and PharmacologySackler School of Medicine, Tel Aviv UniversityTel AvivIsrael

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