Recent Advances in Tumor Targeting Approaches

  • Kaushik Thanki
  • Varun Kushwah
  • Sanyog JainEmail author
Part of the Advances in Delivery Science and Technology book series (ADST)


Tremendous technological advancement has been observed in the past few decades to combat ever increasing mortality rate in cancer therapy. It is now widely accepted that this reduction in mortality can be addressed effectively by materializing the concept of magic bullet, i.e., localizing the drug in concern at the site of action, thereby sparing normal tissues from unwanted toxicities and drastically improving the therapeutic efficacy. The present chapter inculcates such recent advances in the tumor targeting approaches. Basics of the peculiar tumor microenvironment and its discrimination from normal tissues have been primarily covered in brief to provide a background for the better understanding of the design and development of molecular and physicochemical targets. Concomitantly, barriers offered by altered tumor microenvironment to the drug delivery of anticancer drugs have been covered. The subsequent sections covers the conventional strategies for tumor targeting which essentially comprises passive targeting, active targeting, and physical targeting followed by recent advances in the tumor targeting approaches from clinical perspectives. These include deeper insights on molecular targeted therapies, tumor angiogenesis , cancer immunotherapy, and drug delivery of multiple drug resistance tumors. In a nutshell, with the advent of the molecularly targeted therapies, targeting tumor specific surface antigens and intracellular processes and components is a rapidly shifting paradigm of cancer therapy and unexceptional results have been observed till date by appropriately blending it with nanotechnology based approaches.


Tumor targeting Molecular targeted therapies EPR Surface functionalized nanocarriers Multidrug resistant tumors Angiogenesis Immunotherapy 


17 AAG





Antibody dependent cellular cytotoxicity


Antibody directed enzyme prodrug therapy


Monoclonal antinuclear autoantibody


Acid sphingomyelinase


Adenosine triphosphate


Biopharmaceutical classification system


Bromodomain and extra-terminal


Binding protein


Breast cancer gene


Complement-activation dependent cytotoxicity


Cyclin dependent kinases


Central nervous system


Cytotoxic T-lymphocyte antigen


Deglycosylated ricin A chain


5,6-Dimethylxanthenone-4-acetic acid


Deoxy ribose nucleic acid




External-beam radiation therapy


Extracellular matrix


Endothelial precursor cells


Enhancer of Zeste homolog 2


Focal adhesion kinase


2-Deoxy-2-(18F) fluoro-d-glucose


Granulocyte-macrophage colony-stimulating factor


78 kDa glucose-regulated protein


Trimethylation and dimethylation of histone H3 at lysine 4


Human anti-mouse antibody


Human anti-ricin antibody


Human chorionic gonadotrophin


Histone deacetylase


Human epidermal growth factor receptor 2


Hypoxia inducible factor


HSP90 organizing protein


N-(2-hydroxy propyl) methacrylamide


Heat shock proteins


Interstitial fluid pressure




1,4,7,10-Tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid


Jagged 1 protein


Lymphatic endothelial cells


Lewis lung carcinoma


Ligand-targeted therapeutics


Monoclonal antibody


Mitogen-activated protein kinase


Monocarboxylate transporters


Matrix metalloproteinases


Macrophagocytosis systems


Mechanistic target of rapamycin


Myelocytomatosis oncogene


Alternate reading frame


Phosphoinositide 3-kinase


Polymer directed enzyme prodrug therapy


Phosphatidyl ethanolamine


Protein kinase B


26S protease regulatory subunit 7 gene


Retinoblastoma tumor suppressor protein






Red blood cell


Reticuloendothelial system


Structure–activity relationship




2-(4-isothiocyanotobenzyl)-1, 4, 7, 10-tetraaza-1, 4, 7, 10-tetra-(2-carbamonyl methyl)-cyclododecane


Tumor necrosis factors


Tumor protein P53


Vascular endothelial growth factor


Vascular smooth muscle cells


World Health Organization


  1. 1.
    International Agency for Research on Cancer (IARC), World Heatlth Organization (WHO) (2012)Cancer fact sheets. In: Globocan 2012: estimated cancer incidence, mortalitity and prevalence worldwide in 2012. International Agency for Research on Cancer (IARC), World Heatlth Organization (WHO), Lyon, FranceGoogle Scholar
  2. 2.
    Lippman SM, Hong WK (2002) Cancer prevention science and practice. Cancer Res 62:5119–5125, PMID: 12234971PubMedGoogle Scholar
  3. 3.
    Ghose T (2002) The current status of tumor targeting. In: Page M (ed) Tumor targeting in cancer therapy. Springer Science, New York, NY, pp 3–78Google Scholar
  4. 4.
    Poste G, Kirsh R (1983) Site–specific (targeted) drug delivery in cancer therapy. Nat Biotechnol 1:869–878. doi: 10.1038/nbt1283-869 Google Scholar
  5. 5.
    Parveen S, Sahoo SK (2008) Polymeric nanoparticles for cancer therapy. J Drug Target 16:108–123. doi: 10.1080/10611860701794353 PubMedGoogle Scholar
  6. 6.
    Dewhirst MW, Kimura H, Rehmus SW, Braun RD, Papahadjopoulos D, Hong K, Secomb TW (1996) Microvascular studies on the origins of perfusion-limited hypoxia. Br J Cancer 27(Suppl):S247–S251, PMID 8763890Google Scholar
  7. 7.
    Cairns R, Papandreou I, Denko N (2006) Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment. Mol Cancer Res 4:61–70. doi: 10.1158/1541-7786.MCR-06-0002 PubMedGoogle Scholar
  8. 8.
    Heldin CH, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure – an obstacle in cancer therapy. Nat Rev Cancer 4:806–813. doi: 10.1038/nrc1456 PubMedGoogle Scholar
  9. 9.
    van den Berg AP, Wike-Hooley JL, van den Berg-Blok AE, van der Zee J, Reinhold HS (1982) Tumour pH in human mammary carcinoma. Eur J Cancer Clin Oncol 18:457–462. doi: 10.1016/0277-5379(82)90114-6 PubMedGoogle Scholar
  10. 10.
    Tannock IF, Rotin D (1989) Acid pH in tumors and its potential for therapeutic exploitation. Cancer Res 49:4373–4384, PMID: 2545340PubMedGoogle Scholar
  11. 11.
    Weinhouse S (1976) The Warburg hypothesis fifty years later. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 87:115–126, PMID: 136820PubMedGoogle Scholar
  12. 12.
    Yamagata M, Hasuda K, Stamato T, Tannock IF (1998) The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase. Br J Cancer 77:1726–1731. doi: 10.1038/bjc.1998.289 PubMedCentralPubMedGoogle Scholar
  13. 13.
    Izumi H, Torigoe T, Ishiguchi H, Uramoto H, Yoshida Y, Tanabe M, Ise T, Murakami T, Yoshida T, Nomoto M, Kohno K (2003) Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev 29:541–549. doi: 10.1016/S0305-7372(03)00106-3 PubMedGoogle Scholar
  14. 14.
    Griffiths JR, McIntyre DJ, Howe FA, Stubbs M (2001) Why are cancers acidic? A carrier-mediated diffusion model for H + transport in the interstitial fluid. Novartis Found Symp 240:46–62, discussion 62–47, 152–153; PMID: 11727936PubMedGoogle Scholar
  15. 15.
    Narang AS, Varia S (2011) Role of tumor vascular architecture in drug delivery. Adv Drug Deliv Rev 63:640–658. doi: 10.1016/j.addr.2011.04.002 PubMedGoogle Scholar
  16. 16.
    Thanki K, Gangwal RP, Sangamwar AT, Jain S (2013) Oral delivery of anticancer drugs: challenges and opportunities. J Control Release 170:15–40. doi: 10.1016/j.jconrel.2013.04.020 PubMedGoogle Scholar
  17. 17.
    Weissig V, D’Souza GG (2010) Organelle-specific pharmaceutical nanotechnology. Wiley, Hoboken, NJGoogle Scholar
  18. 18.
    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 46:6387–6392, PMID: 2946403PubMedGoogle Scholar
  19. 19.
    Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, Jain RK (1998) Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A 95:4607–4612, PMID: 9539785PubMedCentralPubMedGoogle Scholar
  20. 20.
    Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK (2004) Pathology: cancer cells compress intratumour vessels. Nature 427:695. doi: 10.1038/427695a PubMedGoogle Scholar
  21. 21.
    Rabanel JM, Aoun V, Elkin I, Mokhtar M, Hildgen P (2012) Drug-loaded nanocarriers: passive targeting and crossing of biological barriers. Curr Med Chem 19:3070–3102. doi: 10.2174/092986712800784702 PubMedGoogle Scholar
  22. 22.
    Nag OK, Awasthi V (2013) Surface engineering of liposomes for stealth behavior. Pharmaceutics 5:542–569. doi: 10.3390/pharmaceutics5040542 PubMedCentralPubMedGoogle Scholar
  23. 23.
    Salmaso S, Caliceti P (2013) Stealth properties to improve therapeutic efficacy of drug nanocarriers. J Drug Deliv 2013:374252. doi: 10.1155/2013/374252 PubMedCentralPubMedGoogle Scholar
  24. 24.
    Allen TM, Hansen C, Rutledge J (1989) Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues. Biochim Biophys Acta 981:27–35. doi: 10.1016/0005-2736(89)90078-3 PubMedGoogle Scholar
  25. 25.
    Gabizon A, Papahadjopoulos D (1988) Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci USA 85:6949–6953, PMID: 3413128PubMedCentralPubMedGoogle Scholar
  26. 26.
    Immordino ML, Dosio F, Cattel L (2006) Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine 1:297–315, PMID: 17717971PubMedCentralPubMedGoogle Scholar
  27. 27.
    Tirosh O, Barenholz Y, Katzhendler J, Priev A (1998) Hydration of polyethylene glycol-grafted liposomes. Biophys J 74:1371–1379. doi: 10.1016/S0006-3495(98)77849-X PubMedCentralPubMedGoogle Scholar
  28. 28.
    Lehtonen JY, Kinnunen PK (1995) Poly(ethylene glycol)-induced and temperature-dependent phase separation in fluid binary phospholipid membranes. Biophys J 68:525–535. doi: 10.1016/S0006-3495(95)80214-6 PubMedCentralPubMedGoogle Scholar
  29. 29.
    Szebeni J (2005) Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Toxicology 216:106–121. doi: 10.1016/j.tox.2005.07.023 PubMedGoogle Scholar
  30. 30.
    Yang Q, Ma Y, Zhao Y, She Z, Wang L, Li J, Wang C, Deng Y (2013) Accelerated drug release and clearance of PEGylated epirubicin liposomes following repeated injections: a new challenge for sequential low-dose chemotherapy. Int J Nanomedicine 8:1257–1268. doi: 10.2147/IJN.S41701 PubMedCentralPubMedGoogle Scholar
  31. 31.
    Herold DA, Keil K, Bruns DE (1989) Oxidation of polyethylene glycols by alcohol dehydrogenase. Biochem Pharmacol 38:73–76. doi: 10.1016/0006-2952(89)90151-2 PubMedGoogle Scholar
  32. 32.
    Veronese FM, Pasut G (2005) PEGylation, successful approach to drug delivery. Drug Discov Today 10:1451–1458. doi: 10.1016/S1359-6446(05)03575-0 PubMedGoogle Scholar
  33. 33.
    Allen TM (2002) Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer 2:750–763. doi: 10.1038/nrc903 PubMedGoogle Scholar
  34. 34.
    Gradishar WJ (2006) Albumin-bound paclitaxel: a next-generation taxane. Expert Opin Pharmacother 7:1041–1053. doi: 10.1517/14656566.7.8.1041 PubMedGoogle Scholar
  35. 35.
    John TA, Vogel SM, Tiruppathi C, Malik AB, Minshall RD (2003) Quantitative analysis of albumin uptake and transport in the rat microvessel endothelial monolayer. Am J Physiol Lung Cell Mol Physiol 284:L187–196. doi: 10.1152/ajplung.00152.2002 PubMedGoogle Scholar
  36. 36.
    Minshall RD, Tiruppathi C, Vogel SM, Malik AB (2002) Vesicle formation and trafficking in endothelial cells and regulation of endothelial barrier function. Histochem Cell Biol 117:105–112. doi: 10.1007/s00418-001-0367-x PubMedGoogle Scholar
  37. 37.
    Kumagai AK, Eisenberg JB, Pardridge WM (1987) Absorptive-mediated endocytosis of cationized albumin and a beta-endorphin-cationized albumin chimeric peptide by isolated brain capillaries. Model system of blood-brain barrier transport. J Biol Chem 262:15214–15219, PMID: 2959663PubMedGoogle Scholar
  38. 38.
    Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, Noker P, Yao R, Labao E, Hawkins M, Soon-Shiong P (2006) Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 12:1317–1324. doi: 10.1158/1078-0432.CCR-05-1634 PubMedGoogle Scholar
  39. 39.
    Das M, Mohanty C, Sahoo SK (2009) Ligand-based targeted therapy for cancer tissue. Expert Opin Drug Deliv 6:285–304. doi: 10.1517/17425240902780166 PubMedGoogle Scholar
  40. 40.
    Vasir JK, Labhasetwar V (2005) Targeted drug delivery in cancer therapy. Technol Cancer Res Treat 4:363–374, PMID: 16029056PubMedGoogle Scholar
  41. 41.
    Jain S, Mathur R, Das M, Swarnakar NK, Mishra AK (2011) Synthesis, pharmacoscintigraphic evaluation and antitumor efficacy of methotrexate-loaded, folate-conjugated, stealth albumin nanoparticles. Nanomedicine (Lond) 6:1733–1754. doi: 10.2217/nnm.11.53 Google Scholar
  42. 42.
    Das M, Bandyopadhyay D, Mishra D, Datir S, Dhak P, Jain S, Maiti TK, Basak A, Pramanik P (2011) “Clickable”, trifunctional magnetite nanoparticles and their chemoselective biofunctionalization. Bioconjug Chem 22:1181–1193. doi: 10.1021/bc2000484 PubMedGoogle Scholar
  43. 43.
    Das M, Datir SR, Singh RP, Jain S (2013) Augmented anticancer activity of a targeted, intracellularly activatable, theranostic nanomedicine based on fluorescent and radiolabeled, methotrexate-folic acid-multiwalled carbon nanotube conjugate. Mol Pharm 10:2543–2557. doi: 10.1021/mp300701e PubMedGoogle Scholar
  44. 44.
    Lu YJ, Wei KC, Ma CC, Yang SY, Chen JP (2012) Dual targeted delivery of doxorubicin to cancer cells using folate-conjugated magnetic multi-walled carbon nanotubes. Colloids Surf B: Biointerfaces 89:1–9. doi: 10.1016/j.colsurfb.2011.08.001 PubMedGoogle Scholar
  45. 45.
    Li L, Yang Q, Zhou Z, Zhong J, Huang Y (2014) Doxorubicin-loaded, charge reversible, folate modified HPMA copolymer conjugates for active cancer cell targeting. Biomaterials 35:5171–5187. doi: 10.1016/j.biomaterials.2014.03.027 PubMedGoogle Scholar
  46. 46.
    Corbin IR, Ng KK, Ding L, Jurisicova A, Zheng G (2013) Near-infrared fluorescent imaging of metastatic ovarian cancer using folate receptor-targeted high-density lipoprotein nanocarriers. Nanomedicine 8:875–890. doi: 10.2217/nnm.12.137 PubMedCentralPubMedGoogle Scholar
  47. 47.
    Hong G, Yuan R, Liang B, Shen J, Yang X, Shuai X (2008) Folate-functionalized polymeric micelle as hepatic carcinoma-targeted, MRI-ultrasensitive delivery system of antitumor drugs. Biomed Microdevices 10:693–700. doi: 10.1007/s10544-008-9180-9 PubMedGoogle Scholar
  48. 48.
    Tyagi N, Ghosh PC (2011) Folate receptor mediated targeted delivery of ricin entrapped into sterically stabilized liposomes to human epidermoid carcinoma (KB) cells: effect of monensin intercalated into folate-tagged liposomes. Eur J Pharm Sci 43:343–353. doi: 10.1016/j.ejps.2011.05.010 PubMedGoogle Scholar
  49. 49.
    Lale SV, GA R, Aravind A, Kumar DS, Koul V (2014) AS1411 Aptamer and folic acid functionalized pH-responsive ATRP fabricated pPEGMA-PCL-pPEGMA polymeric nanoparticles for targeted drug delivery in cancer therapy. Biomacromolecules 15:1737–1752. doi: 10.1021/bm5001263 PubMedGoogle Scholar
  50. 50.
    El-Gogary RI, Rubio N, Wang JT, Al-Jamal WT, Bourgognon M, Kafa H, Naeem M, Klippstein R, Abbate V, Leroux F, Bals S, Van Tendeloo G, Kamel AO, Awad GA, Mortada ND, Al-Jamal KT (2014) Polyethylene glycol conjugated polymeric nanocapsules for targeted delivery of quercetin to folate-expressing cancer cells in vitro and in vivo. ACS Nano 8:1384–1401. doi: 10.1021/nn405155b PubMedGoogle Scholar
  51. 51.
    Tavassolian F, Kamalinia G, Rouhani H, Amini M, Ostad SN, Khoshayand MR, Atyabi F, Tehrani MR, Dinarvand R (2014) Targeted poly (L-gamma-glutamyl glutamine) nanoparticles of docetaxel against folate over-expressed breast cancer cells. Int J Pharm 467:123–138. doi: 10.1016/j.ijpharm.2014.03.033 PubMedGoogle Scholar
  52. 52.
    Nair BP, Vaikkath D, Nair PD (2014) Polyhedral oligomeric silsesquioxane-F68 hybrid vesicles for folate receptor targeted anti-cancer drug delivery. Langmuir 30:340–347. doi: 10.1021/la4036997 PubMedGoogle Scholar
  53. 53.
    Chen YC, Chiang CF, Chen LF, Liang PC, Hsieh WY, Lin WL (2014) Polymersomes conjugated with des-octanoyl ghrelin and folate as a BBB-penetrating cancer cell-targeting delivery system. Biomaterials 35:4066–4081. doi: 10.1016/j.biomaterials.2014.01.042 PubMedGoogle Scholar
  54. 54.
    Dowlati A, Loo M, Bury T, Fillet G, Beguin Y (1997) Soluble and cell-associated transferrin receptor in lung cancer. Br J Cancer 75:1802–1806. doi: 10.1038/bjc.1997.307 PubMedCentralPubMedGoogle Scholar
  55. 55.
    Gosk S, Vermehren C, Storm G, Moos T (2004) Targeting anti-transferrin receptor antibody (OX26) and OX26-conjugated liposomes to brain capillary endothelial cells using in situ perfusion. J Cereb Blood Flow Metab 24:1193–1204. doi: 10.1097/01.WCB.0000135592.28823.47 PubMedGoogle Scholar
  56. 56.
    Sahoo SK, Labhasetwar V (2005) Enhanced antiproliferative activity of transferrin-conjugated paclitaxel-loaded nanoparticles is mediated via sustained intracellular drug retention. Mol Pharm 2:373–383. doi: 10.1021/mp050032z PubMedGoogle Scholar
  57. 57.
    Sahoo SK, Ma W, Labhasetwar V (2004) Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. Int J Cancer 112:335–340. doi: 10.1002/ijc.20405 PubMedGoogle Scholar
  58. 58.
    Ferris DP, Lu J, Gothard C, Yanes R, Thomas CR, Olsen JC, Stoddart JF, Tamanoi F, Zink JI (2011) Synthesis of biomolecule-modified mesoporous silica nanoparticles for targeted hydrophobic drug delivery to cancer cells. Small 7:1816–1826. doi: 10.1002/smll.201002300 PubMedCentralPubMedGoogle Scholar
  59. 59.
    Kim TH, Jo YG, Jiang HH, Lim SM, Youn YS, Lee S, Chen X, Byun Y, Lee KC (2012) PEG-transferrin conjugated TRAIL (TNF-related apoptosis-inducing ligand) for therapeutic tumor targeting. J Control Release 162:422–428. doi: 10.1016/j.jconrel.2012.07.021 PubMedCentralPubMedGoogle Scholar
  60. 60.
    Gaspar MM, Radomska A, Gobbo OL, Bakowsky U, Radomski MW, Ehrhardt C (2012) Targeted delivery of transferrin-conjugated liposomes to an orthotopic model of lung cancer in nude rats. J Aerosol Med Pulm Drug Deliv 25:310–318. doi: 10.1089/jamp.2011.0928 PubMedGoogle Scholar
  61. 61.
    Liu G, Shen H, Mao J, Zhang L, Jiang Z, Sun T, Lan Q, Zhang Z (2013) Transferrin modified graphene oxide for glioma-targeted drug delivery: in vitro and in vivo evaluations. ACS Appl Mater Interfaces 5:6909–6914. doi: 10.1021/am402128s PubMedGoogle Scholar
  62. 62.
    Neves S, Faneca H, Bertin S, Konopka K, Duzgunes N, Pierrefite-Carle V, Simoes S, Pedroso de Lima MC (2009) Transferrin lipoplex-mediated suicide gene therapy of oral squamous cell carcinoma in an immunocompetent murine model and mechanisms involved in the antitumoral response. Cancer Gene Ther 16:91–101. doi: 10.1038/cgt.2008.60 PubMedGoogle Scholar
  63. 63.
    Vaidya B, Vyas SP (2012) Transferrin coupled vesicular system for intracellular drug delivery for the treatment of cancer: development and characterization. J Drug Target 20:372–380. doi: 10.3109/1061186X.2012.662687 PubMedGoogle Scholar
  64. 64.
    Abouzeid AH, Patel NR, Sarisozen C, Torchilin VP (2014) Transferrin-targeted polymeric micelles co-loaded with curcumin and paclitaxel: efficient killing of paclitaxel-resistant cancer cells. Pharm Res 1-8. doi:  10.1007/s11095-013-1295-x
  65. 65.
    Yhee JY, Lee SJ, Lee S, Song S, Min HS, Kang SW, Son S, Jeong SY, Kwon IC, Kim SH, Kim K (2013) Tumor-targeting transferrin nanoparticles for systemic polymerized siRNA delivery in tumor-bearing mice. Bioconjug Chem 24:1850–1860. doi: 10.1021/bc400226b PubMedGoogle Scholar
  66. 66.
    Huang Y, He L, Liu W, Fan C, Zheng W, Wong Y-S, Chen T (2013) Selective cellular uptake and induction of apoptosis of cancer-targeted selenium nanoparticles. Biomaterials 34:7106–7116. doi: 10.1016/j.biomaterials.2013.04.067 PubMedGoogle Scholar
  67. 67.
    Bies C, Lehr CM, Woodley JF (2004) Lectin-mediated drug targeting: history and applications. Adv Drug Deliv Rev 56:425–435. doi: 10.1016/j.addr.2003.10.030 PubMedGoogle Scholar
  68. 68.
    Baenziger JU, Maynard Y (1980) Human hepatic lectin. Physiochemical properties and specificity. J Biol Chem 255:4607–4613, PMID: 7372599PubMedGoogle Scholar
  69. 69.
    Duncan R (2003) The dawning era of polymer therapeutics. Nat Rev Drug Discov 2:347–360. doi: 10.1038/nrd1088 PubMedGoogle Scholar
  70. 70.
    Yu HY, Lin JH (2000) Intracellular delivery of membrane-impermeable hydrophilic molecules to a hepatoblastoma cell line by asialoglycoprotein-labeled liposomes. J Formos Med Assoc 99:936–941, PMID: 11155748PubMedGoogle Scholar
  71. 71.
    Dubey PK, Mishra V, Jain S, Mahor S, Vyas SP (2004) Liposomes modified with cyclic RGD peptide for tumor targeting. J Drug Target 12:257–264. doi: 10.1080/10611860410001728040 PubMedGoogle Scholar
  72. 72.
    Aina OH, Sroka TC, Chen ML, Lam KS (2002) Therapeutic cancer targeting peptides. Biopolymers 66:184–199. doi: 10.1002/bip.10257 PubMedGoogle Scholar
  73. 73.
    Torchilin VP (2000) Drug targeting. Eur J Pharm Sci 11(Suppl 2):S81–91. doi: 10.1016/S0928-0987(00)00166-4 PubMedGoogle Scholar
  74. 74.
    Husseini GA, Diaz de la Rosa MA, Gabuji T, Zeng Y, Christensen DA, Pitt WG (2007) Release of doxorubicin from unstabilized and stabilized micelles under the action of ultrasound. J Nanosci Nanotechnol 7:1028–1033. doi: 10.1166/jnn.2007.218 PubMedCentralPubMedGoogle Scholar
  75. 75.
    Knights CD, Pestell RG (2008) The cell cycle: therapeutic targeting of cell cycle regulatory components and effector pathways in cancer. In: Kaufman HL, Wadler S, Antman K (eds) Molecular targeting in oncology. Humana, Totowa, NJGoogle Scholar
  76. 76.
    Liu MC, Marshall JL, Pestell RG (2004) Novel strategies in cancer therapeutics: targeting enzymes involved in cell cycle regulation and cellular proliferation. Curr Cancer Drug Targets 4:403–424. doi: 10.2174/1568009043332907 PubMedGoogle Scholar
  77. 77.
    Chin K, de Solorzano CO, Knowles D, Jones A, Chou W, Rodriguez EG, Kuo WL, Ljung BM, Chew K, Myambo K, Miranda M, Krig S, Garbe J, Stampfer M, Yaswen P, Gray JW, Lockett SJ (2004) In situ analyses of genome instability in breast cancer. Nat Genet 36:984–988. doi: 10.1038/ng1409 PubMedGoogle Scholar
  78. 78.
    Deshpande A, Sicinski P, Hinds PW (2005) Cyclins and cdks in development and cancer: a perspective. Oncogene 24:2909–2915. doi: 10.1038/sj.onc.1208618 PubMedGoogle Scholar
  79. 79.
    Hedenfalk I, Duggan D, Chen Y, Radmacher M, Bittner M, Simon R, Meltzer P, Gusterson B, Esteller M, Kallioniemi OP, Wilfond B, Borg A, Trent J, Raffeld M, Yakhini Z, Ben-Dor A, Dougherty E, Kononen J, Bubendorf L, Fehrle W, Pittaluga S, Gruvberger S, Loman N, Johannsson O, Olsson H, Sauter G (2001) Gene-expression profiles in hereditary breast cancer. N Engl J Med 344:539–548. doi: 10.1056/NEJM200102223440801 PubMedGoogle Scholar
  80. 80.
    Dobbelstein M, Moll U (2014) Targeting tumour-supportive cellular machineries in anticancer drug development. Nat Rev Drug Discov 13:179–196. doi: 10.1038/nrd4201 PubMedGoogle Scholar
  81. 81.
    Armstrong GT, Liu W, Leisenring W, Yasui Y, Hammond S, Bhatia S, Neglia JP, Stovall M, Srivastava D, Robison LL (2011) Occurrence of multiple subsequent neoplasms in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 29:3056–3064. doi: 10.1200/JCO.2011.34.6585 PubMedCentralPubMedGoogle Scholar
  82. 82.
    Travis LB, Fossa SD, Schonfeld SJ, McMaster ML, Lynch CF, Storm H, Hall P, Holowaty E, Andersen A, Pukkala E, Andersson M, Kaijser M, Gospodarowicz M, Joensuu T, Cohen RJ, Boice JD Jr, Dores GM, Gilbert ES (2005) Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 97:1354–1365. doi: 10.1093/jnci/dji278 PubMedGoogle Scholar
  83. 83.
    De Koning P, Neijt JP, Jennekens FG, Gispen WH (1987) Evaluation of cis-diamminedichloroplatinum (II) (cisplatin) neurotoxicity in rats. Toxicol Appl Pharmacol 89:81–87. doi: 10.1016/0041-008X(87)90178-5 PubMedGoogle Scholar
  84. 84.
    Marullo R, Werner E, Degtyareva N, Moore B, Altavilla G, Ramalingam SS, Doetsch PW (2013) Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS One 8:e81162. doi: 10.1371/journal.pone.0081162 PubMedCentralPubMedGoogle Scholar
  85. 85.
    Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823–837. doi: 10.1016/j.cell.2009.02.024 PubMedCentralPubMedGoogle Scholar
  86. 86.
    Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O’Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR (2007) Patterns of somatic mutation in human cancer genomes. Nature 446:153–158. doi: 10.1038/nature05610 PubMedCentralPubMedGoogle Scholar
  87. 87.
    Capdeville R, Buchdunger E, Zimmermann J, Matter A (2002) Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1:493–502. doi: 10.1038/nrd839 PubMedGoogle Scholar
  88. 88.
    Ashwell S, Zabludoff S (2008) DNA damage detection and repair pathways–recent advances with inhibitors of checkpoint kinases in cancer therapy. Clin Cancer Res 14:4032–4037. doi: 10.1158/1078-0432.CCR-07-5138 PubMedGoogle Scholar
  89. 89.
    Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22. doi: 10.1016/j.ccr.2007.05.008 PubMedGoogle Scholar
  90. 90.
    Taipale M, Jarosz DF, Lindquist S (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11:515–528. doi: 10.1038/nrm2918 PubMedGoogle Scholar
  91. 91.
    Stadtman ER (2001) Protein oxidation in aging and age-related diseases. Ann N Y Acad Sci 928:22–38. doi: 10.1111/j.1749-6632.2001.tb05632.x PubMedGoogle Scholar
  92. 92.
    Soga S, Akinaga S, Shiotsu Y (2013) Hsp90 inhibitors as anti-cancer agents, from basic discoveries to clinical development. Curr Pharm Des 19:366–376. doi: 10.2174/1381612811306030366 PubMedGoogle Scholar
  93. 93.
    Shen M, Ping Dou Q (2013) Proteasome inhibition as a novel strategy for cancer treatment. In: Johnson DE (ed) Cell death signaling in cancer biology and treatment. Springer Sciences, New York, NY, pp 303–329Google Scholar
  94. 94.
    Groll M, Berkers CR, Ploegh HL, Ovaa H (2006) Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure 14:451–456. doi: 10.1016/j.str.2005.11.019 PubMedGoogle Scholar
  95. 95.
    D’Arcy P, Brnjic S, Olofsson MH, Fryknas M, Lindsten K, De Cesare M, Perego P, Sadeghi B, Hassan M, Larsson R, Linder S (2011) Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat Med 17:1636–1640. doi: 10.1038/nm.2536 PubMedGoogle Scholar
  96. 96.
    Lee BH, Lee MJ, Park S, Oh DC, Elsasser S, Chen PC, Gartner C, Dimova N, Hanna J, Gygi SP, Wilson SM, King RW, Finley D (2010) Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467:179–184. doi: 10.1038/nature09299 PubMedCentralPubMedGoogle Scholar
  97. 97.
    Ceccarelli DF, Tang X, Pelletier B, Orlicky S, Xie W, Plantevin V, Neculai D, Chou YC, Ogunjimi A, Al-Hakim A, Varelas X, Koszela J, Wasney GA, Vedadi M, Dhe-Paganon S, Cox S, Xu S, Lopez-Girona A, Mercurio F, Wrana J, Durocher D, Meloche S, Webb DR, Tyers M, Sicheri F (2011) An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. Cell 145:1075–1087. doi: 10.1016/j.cell.2011.05.039 PubMedGoogle Scholar
  98. 98.
    Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Critchley S, Cullis CA, Doucette A, Garnsey JJ, Gaulin JL, Gershman RE, Lublinsky AR, McDonald A, Mizutani H, Narayanan U, Olhava EJ, Peluso S, Rezaei M, Sintchak MD, Talreja T, Thomas MP, Traore T, Vyskocil S, Weatherhead GS, Yu J, Zhang J, Dick LR, Claiborne CF, Rolfe M, Bolen JB, Langston SP (2009) An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458:732–736. doi: 10.1038/nature07884 PubMedGoogle Scholar
  99. 99.
    Deshpande AJ, Bradner J, Armstrong SA (2012) Chromatin modifications as therapeutic targets in MLL-rearranged leukemia. Trends Immunol 33:563–570. doi: 10.1016/ PubMedCentralPubMedGoogle Scholar
  100. 100.
    Chi P, Allis CD, Wang GG (2010) Covalent histone modifications–miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 10:457–469. doi: 10.1038/nrc2876 PubMedCentralPubMedGoogle Scholar
  101. 101.
    Kubota Y (2012) Tumor angiogenesis and anti-angiogenic therapy. Keio J Med 61:47–56. doi: 10.2302/kjm.61.47 PubMedGoogle Scholar
  102. 102.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674. doi: 10.1038/386671a0 PubMedGoogle Scholar
  103. 103.
    Bikfalvi A, Bicknell R (2002) Recent advances in angiogenesis, anti-angiogenesis and vascular targeting. Trends Pharmacol Sci 23:576–582. doi: 10.1016/S0165-6147(02)02109-0 PubMedGoogle Scholar
  104. 104.
    Chung AS, Ferrara N (2011) Developmental and pathological angiogenesis. Annu Rev Cell Dev Biol 27:563–584. doi: 10.1146/annurev-cellbio-092910-154002 PubMedGoogle Scholar
  105. 105.
    Dayan F, Mazure NM, Brahimi-Horn MC, Pouyssegur J (2008) A dialogue between the hypoxia-inducible factor and the tumor microenvironment. Cancer Microenviron 1:53–68. doi: 10.1007/s12307-008-0006-3 PubMedCentralPubMedGoogle Scholar
  106. 106.
    Nagy JA, Dvorak AM, Dvorak HF (2007) VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol 2:251–275. doi: 10.1146/annurev.pathol.2.010506.134925 PubMedGoogle Scholar
  107. 107.
    Hendrix MJ, Seftor EA, Hess AR, Seftor RE (2003) Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 3:411–421. doi: 10.1038/nrc1092 PubMedGoogle Scholar
  108. 108.
    Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478. doi: 10.1038/nrm2183 PubMedGoogle Scholar
  109. 109.
    Shojaei F (2012) Anti-angiogenesis therapy in cancer: current challenges and future perspectives. Cancer Lett 320:130–137. doi: 10.1016/j.canlet.2012.03.008 PubMedGoogle Scholar
  110. 110.
    Deng T, Zhang L, Liu XJ, Xu JM, Bai YX, Wang Y, Han Y, Li YH, Ba Y (2013) Bevacizumab plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as the second-line therapy for patients with metastatic colorectal cancer, a multicenter study. Med Oncol 30:752. doi: 10.1007/s12032-013-0752-z PubMedGoogle Scholar
  111. 111.
    Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry D, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30:3499–3506. doi: 10.1200/JCO.2012.42.8201 PubMedGoogle Scholar
  112. 112.
    Smith NR, Baker D, Farren M, Pommier A, Swann R, Wang X, Mistry S, McDaid K, Kendrew J, Womack C, Wedge SR, Barry ST (2013) Tumor stromal architecture can define the intrinsic tumor response to VEGF-targeted therapy. Clin Cancer Res 19:6943–6956. doi: 10.1158/1078-0432.CCR-13-1637 PubMedGoogle Scholar
  113. 113.
    Vasudev NS, Reynolds AR (2014) Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis. doi: 10.1007/s10456-014-9420-y PubMedCentralPubMedGoogle Scholar
  114. 114.
    Henkin J, Volpert OV (2011) Therapies using anti-angiogenic peptide mimetics of thrombospondin-1. Expert Opin Ther Targets 15:1369–1386. doi: 10.1517/14728222.2011.640319 PubMedGoogle Scholar
  115. 115.
    Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O’Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886, PMID: 10766175PubMedGoogle Scholar
  116. 116.
    Damber JE, Vallbo C, Albertsson P, Lennernas B, Norrby K (2006) The anti-tumour effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin. Cancer Chemother Pharmacol 58:354–360. doi: 10.1007/s00280-005-0163-8 PubMedGoogle Scholar
  117. 117.
    Yap R, Veliceasa D, Emmenegger U, Kerbel RS, McKay LM, Henkin J, Volpert OV (2005) Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: a complementation antiangiogenic strategy. Clin Cancer Res 11:6678–6685. doi: 10.1158/1078-0432.CCR-05-0621 PubMedGoogle Scholar
  118. 118.
    Streit M, Stephen AE, Hawighorst T, Matsuda K, Lange-Asschenfeldt B, Brown LF, Vacanti JP, Detmar M (2002) Systemic inhibition of tumor growth and angiogenesis by thrombospondin-2 using cell-based antiangiogenic gene therapy. Cancer Res 62:2004–2012, PMID: 11929817PubMedGoogle Scholar
  119. 119.
    Butler GS, Overall CM (2009) Proteomic identification of multitasking proteins in unexpected locations complicates drug targeting. Nat Rev Drug Discov 8:935–948. doi: 10.1038/nrd2945 PubMedGoogle Scholar
  120. 120.
    Hadler-Olsen E, Winberg JO, Uhlin-Hansen L (2013) Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol 34:2041–2051. doi: 10.1007/s13277-013-0842-8 PubMedGoogle Scholar
  121. 121.
    Cooney MM, van Heeckeren W, Bhakta S, Ortiz J, Remick SC (2006) Drug insight: vascular disrupting agents and angiogenesis–novel approaches for drug delivery. Nat Clin Pract Oncol 3:682–692. doi: 10.1038/ncponc0663 PubMedGoogle Scholar
  122. 122.
    Dark GG, Hill SA, Prise VE, Tozer GM, Pettit GR, Chaplin DJ (1997) Combretastatin A-4, an agent that displays potent and selective toxicity toward tumor vasculature. Cancer Res 57:1829–1834, PMID: 9157969PubMedGoogle Scholar
  123. 123.
    Zhou S, Kestell P, Baguley BC, Paxton JW (2002) 5,6-dimethylxanthenone-4-acetic acid (DMXAA): a new biological response modifier for cancer therapy. Invest New Drugs 20:281–295. doi: 10.1023/A:1016215015530 PubMedGoogle Scholar
  124. 124.
    Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014–1022. doi: 10.1038/ni.2703 PubMedCentralPubMedGoogle Scholar
  125. 125.
    Engels B, Engelhard VH, Sidney J, Sette A, Binder DC, Liu RB, Kranz DM, Meredith SC, Rowley DA, Schreiber H (2013) Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity. Cancer Cell 23:516–526. doi: 10.1016/j.ccr.2013.03.018 PubMedCentralPubMedGoogle Scholar
  126. 126.
    Robbins PF, Lu YC, El-Gamil M, Li YF, Gross C, Gartner J, Lin JC, Teer JK, Cliften P, Tycksen E, Samuels Y, Rosenberg SA (2013) Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med 19:747–752. doi: 10.1038/nm.3161 PubMedCentralPubMedGoogle Scholar
  127. 127.
    Goldenberg DM (1993) Monoclonal antibodies in cancer detection and therapy. Am J Med 94:297–312. doi: 10.1016/0002-9343(93)90062-T PubMedGoogle Scholar
  128. 128.
    Carter P (2001) Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 1:118–129. doi: 10.1038/35101072 PubMedGoogle Scholar
  129. 129.
    Monoclonal antibody therapy (2014). Accessed Mar 2014.
  130. 130.
    Sharkey RM, Goldenberg DM (2011) Cancer radioimmunotherapy. Immunotherapy 3:349–370. doi: 10.2217/imt.10.114 PubMedCentralPubMedGoogle Scholar
  131. 131.
    Pressman D, Korngold L (1953) The in vivo localization of anti-Wagner-osteogenic-sarcoma antibodies. Cancer 6:619–623, PMID: 13042784PubMedGoogle Scholar
  132. 132.
    DeNardo SJ, DeNardo GL, O’Grady LF, Macey DJ, Mills SL, Epstein AL, Peng JS, McGahan JP (1987) Treatment of a patient with B cell lymphoma by I-131 LYM-1 monoclonal antibodies. Int J Biol Markers 2:49–53, PMID: 3501448PubMedGoogle Scholar
  133. 133.
    Press OW, Eary JF, Badger CC, Martin PJ, Appelbaum FR, Levy R, Miller R, Brown S, Nelp WB, Krohn KA et al (1989) Treatment of refractory non-Hodgkin’s lymphoma with radiolabeled MB-1 (anti-CD37) antibody. J Clin Oncol 7:1027–1038, PMID: 2666588PubMedGoogle Scholar
  134. 134.
    Kaminski MS, Zasadny KR, Francis IR, Milik AW, Ross CW, Moon SD, Crawford SM, Burgess JM, Petry NA, Butchko GM et al (1993) Radioimmunotherapy of B-cell lymphoma with [131I]anti-B1 (anti-CD20) antibody. N Engl J Med 329:459–465. doi: 10.1056/NEJM199308123290703 PubMedGoogle Scholar
  135. 135.
    Goldenberg DM (2002) Targeted therapy of cancer with radiolabeled antibodies. J Nucl Med 43:693–713, PMID: 11994535PubMedGoogle Scholar
  136. 136.
    Vacchelli E, Vitale I, Tartour E, Eggermont A, Sautes-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L (2013) Trial watch: anticancer radioimmunotherapy. Oncoimmunology 2:e25595. doi: 10.4161/onci.25595 PubMedCentralPubMedGoogle Scholar
  137. 137. Accessed in Mar 2014
  138. 138.
    Almqvist Y, Orlova A, Sjöström A, Jensen HJ, Lundqvist H, Sundin A, Tolmachev V (2005) In vitro characterization of 211At-labeled antibody A33-a potential therapeutic agent against metastatic colorectal carcinoma. Cancer Biother Radiopharm 20:514–523. doi: 10.1089/cbr.2005.20.514 PubMedGoogle Scholar
  139. 139.
    Pickhard A, Piontek G, Seidl C, Kopping S, Blechert B, Misslbeck M, Brockhoff G, Bruchertseifer F, Morgenstern A, Essler M (2014) (2)(1)(3)Bi-anti-EGFR radioimmunoconjugates and X-ray irradiation trigger different cell death pathways in squamous cell carcinoma cells. Nucl Med Biol 41:68–76. doi: 10.1016/j.nucmedbio.2013.09.010 PubMedGoogle Scholar
  140. 140.
    Qu C, Li Y, Song Y, Rizvi S, Raja C, Zhang D, Samra J, Smith R, Perkins A, Apostolidis C (2004) MUC1 expression in primary and metastatic pancreatic cancer cells for in vitro treatment by 213Bi-C595 radioimmunoconjugate. Br J Cancer 91:2086–2093. doi: 10.1038/sj.bjc.6602232 PubMedCentralPubMedGoogle Scholar
  141. 141.
    Zhang DY, Li Y, Rizvi SMA, Qu C, Kearsley J, Allen BJ (2005) Cytotoxicity of breast cancer cells overexpressing HER2/neu by 213Bi-Herceptin radioimmunoconjugate. Cancer Lett 218:181–190. doi: 10.1016/j.canlet.2004.07.050 PubMedGoogle Scholar
  142. 142.
    Li Y, Song E, Abbas Rizvi SM, Power CA, Beretov J, Raja C, Cozzi PJ, Morgenstern A, Apostolidis C, Allen BJ, Russell PJ (2009) Inhibition of micrometastatic prostate cancer cell spread in animal models by 213Bilabeled multiple targeted alpha radioimmunoconjugates. Clin Cancer Res 15:865–875. doi: 10.1158/1078-0432.CCR-08-1203 PubMedGoogle Scholar
  143. 143.
    Pavlinkova G, Booth BJ, Batra SK, Colcher D (1999) Radioimmunotherapy of human colon cancer xenografts using a dimeric single-chain Fv antibody construct. Clin Cancer Res 5:2613–2619, PMID: 10499640PubMedGoogle Scholar
  144. 144.
    Hu M, Chen P, Wang J, Scollard DA, Vallis KA, Reilly RM (2007) 123I-labeled HIV-1 tat peptide radioimmunoconjugates are imported into the nucleus of human breast cancer cells and functionally interact in vitro and in vivo with the cyclin-dependent kinase inhibitor, p21WAF-1/Cip-1. Eur J Nucl Med Mol Imaging 34:368–377. doi: 10.1007/s00259-006-0189-0 PubMedGoogle Scholar
  145. 145.
    Brouwers AH, van Eerd JE, Frielink C, Oosterwijk E, Oyen WJ, Corstens FH, Boerman OC (2004) Optimization of radioimmunotherapy of renal cell carcinoma: labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re. J Nucl Med 45:327–337, PMID: 14960657PubMedGoogle Scholar
  146. 146.
    Sharkey RM, Blumenthal RD, Behr TM, Wong GY, Haywood L, Forman D, Griffiths GL, Goldenberg DM (1997) Selection of radioimmunoconjugates for the therapy of well-established or micrometastatic colon carcinoma. Int J Cancer 72:477–485. doi: 10.1002/(SICI)1097-0215(19970729)72:3<477::AID-IJC16>3.0.CO;2-9 PubMedGoogle Scholar
  147. 147.
    Cornelissen B, Darbar S, Kersemans V, Allen D, Falzone N, Barbeau J, Smart S, Vallis KA (2012) Amplification of DNA damage by a gammaH2AX-targeted radiopharmaceutical. Nucl Med Biol 39:1142–1151. doi: 10.1016/j.nucmedbio.2012.06.001 PubMedGoogle Scholar
  148. 148.
    Chinn PC, Morena RA, Santoro DA, Kazules T, Kashmiri SV, Schlom J, Hanna N, Braslawsky G (2006) Pharmacokinetics and tumor localization of 111In-labeled HuCC49ΔCH2 in BALB/c mice and athymic murine colon carcinoma xenograft. Cancer Biother Radiopharm 21:106–116. doi: 10.1089/cbr.2006.21.106 PubMedGoogle Scholar
  149. 149.
    Cornelissen B, McLarty K, Kersemans V, Scollard DA, Reilly RM (2008) Properties of [(111)In]-labeled HIV-1 tat peptide radioimmunoconjugates in tumor-bearing mice following intravenous or intratumoral injection. Nucl Med Biol 35:101–110. doi: 10.1016/j.nucmedbio.2007.09.007 PubMedGoogle Scholar
  150. 150.
    Liu P, Boyle AJ, Lu Y, Reilly RM, Winnik MA (2012) Biotinylated polyacrylamide-based metal-chelating polymers and their influence on antigen recognition following conjugation to a trastuzumab Fab fragment. Biomacromolecules 13:2831–2842. doi: 10.1021/bm300843u PubMedGoogle Scholar
  151. 151.
    Sandstrom K, Nestor M, Ekberg T, Engstrom M, Anniko M, Lundqvist H (2008) Targeting CD44v6 expressed in head and neck squamous cell carcinoma: preclinical characterization of an 111In-labeled monoclonal antibody. Tumour Biol 29:137–144. doi: 10.1159/000143399 PubMedGoogle Scholar
  152. 152.
    Price EW, Zeglis BM, Cawthray JF, Ramogida CF, Ramos N, Lewis JS, Adam MJ, Orvig C (2013) H(4)octapa-trastuzumab: versatile acyclic chelate system for 111In and 177Lu imaging and therapy. J Am Chem Soc 135:12707–12721. doi: 10.1021/ja4049493 PubMedCentralPubMedGoogle Scholar
  153. 153.
    Tempero M, Leichner P, Baranowska-Kortylewicz J, Harrison K, Augustine S, Schlom J, Anderson J, Wisecarver J, Colcher D (2000) High-dose therapy with 90Yttrium-labeled monoclonal antibody CC49: a phase I trial. Clin Cancer Res 6:3095–3102, PMID: 10955789PubMedGoogle Scholar
  154. 154.
    Fischer E, Grunberg J, Cohrs S, Hohn A, Waldner-Knogler K, Jeger S, Zimmermann K, Novak-Hofer I, Schibli R (2012) L1-CAM-targeted antibody therapy and (177)Lu-radioimmunotherapy of disseminated ovarian cancer. Int J Cancer 130:2715–2721. doi: 10.1002/ijc.26321 PubMedGoogle Scholar
  155. 155.
    Nilsson R, Eriksson SE, Sjogren HO, Tennvall J (2011) Different toxicity profiles for drug- versus radionuclide-conjugated BR96 monoclonal antibodies in a syngeneic rat colon carcinoma model. Acta Oncol 50:711–718. doi: 10.3109/0284186X.2010.547215 PubMedGoogle Scholar
  156. 156.
    Schneider N, Lobaugh M, Tan Z, Sandwall P, Chen P, Glover S, Cui L, Murry M, Dong Z, Torgue J (2013) Biodistribution of 212Pb conjugated trastuzumab in mice. J Radioanal Nucl Chem 296:75–81. doi: 10.1007/s10967-012-2243-7 Google Scholar
  157. 157.
    Mohsin H, Jia F, Sivaguru G, Hudson MJ, Shelton TD, Hoffman TJ, Cutler CS, Ketring AR, Athey PS, Simón J (2006) Radiolanthanide-labeled monoclonal antibody CC49 for radioimmunotherapy of cancer: biological comparison of DOTA conjugates and 149Pm, 166Ho, and 177Lu. Bioconjug Chem 17:485–492. doi: 10.1021/bc0502356 PubMedGoogle Scholar
  158. 158.
    Stroomer JW, Roos JC, Sproll M, Quak JJ, Heider KH, Wilhelm BJ, Castelijns JA, Meyer R, Kwakkelstein MO, Snow GB, Adolf GR, van Dongen GA (2000) Safety and biodistribution of 99mTechnetium-labeled anti-CD44v6 monoclonal antibody BIWA 1 in head and neck cancer patients. Clin Cancer Res 6:3046–3055, PMID: 10955783PubMedGoogle Scholar
  159. 159.
    Dahle J, Borrebaek J, Jonasdottir TJ, Hjelmerud AK, Melhus KB, Bruland OS, Press OW, Larsen RH (2007) Targeted cancer therapy with a novel low-dose rate alpha-emitting radioimmunoconjugate. Blood 110:2049–2056. doi: 10.1182/blood-2007-01-066803 PubMedGoogle Scholar
  160. 160.
    Heyerdahl H, Abbas N, Brevik EM, Mollatt C, Dahle J (2012) Fractionated therapy of HER2-expressing breast and ovarian cancer xenografts in mice with targeted alpha emitting 227Th-DOTA-p-benzyl-trastuzumab. PLoS One 7:e42345. doi: 10.1371/journal.pone.0042345 PubMedCentralPubMedGoogle Scholar
  161. 161.
    Maraveyas A, Snook D, Hird V, Kosmas C, Meares CF, Lambert HE, Epenetos AA (1994) Pharmacokinetics and toxicity of an yttrium-90-CITC-DTPA-HMFG1 radioimmunoconjugate for intraperitoneal radioimmunotherapy of ovarian cancer. Cancer 73:1067–1075, PMID: 8306249PubMedGoogle Scholar
  162. 162.
    Jia F, Liu X, Li L, Mallapragada S, Narasimhan B, Wang Q (2013) Multifunctional nanoparticles for targeted delivery of immune activating and cancer therapeutic agents. J Control Release 172:1020–1034. doi: 10.1016/j.jconrel.2013.10.012 PubMedGoogle Scholar
  163. 163.
    Kitson SL, Cuccurullo V, Moody TS, Mansi L (2013) Radionuclide antibody-conjugates, a targeted therapy towards cancer. Curr Radiopharm 6:57–71. doi: 10.2174/1874471011306020001 PubMedGoogle Scholar
  164. 164.
    Zhang L, Chen H, Wang L, Liu T, Yeh J, Lu G, Yang L, Mao H (2010) Delivery of therapeutic radioisotopes using nanoparticle platforms: potential benefit in systemic radiation therapy. Nanotechnol Sci Appl 3:159–170. doi: 10.2147/NSA.S7462 PubMedCentralPubMedGoogle Scholar
  165. 165.
    Barrett T, Ravizzini G, Choyke PL, Kobayashi H (2009) Dendrimers in medical nanotechnology. IEEE Eng Med Biol Mag 28:12–22. doi: 10.1109/MEMB.2008.931012 PubMedCentralPubMedGoogle Scholar
  166. 166.
    Veiseh O, Kievit FM, Ellenbogen RG, Zhang M (2011) Cancer cell invasion: treatment and monitoring opportunities in nanomedicine. Adv Drug Deliv Rev 63:582–596. doi: 10.1016/j.addr.2011.01.010 PubMedCentralPubMedGoogle Scholar
  167. 167.
    Li L, Wartchow CA, Danthi SN, Shen Z, Dechene N, Pease J, Choi HS, Doede T, Chu P, Ning S, Lee DY, Bednarski MD, Knox SJ (2004) A novel antiangiogenesis therapy using an integrin antagonist or anti-Flk-1 antibody coated 90Y-labeled nanoparticles. Int J Radiat Oncol Biol Phys 58:1215–1227. doi: 10.1016/j.ijrobp.2003.10.057 PubMedGoogle Scholar
  168. 168.
    Belhaj-Tayeb H, Briane D, Vergote J, Kothan S, Leger G, Bendada SE, Tofighi M, Tamgac F, Cao A, Moretti JL (2003) In vitro and in vivo study of 99mTc-MIBI encapsulated in PEG-liposomes: a promising radiotracer for tumour imaging. Eur J Nucl Med Mol Imaging 30:502–509. doi: 10.1007/s00259-002-1038-4 PubMedGoogle Scholar
  169. 169.
    Kobayashi H, Wu C, Kim MK, Paik CH, Carrasquillo JA, Brechbiel MW (1999) Evaluation of the in vivo biodistribution of indium-111 and yttrium-88 labeled dendrimer-1B4M-DTPA and its conjugation with anti-Tac monoclonal antibody. Bioconjug Chem 10:103–111. doi: 10.1021/bc980091d PubMedGoogle Scholar
  170. 170.
    Torchilin VP (2002) PEG based micelles as carriers of contrast agents for different imaging modalities. Adv Drug Deliv Rev 54:235–252. doi: 10.1016/S0169-409X(02)00019-4 PubMedGoogle Scholar
  171. 171.
    Hallahan D, Geng L, Qu S, Scarfone C, Giorgio T, Donnelly E, Gao X, Clanton J (2003) Integrin-mediated targeting of drug delivery to irradiated tumor blood vessels. Cancer Cell 3:63–74. doi: 10.1016/S1535-6108(02)00238-6 PubMedGoogle Scholar
  172. 172.
    Hu G, Lijowski M, Zhang H, Partlow KC, Caruthers SD, Kiefer G, Gulyas G, Athey P, Scott MJ, Wickline SA, Lanza GM (2007) Imaging of Vx-2 rabbit tumors with alpha(nu)beta3-integrin-targeted 111In nanoparticles. Int J Cancer 120:1951–1957. doi: 10.1002/ijc.22581 PubMedGoogle Scholar
  173. 173.
    Chang YJ, Chang CH, Yu CY, Chang TJ, Chen LC, Chen MH, Lee TW, Ting G (2010) Therapeutic efficacy and microSPECT/CT imaging of 188Re-DXR-liposome in a C26 murine colon carcinoma solid tumor model. Nucl Med Biol 37:95–104. doi: 10.1016/j.nucmedbio.2009.08.006 PubMedGoogle Scholar
  174. 174.
    Vicente S, Goins BA, Sanchez A, Alonso MJ, Phillips WT (2014) Biodistribution and lymph node retention of polysaccharide-based immunostimulating nanocapsules. Vaccine 32:1685–1692. doi: 10.1016/j.vaccine.2014.01.059 PubMedGoogle Scholar
  175. 175.
    Chen J, Wu H, Han D, Xie C (2006) Using anti-VEGF McAb and magnetic nanoparticles as double-targeting vector for the radioimmunotherapy of liver cancer. Cancer Lett 231:169–175. doi: 10.1016/j.canlet.2005.01.024 PubMedGoogle Scholar
  176. 176.
    Wu H, Wang J, Wang Z, Fisher DR, Lin Y (2008) Apoferritin-templated yttrium phosphate nanoparticle conjugates for radioimmunotherapy of cancers. J Nanosci Nanotechnol 8:2316–2322, PMID: 18572643PubMedGoogle Scholar
  177. 177.
    Woodward JD, Kennel SJ, Mirzadeh S, Dai S, Wall JS, Richey T, Avenell J, Rondinone AJ (2007) In vivo SPECT/CT imaging and biodistribution using radioactive Cd125mTe/ZnS nanoparticles. Nanotechnology 18:175103. doi: 10.1088/0957-4484/18/17/175103 Google Scholar
  178. 178.
    Liu Z, Cai W, He L, Nakayama N, Chen K, Sun X, Chen X, Dai H (2007) In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nat Nanotechnol 2:47–52. doi: 10.1038/nnano.2006.170 PubMedGoogle Scholar
  179. 179.
    Bandekar A, Zhu C, Jindal R, Bruchertseifer F, Morgenstern A, Sofou S (2014) Anti-prostate-specific membrane antigen liposomes loaded with 225Ac for potential targeted antivascular alpha-particle therapy of cancer. J Nucl Med 55:107–114. doi: 10.2967/jnumed.113.125476 PubMedGoogle Scholar
  180. 180.
    Wayne AS, Fitzgerald DJ, Kreitman RJ, Pastan I (2014) Immunotoxins for leukemia. Blood. doi: 10.1182/blood-2014-01-492256 Google Scholar
  181. 181.
    Antignani A, Fitzgerald D (2013) Immunotoxins: the role of the toxin. Toxins (Basel) 5:1486–1502. doi: 10.3390/toxins5081486 Google Scholar
  182. 182.
    Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, Jegasothy B, Wood G, Gordon M, Heald P, Oseroff A, Pinter-Brown L, Bowen G, Kuzel T, Fivenson D, Foss F, Glode M, Molina A, Knobler E, Stewart S, Cooper K, Stevens S, Craig F, Reuben J, Bacha P, Nichols J (2001) Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 19:376–388, PMID: 11208829PubMedGoogle Scholar
  183. 183.
    Jansen FK, Bourrie B, Casellas P, Dussossoy D, Gros O, Vic P, Vidal H, Gros P (1988) Toxin selection and modification: utilization of the A chain of ricin. Cancer Treat Res 37:97–111. doi: 10.1007/978-1-4613-1083-9_7 PubMedGoogle Scholar
  184. 184.
    Hudson TH, Neville DM Jr (1988) Enhancement of immunotoxin action: manipulation of the cellular routing of proteins. Cancer Treat Res 37:371–389. doi: 10.1007/978-1-4613-1083-9_20 PubMedGoogle Scholar
  185. 185.
    Casellas P, Jansen FK (1988) Immunotoxin enhancers. Cancer Treat Res 37:351–369. doi: 10.1007/978-1-4613-1083-9_19 PubMedGoogle Scholar
  186. 186.
    Kantarjian H, Thomas D, Wayne AS, O’Brien S (2012) Monoclonal antibody-based therapies: a new dawn in the treatment of acute lymphoblastic leukemia. J Clin Oncol 30:3876–3883. doi: 10.1200/JCO.2012.41.6768 PubMedCentralPubMedGoogle Scholar
  187. 187.
    Messmann RA, Vitetta ES, Headlee D, Senderowicz AM, Figg WD, Schindler J, Michiel DF, Creekmore S, Steinberg SM, Kohler D, Jaffe ES, Stetler-Stevenson M, Chen H, Ghetie V, Sausville EA (2000) A phase I study of combination therapy with immunotoxins IgG-HD37-deglycosylated ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients with refractory CD19(+), CD22(+) B cell lymphoma. Clin Cancer Res 6:1302–1313, PMID: 10778955PubMedGoogle Scholar
  188. 188.
    Grossbard ML, Multani PS, Freedman AS, O’Day S, Gribben JG, Rhuda C, Neuberg D, Nadler LM (1999) A Phase II study of adjuvant therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with relapsed B-cell non-Hodgkin’s lymphoma. Clin Cancer Res 5:2392–2398, PMID: 10499609PubMedGoogle Scholar
  189. 189.
    Vitetta ES (2000) Immunotoxins and vascular leak syndrome. Cancer J 6(Suppl 3):S218–224, PMID: 10874491PubMedGoogle Scholar
  190. 190.
    Siegall CB, Liggitt D, Chace D, Mixan B, Sugai J, Davidson T, Steinitz M (1997) Characterization of vascular leak syndrome induced by the toxin component of Pseudomonas exotoxin-based immunotoxins and its potential inhibition with nonsteroidal anti-inflammatory drugs. Clin Cancer Res 3:339–345, PMID: 9815690PubMedGoogle Scholar
  191. 191.
    Hu RG, Zhai QW, He WJ, Mei L, Liu WY (2002) Bioactivities of ricin retained and its immunoreactivity to anti-ricin polyclonal antibodies alleviated through pegylation. Int J Biochem Cell Biol 34:396–402. doi: 10.1016/S1357-2725(01)00128-5 PubMedGoogle Scholar
  192. 192.
    Oraki Kohshour M, Mirzaie S, Zeinali M, Amin M, Said Hakhamaneshi M, Jalaili A, Mosaveri N, Jamalan M (2014) Ablation of breast cancer cells using trastuzumab-functionalized multi-walled carbon nanotubes and trastuzumab-diphtheria toxin conjugate. Chem Biol Drug Des 83:259–265. doi: 10.1111/cbdd.12244 PubMedGoogle Scholar
  193. 193.
    Ramakrishnan S, Olson TA, Bautch VL, Mohanraj D (1996) Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk-1-positive endothelial cell proliferation in vitro and angiogenesis in vivo. Cancer Res 56:1324–1330, PMID: 8640821PubMedGoogle Scholar
  194. 194.
    Selbo PK, Kaalhus O, Sivam G, Berg K (2001) 5-Aminolevulinic acid-based photochemical internalization of the immunotoxin MOC31-gelonin generates synergistic cytotoxic effects in vitro. Photochem Photobiol 74:303–310. doi: 10.1562/0031-8655(2001)0740303AABPIO2.0.CO2 PubMedGoogle Scholar
  195. 195.
    Schiffer S, Letzian S, Jost E, Mladenov R, Hristodorov D, Huhn M, Fischer R, Barth S, Thepen T (2013) Granzyme M as a novel effector molecule for human cytolytic fusion proteins: CD64-specific cytotoxicity of Gm-H22 (scFv) against leukemic cells. Cancer Lett 341:178–185. doi: 10.1016/j.canlet.2013.08.005 PubMedGoogle Scholar
  196. 196.
    Bergelt S, Frost S, Lilie H (2009) Listeriolysin O as cytotoxic component of an immunotoxin. Protein Sci 18:1210–1220. doi: 10.1002/pro.130 PubMedCentralPubMedGoogle Scholar
  197. 197.
    Hassan R, Viner JL, Wang QC, Margulies I, Kreitman RJ, Pastan I (2000) Anti-tumor activity of K1-LysPE38QQR, an immunotoxin targeting mesothelin, a cell-surface antigen overexpressed in ovarian cancer and malignant mesothelioma. J Immunother 23:473–479. doi: 10.1097/00002371-200007000-00011 PubMedGoogle Scholar
  198. 198.
    Bruell D, Stocker M, Huhn M, Redding N, Kupper M, Schumacher P, Paetz A, Bruns CJ, Haisma HJ, Fischer R, Finnern R, Barth S (2003) The recombinant anti-EGF receptor immunotoxin 425(scFv)-ETA′ suppresses growth of a highly metastatic pancreatic carcinoma cell line. Int J Oncol 23:1179–1186, PMID: 12964002PubMedGoogle Scholar
  199. 199.
    Park JH, Kwon HW, Chung HK, Kim IH, Ahn K, Choi EJ, Pastan I, Choe M (2001) A divalent recombinant immunotoxin formed by a disulfide bond between the extension peptide chains. Mol Cells 12:398–402, PMID: 11804341PubMedGoogle Scholar
  200. 200.
    Beers R, Chowdhury P, Bigner D, Pastan I (2000) Immunotoxins with increased activity against epidermal growth factor receptor vIII-expressing cells produced by antibody phage display. Clin Cancer Res 6:2835–2843, PMID: 10914732PubMedGoogle Scholar
  201. 201.
    Salvatore G, Beers R, Margulies I, Kreitman RJ, Pastan I (2002) Improved cytotoxic activity toward cell lines and fresh leukemia cells of a mutant anti-CD22 immunotoxin obtained by antibody phage display. Clin Cancer Res 8:995–1002, PMID: 11948105PubMedGoogle Scholar
  202. 202.
    Akamatsu Y, Murphy JC, Nolan KF, Thomas P, Kreitman RJ, Leung SO, Junghans RP (1998) A single-chain immunotoxin against carcinoembryonic antigen that suppresses growth of colorectal carcinoma cells. Clin Cancer Res 4:2825–2832, PMID: 9829749PubMedGoogle Scholar
  203. 203.
    Liu W, Onda M, Kim C, Xiang L, Weldon JE, Lee B, Pastan I (2012) A recombinant immunotoxin engineered for increased stability by adding a disulfide bond has decreased immunogenicity. Protein Eng Des Sel 25:1–6. doi: 10.1093/protein/gzr053 PubMedCentralPubMedGoogle Scholar
  204. 204.
    Wang L, Liu B, Schmidt M, Lu Y, Wels W, Fan Z (2001) Antitumor effect of an HER2-specific antibody-toxin fusion protein on human prostate cancer cells. Prostate 47:21–28. doi: 10.1002/pros.1043 PubMedGoogle Scholar
  205. 205.
    Gadadhar S, Karande AA (2013) Abrin immunotoxin: targeted cytotoxicity and intracellular trafficking pathway. PLoS One 8:e58304. doi: 10.1371/journal.pone.0058304 PubMedCentralPubMedGoogle Scholar
  206. 206.
    Martinez-Torrecuadrada JL, Cheung LH, Lopez-Serra P, Barderas R, Canamero M, Ferreiro S, Rosenblum MG, Casal JI (2008) Antitumor activity of fibroblast growth factor receptor 3-specific immunotoxins in a xenograft mouse model of bladder carcinoma is mediated by apoptosis. Mol Cancer Ther 7:862–873. doi: 10.1158/1535-7163.MCT-07-0394 PubMedGoogle Scholar
  207. 207.
    Fracasso G, Bellisola G, Cingarlini S, Castelletti D, Prayer-Galetti T, Pagano F, Tridente G, Colombatti M (2002) Anti-tumor effects of toxins targeted to the prostate specific membrane antigen. Prostate 53:9–23. doi: 10.1002/pros.10117 PubMedGoogle Scholar
  208. 208.
    Gilabert-Oriol R, Thakur M, von Mallinckrodt B, Hug T, Wiesner B, Eichhorst J, Melzig MF, Fuchs H, Weng A (2013) Modified trastuzumab and cetuximab mediate efficient toxin delivery while retaining antibody-dependent cell-mediated cytotoxicity in target cells. Mol Pharm 10:4347–4357. doi: 10.1021/mp400444q PubMedGoogle Scholar
  209. 209.
    Wei BR, Ghetie MA, Vitetta ES (2000) The combined use of an immunotoxin and a radioimmunoconjugate to treat disseminated human B-cell lymphoma in immunodeficient mice. Clin Cancer Res 6:631–642, PMID: 10690549PubMedGoogle Scholar
  210. 210.
    Gillies SD, Young D, Lo KM, Roberts S (1993) Biological activity and in vivo clearance of antitumor antibody/cytokine fusion proteins. Bioconjug Chem 4:230–235. doi: 10.1021/bc00021a008 PubMedGoogle Scholar
  211. 211.
    Schrama D, Reisfeld RA, Becker JC (2006) Antibody targeted drugs as cancer therapeutics. Nat Rev Drug Discov 5:147–159. doi: 10.1038/nrd1957 PubMedGoogle Scholar
  212. 212.
    Manusama ER, Nooijen PT, Ten Hagen TL, Van Der Veen AH, De Vries MW, De Wilt JH, Van Ijken MG, Marquet RL, Eggermont AM (1998) Tumor necrosis factor-alpha in isolated perfusion systems in the treatment of cancer: the Rotterdam preclinical-clinical program. Semin Surg Oncol 14:232–237. doi: 10.1002/(SICI)1098-2388(199804/05)14:3<232::AID-SSU7>3.0.CO;2-9 PubMedGoogle Scholar
  213. 213.
    Cohen J (1995) IL-12 deaths: explanation and a puzzle. Science 270:908. doi: 10.1126/science.270.5238.908a PubMedGoogle Scholar
  214. 214.
    Mattijssen V, De Mulder PH, De Graeff A, Hupperets PS, Joosten F, Ruiter DJ, Bier H, Palmer PA, Van den Broek P (1994) Intratumoral PEG-interleukin-2 therapy in patients with locoregionally recurrent head and neck squamous-cell carcinoma. Ann Oncol 5:957–960, PMID 7696170PubMedGoogle Scholar
  215. 215.
    Lienard D, Ewalenko P, Delmotte JJ, Renard N, Lejeune FJ (1992) High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 10:52–60, PMID: 1727926PubMedGoogle Scholar
  216. 216.
    Atkins MB, Kunkel L, Sznol M, Rosenberg SA (2000) High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6(Suppl 1):S11–S14, PMID: 10685652PubMedGoogle Scholar
  217. 217.
    Becker JC, Pancook JD, Gillies SD, Furukawa K, Reisfeld RA (1996) T cell-mediated eradication of murine metastatic melanoma induced by targeted interleukin 2 therapy. J Exp Med 183:2361–2366, PMID: 8642346PubMedGoogle Scholar
  218. 218.
    Halin C, Rondini S, Nilsson F, Berndt A, Kosmehl H, Zardi L, Neri D (2002) Enhancement of the antitumor activity of interleukin-12 by targeted delivery to neovasculature. Nat Biotechnol 20:264–269. doi: 10.1038/nbt0302-264 PubMedGoogle Scholar
  219. 219.
    List T, Neri D (2013) Immunocytokines: a review of molecules in clinical development for cancer therapy. Clin Pharmacol 5:29–45. doi: 10.2147/CPAA.S49231 PubMedCentralPubMedGoogle Scholar
  220. 220.
    Schrama D, Xiang R, Eggert AO, Andersen MH, Pedersen Ls LO, Kampgen E, Schumacher TN, Reisfeld RR, Becker JC (2004) Shift from systemic to site-specific memory by tumor-targeted IL-2. J Immunol 172:5843–5850, PMID: 15128763PubMedGoogle Scholar
  221. 221.
    Schliemann C, Palumbo A, Zuberbuhler K, Villa A, Kaspar M, Trachsel E, Klapper W, Menssen HD, Neri D (2009) Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. Blood 113:2275–2283. doi: 10.1182/blood-2008-05-160747 PubMedGoogle Scholar
  222. 222.
    Schwager K, Hemmerle T, Aebischer D, Neri D (2013) The immunocytokine L19-IL2 eradicates cancer when used in combination with CTLA-4 blockade or with L19-TNF. J Invest Dermatol 133:751–758. doi: 10.1038/jid.2012.376 PubMedGoogle Scholar
  223. 223.
    Bauer J, Namineni S, Reisinger F, Zoller J, Yuan D, Heikenwalder M (2012) Lymphotoxin, NF-kB, and cancer: the dark side of cytokines. Dig Dis 30:453–468. doi: 10.1159/000341690 PubMedGoogle Scholar
  224. 224.
    Huang X, Ye D, Thorpe PE (2011) Enhancing the potency of a whole-cell breast cancer vaccine in mice with an antibody-IL-2 immunocytokine that targets exposed phosphatidylserine. Vaccine 29:4785–4793. doi: 10.1016/j.vaccine.2011.04.082 PubMedGoogle Scholar
  225. 225.
    Ziebarth AJ, Felder MA, Harter J, Connor JP (2012) Uterine leiomyosarcoma diffusely express disialoganglioside GD2 and bind the therapeutic immunocytokine 14.18-IL2: implications for immunotherapy. Cancer Immunol Immunother 61:1149–1153PubMedGoogle Scholar
  226. 226.
    Moschetta M, Pretto F, Berndt A, Galler K, Richter P, Bassi A, Oliva P, Micotti E, Valbusa G, Schwager K, Kaspar M, Trachsel E, Kosmehl H, Bani MR, Neri D, Giavazzi R (2012) Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts. Cancer Res 72:1814–1824. doi: 10.1158/0008-5472.CAN-11-1919 PubMedGoogle Scholar
  227. 227.
    Pedretti M, Verpelli C, Marlind J, Bertani G, Sala C, Neri D, Bello L (2010) Combination of temozolomide with immunocytokine F16-IL2 for the treatment of glioblastoma. Br J Cancer 103:827–836. doi: 10.1038/sj.bjc.6605832 PubMedCentralPubMedGoogle Scholar
  228. 228.
    Frey K, Schliemann C, Schwager K, Giavazzi R, Johannsen M, Neri D (2010) The immunocytokine F8-IL2 improves the therapeutic performance of sunitinib in a mouse model of renal cell carcinoma. J Urol 184:2540–2548. doi: 10.1016/j.juro.2010.07.030 PubMedGoogle Scholar
  229. 229.
    Hank JA, Gan J, Ryu H, Ostendorf A, Stauder MC, Sternberg A, Albertini M, Lo KM, Gillies SD, Eickhoff J, Sondel PM (2009) Immunogenicity of the hu14.18-IL2 immunocytokine molecule in adults with melanoma and children with neuroblastoma. Clin Cancer Res 15:5923–5930PubMedCentralPubMedGoogle Scholar
  230. 230.
    Holden SA, Lan Y, Pardo AM, Wesolowski JS, Gillies SD (2001) Augmentation of antitumor activity of an antibody-interleukin 2 immunocytokine with chemotherapeutic agents. Clin Cancer Res 7:2862–2869, PMID: 11555604PubMedGoogle Scholar
  231. 231.
    Johnson EE, Yamane BH, Buhtoiarov IN, Lum HD, Rakhmilevich AL, Mahvi DM, Gillies SD, Sondel PM (2009) Radiofrequency ablation combined with KS-IL2 immunocytokine (EMD 273066) results in an enhanced antitumor effect against murine colon adenocarcinoma. Clin Cancer Res 15:4875–4884. doi: 10.1158/1078-0432.CCR-09-0110 PubMedCentralPubMedGoogle Scholar
  232. 232.
    Pasche N, Woytschak J, Wulhfard S, Villa A, Frey K, Neri D (2011) Cloning and characterization of novel tumor-targeting immunocytokines based on murine IL7. J Biotechnol 154:84–92. doi: 10.1016/j.jbiotec.2011.04.003 PubMedGoogle Scholar
  233. 233.
    Fallon J, Tighe R, Kradjian G, Guzman W, Bernhardt A, Neuteboom B, Lan Y, Sabzevari H, Schlom J, Greiner JW (2014) The immunocytokine NHS-IL12 as a potential cancer therapeutic. Oncotarget 5:1869–1884, PMID: 24681847PubMedCentralPubMedGoogle Scholar
  234. 234.
    Kim H, Gao W, Ho M (2013) Novel immunocytokine IL12-SS1 (Fv) inhibits mesothelioma tumor growth in nude mice. PLoS One 8:e81919. doi: 10.1371/journal.pone.0081919 PubMedCentralPubMedGoogle Scholar
  235. 235.
    Gillessen S, Gnad-Vogt US, Gallerani E, Beck J, Sessa C, Omlin A, Mattiacci MR, Liedert B, Kramer D, Laurent J, Speiser DE, Stupp R (2013) A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours. Eur J Cancer 49:35–44. doi: 10.1016/j.ejca.2012.07.015 PubMedGoogle Scholar
  236. 236.
    Kaspar M, Trachsel E, Neri D (2007) The antibody-mediated targeted delivery of interleukin-15 and GM-CSF to the tumor neovasculature inhibits tumor growth and metastasis. Cancer Res 67:4940–4948. doi: 10.1158/0008-5472.CAN-07-0283 PubMedGoogle Scholar
  237. 237.
    Liu D, Chang CH, Rossi EA, Cardillo TM, Goldenberg DM (2013) Interferon-lambda1 linked to a stabilized dimer of Fab potently enhances both antitumor and antiviral activities in targeted cells. PLoS One 8:e63940. doi: 10.1371/journal.pone.0063940 PubMedCentralPubMedGoogle Scholar
  238. 238.
    Chen P, Nogusa S, Thapa RJ, Shaller C, Simmons H, Peri S, Adams GP, Balachandran S (2013) Anti-CD70 immunocytokines for exploitation of interferon-gamma-induced RIP1-dependent necrosis in renal cell carcinoma. PLoS One 8:e61446. doi: 10.1371/journal.pone.0061446 PubMedCentralPubMedGoogle Scholar
  239. 239.
    Lyu MA, Kurzrock R, Rosenblum MG (2008) The immunocytokine scFv23/TNF targeting HER-2/neu induces synergistic cytotoxic effects with 5-fluorouracil in TNF-resistant pancreatic cancer cell lines. Biochem Pharmacol 75:836–846. doi: 10.1016/j.bcp.2007.10.013 PubMedGoogle Scholar
  240. 240.
    Bagshawe KD (2006) Antibody-directed enzyme prodrug therapy (ADEPT) for cancer. Expert Rev Anticancer Ther 6:1421–1431. doi: 10.1586/14737140.6.10.1421 PubMedGoogle Scholar
  241. 241.
    Cheng TL, Wei SL, Chen BM, Chern JW, Wu MF, Liu PW, Roffler SR (1999) Bystander killing of tumour cells by antibody-targeted enzymatic activation of a glucuronide prodrug. Br J Cancer 79:1378–1385. doi: 10.1038/sj.bjc.6690221 PubMedCentralPubMedGoogle Scholar
  242. 242.
    Sharma SK (2013) Antibody-directed enzyme prodrug therapy (ADEPT). In: Schmidt SR (ed) Fusion proteins technologies for biopharmaceuticals. Wiley, New Jersey, pp 354–363Google Scholar
  243. 243.
    Begent RH, Bagshawe KD, Green AJ, Searle F (1987) The clinical value of imaging with antibody to human chorionic gonadotrophin in the detection of residual choriocarcinoma. Br J Cancer 55:657–660. doi: 10.1038/bjc.1987.134 PubMedCentralPubMedGoogle Scholar
  244. 244.
    Bagshawe KD (2012) Antibody-directed enzyme prodrug therapy (ADEPT) – basic principles and its practice so far. In: Kratz F, Senter P, Steinhagen H (eds) Drug delivery in oncology. Wiley, Germany, pp 169–186Google Scholar
  245. 245.
    Baker M, Carr F (2010) Pre-clinical considerations in the assessment of immunogenicity for protein therapeutics. Curr Drug Saf 5:308–313. doi: 10.2174/157488610792246000 PubMedGoogle Scholar
  246. 246.
    Holgate RG, Baker MP (2009) Circumventing immunogenicity in the development of therapeutic antibodies. IDrugs 12:233–237, PMID: 19350467PubMedGoogle Scholar
  247. 247.
    Smith GK, Banks S, Blumenkopf TA, Cory M, Humphreys J, Laethem RM, Miller J, Moxham CP, Mullin R, Ray PH, Walton LM, Wolfe LA 3rd (1997) Toward antibody-directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase A1 and novel in vivo stable prodrugs of methotrexate. J Biol Chem 272:15804–15816, PMID: 9188478PubMedGoogle Scholar
  248. 248.
    Syrigos KN, Rowlinson-Busza G, Epenetos AA (1998) In vitro cytotoxicity following specific activation of amygdalin by beta-glucosidase conjugated to a bladder cancer-associated monoclonal antibody. Int J Cancer 78:712–719. doi: 10.1002/(SICI)1097-0215(19981209)78:6<712::AID-IJC8>3.0.CO;2-D PubMedGoogle Scholar
  249. 249.
    Chen KC, Wu SY, Leu YL, Prijovich ZM, Chen BM, Wang HE, Cheng TL, Roffler SR (2011) A humanized immunoenzyme with enhanced activity for glucuronide prodrug activation in the tumor microenvironment. Bioconjug Chem 22:938–948. doi: 10.1021/bc1005784 PubMedGoogle Scholar
  250. 250.
    Alderson RF, Toki BE, Roberge M, Geng W, Basler J, Chin R, Liu A, Ueda R, Hodges D, Escandon E (2006) Characterization of a CC49-based single-chain fragment-β-lactamase fusion protein for antibody-directed enzyme prodrug therapy (ADEPT). Bioconjug Chem 17:410–418. doi: 10.1021/bc0503521 PubMedGoogle Scholar
  251. 251.
    Wang H, Shi PJ, Wu MF, Li N, Zhou XL, Fan FY (2010) Construction, expression and functional characterization of the beta-lactamase with alphav integrin ligands. Protein Pept Lett 17:1562–1565. doi: 10.2174/0929866511009011562 PubMedGoogle Scholar
  252. 252.
    Hao XK, Liu JY, Yue QH, Wu GJ, Bai YJ, Yin Y (2006) In vitro and in vivo prodrug therapy of prostate cancer using anti-gamma-Sm-scFv/hCPA fusion protein. Prostate 66:858–866. doi: 10.1002/pros.20402 PubMedGoogle Scholar
  253. 253.
    Deckert PM, Bornmann WG, Ritter G, Williams C Jr, Franke J, Keilholz U, Thiel E, Old LJ, Bertino JR, Welt S (2004) Specific tumour localisation of a huA33 antibody–carboxypeptidase A conjugate and activation of methotrexate-phenylalanine. Int J Oncol 24:1289–1295, PMID: 15067353PubMedGoogle Scholar
  254. 254.
    Sharma SK, Bagshawe KD, Burke PJ, Boden JA, Rogers GT, Springer CJ, Melton RG, Sherwood RF (1994) Galactosylated antibodies and antibody-enzyme conjugates in antibody-directed enzyme prodrug therapy. Cancer 73:1114–1120, PMID: 8306255PubMedGoogle Scholar
  255. 255.
    Webley SD, Francis RJ, Pedley RB, Sharma SK, Begent RH, Hartley JA, Hochhauser D (2001) Measurement of the critical DNA lesions produced by antibody-directed enzyme prodrug therapy (ADEPT) in vitro, in vivo and in clinical material. Br J Cancer 84:1671–1676. doi: 10.1054/bjoc.2001.1843 PubMedCentralPubMedGoogle Scholar
  256. 256.
    Pedley RB, Sharma SK, Boxer GM, Boden R, Stribbling SM, Davies L, Springer CJ, Begent RH (1999) Enhancement of antibody-directed enzyme prodrug therapy in colorectal xenografts by an antivascular agent. Cancer Res 59:3998–4003, PMID: 10463598PubMedGoogle Scholar
  257. 257.
    Mayer A, Sharma SK, Tolner B, Minton NP, Purdy D, Amlot P, Tharakan G, Begent RH, Chester KA (2004) Modifying an immunogenic epitope on a therapeutic protein: a step towards an improved system for antibody-directed enzyme prodrug therapy (ADEPT). Br J Cancer 90:2402–2410. doi: 10.1038/sj.bjc.6601888 PubMedCentralPubMedGoogle Scholar
  258. 258.
    Park JI, Cao L, Platt VM, Huang Z, Stull RA, Dy EE, Sperinde JJ, Yokoyama JS, Szoka FC (2009) Antitumor therapy mediated by 5-fluorocytosine and a recombinant fusion protein containing TSG-6 hyaluronan binding domain and yeast cytosine deaminase. Mol Pharm 6:801–812. doi: 10.1021/mp800013c PubMedCentralPubMedGoogle Scholar
  259. 259.
    Coelho V, Dernedde J, Petrausch U, Panjideh H, Fuchs H, Menzel C, Dubel S, Keilholz U, Thiel E, Deckert PM (2007) Design, construction, and in vitro analysis of A33scFv::CDy, a recombinant fusion protein for antibody-directed enzyme prodrug therapy in colon cancer. Int J Oncol 31:951–957, PMID: 17786329PubMedGoogle Scholar
  260. 260.
    Biela BH, Khawli LA, Hu P, Epstein AL (2003) Chimeric TNT-3/human beta-glucuronidase fusion proteins for antibody-directed enzyme prodrug therapy (ADEPT). Cancer Biother Radiopharm 18:339–353. doi: 10.1089/108497803322285099 PubMedGoogle Scholar
  261. 261.
    Florent JC, Dong X, Gaudel G, Mitaku S, Monneret C, Gesson JP, Jacquesy JC, Mondon M, Renoux B, Andrianomenjanahary S, Michel S, Koch M, Tillequin F, Gerken M, Czech J, Straub R, Bosslet K (1998) Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy. J Med Chem 41:3572–3581. doi: 10.1021/jm970589l PubMedGoogle Scholar
  262. 262.
    Haisma HJ, Sernee MF, Hooijberg E, Brakenhoff RH, Vd Meulen-Muileman IH, Pinedo HM, Boven E (1998) Construction and characterization of a fusion protein of single-chain anti-CD20 antibody and human beta-glucuronidase for antibody-directed enzyme prodrug therapy. Blood 92:184–190, PMID 9639515PubMedGoogle Scholar
  263. 263.
    Afshar S, Asai T, Morrison SL (2009) Humanized ADEPT comprised of an engineered human purine nucleoside phosphorylase and a tumor targeting peptide for treatment of cancer. Mol Cancer Ther 8:185–193. doi: 10.1158/1535-7163.MCT-08-0652 PubMedCentralPubMedGoogle Scholar
  264. 264.
    Heinis C, Alessi P, Neri D (2004) Engineering a thermostable human prolyl endopeptidase for antibody-directed enzyme prodrug therapy. Biochemistry 43:6293–6303. doi: 10.1021/bi0361160 PubMedGoogle Scholar
  265. 265.
    Knox RJ, Friedlos F, Boland MP (1993) The bioactivation of CB 1954 and its use as a prodrug in antibody-directed enzyme prodrug therapy (ADEPT). Cancer Metastasis Rev 12:195–212. doi: 10.1007/bf00689810 PubMedGoogle Scholar
  266. 266.
    Lu JY, Lowe DA, Kennedy MD, Low PS (1999) Folate-targeted enzyme prodrug cancer therapy utilizing penicillin-V amidase and a doxorubicin prodrug. J Drug Target 7:43–53. doi: 10.3109/10611869909085491 PubMedGoogle Scholar
  267. 267.
    Padiolleau-Lefevre S, Naya RB, Shahsavarian MA, Friboulet A, Avalle B (2014) Catalytic antibodies and their applications in biotechnology: state of the art. Biotechnol Lett 36(7):1369–79. doi: 10.1007/s10529-014-1503-8 PubMedGoogle Scholar
  268. 268.
    Abraham S, Guo F, Li LS, Rader C, Liu C, Barbas CF 3rd, Lerner RA, Sinha SC (2007) Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation. Proc Natl Acad Sci USA 104:5584–5589. doi: 10.1073/pnas.0700223104 PubMedCentralPubMedGoogle Scholar
  269. 269.
    Zawilska JB, Wojcieszak J, Olejniczak AB (2013) Prodrugs: a challenge for the drug development. Pharmacol Rep 65:1–14. doi: 10.1016/S1734-1140(13)70959-9 PubMedGoogle Scholar
  270. 270.
    Jain S, Kumar D, Swarnakar NK, Thanki K (2012) Polyelectrolyte stabilized multilayered liposomes for oral delivery of paclitaxel. Biomaterials 33:6758–6768. doi: 10.1016/j.biomaterials.2012.05.026 PubMedGoogle Scholar
  271. 271.
    Sapra P, Shor B (2013) Monoclonal antibody-based therapies in cancer: advances and challenges. Pharmacol Ther 138:452–469. doi: 10.1016/j.pharmthera.2013.03.004 PubMedGoogle Scholar
  272. 272.
    Iden DL, Allen TM (2001) In vitro and in vivo comparison of immunoliposomes made by conventional coupling techniques with those made by a new post-insertion approach. Biochim Biophys Acta 1513:207–216. doi: 10.1016/S0005-2736(01)00357-1 PubMedGoogle Scholar
  273. 273.
    Ishida T, Iden DL, Allen TM (1999) A combinatorial approach to producing sterically stabilized (stealth) immunoliposomal drugs. FEBS Lett 460:129–133. doi: 10.1016/S0014-5793(99)01320-4 PubMedGoogle Scholar
  274. 274.
    Sofou S, Sgouros G (2008) Antibody-targeted liposomes in cancer therapy and imaging. Expert Opin Drug Deliv 5:189–204. doi: 10.1517/17425247.5.2.189 PubMedGoogle Scholar
  275. 275.
    Sapra P, Allen TM (2002) Internalizing antibodies are necessary for improved therapeutic efficacy of antibody-targeted liposomal drugs. Cancer Res 62:7190–7194, PMID: 12499256PubMedGoogle Scholar
  276. 276.
    Mastrobattista E, Koning GA, van Bloois L, Filipe AC, Jiskoot W, Storm G (2002) Functional characterization of an endosome-disruptive peptide and its application in cytosolic delivery of immunoliposome-entrapped proteins. J Biol Chem 277:27135–27143. doi: 10.1074/jbc.M200429200 PubMedGoogle Scholar
  277. 277.
    Torchilin VP (2005) Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 4:145–160. doi: 10.1038/nrd1632 PubMedGoogle Scholar
  278. 278.
    Gao J, Chen H, Yu Y, Song J, Song H, Su X, Li W, Tong X, Qian W, Wang H (2013) Inhibition of hepatocellular carcinoma growth using immunoliposomes for co-delivery of adriamycin and ribonucleotide reductase M2 siRNA. Biomaterials 34:10084–10098. doi: 10.1016/j.biomaterials.2013.08.088 PubMedGoogle Scholar
  279. 279.
    Gao J, Liu W, Xia Y, Li W, Sun J, Chen H, Li B, Zhang D, Qian W, Meng Y (2011) The promotion of siRNA delivery to breast cancer overexpressing epidermal growth factor receptor through anti-EGFR antibody conjugation by immunoliposomes. Biomaterials 32:3459–3470. doi: 10.1016/j.biomaterials.2011.01.034 PubMedGoogle Scholar
  280. 280.
    Deng L, Zhang Y, Ma L, Jing X, Ke X, Lian J, Zhao Q, Yan B, Zhang J, Yao J, Chen J (2013) Comparison of anti-EGFR-Fab′ conjugated immunoliposomes modified with two different conjugation linkers for siRNa delivery in SMMC-7721 cells. Int J Nanomedicine 8:3271–3283. doi: 10.2147/IJN.S47597 PubMedCentralPubMedGoogle Scholar
  281. 281.
    Drummond DC, Noble CO, Guo Z, Hayes ME, Connolly-Ingram C, Gabriel BS, Hann B, Liu B, Park JW, Hong K, Benz CC, Marks JD, Kirpotin DB (2010) Development of a highly stable and targetable nanoliposomal formulation of topotecan. J Control Release 141:13–21. doi: 10.1016/j.jconrel.2009.08.006 PubMedGoogle Scholar
  282. 282.
    Nishikawa K, Asai T, Shigematsu H, Shimizu K, Kato H, Asano Y, Takashima S, Mekada E, Oku N, Minamino T (2012) Development of anti-HB-EGF immunoliposomes for the treatment of breast cancer. J Control Release 160:274–280. doi: 10.1016/j.jconrel.2011.10.010 PubMedGoogle Scholar
  283. 283.
    Apte A, Koren E, Koshkaryev A, Torchilin VP (2014) Doxorubicin in TAT peptide-modified multifunctional immunoliposomes demonstrates increased activity against both drug-sensitive and drug-resistant ovarian cancer models. Cancer Biol Ther 15:69–80. doi: 10.4161/cbt.26609 PubMedGoogle Scholar
  284. 284.
    Wicki A, Rochlitz C, Orleth A, Ritschard R, Albrecht I, Herrmann R, Christofori G, Mamot C (2012) Targeting tumor-associated endothelial cells: anti-VEGFR2 immunoliposomes mediate tumor vessel disruption and inhibit tumor growth. Clin Cancer Res 18:454–464. doi: 10.1158/1078-0432.CCR-11-1102 PubMedGoogle Scholar
  285. 285.
    Padhye SS, Guin S, Yao HP, Zhou YQ, Zhang R, Wang MH (2011) Sustained expression of the RON receptor tyrosine kinase by pancreatic cancer stem cells as a potential targeting moiety for antibody-directed chemotherapeutics. Mol Pharm 8:2310–2319. doi: 10.1021/mp200193u PubMedGoogle Scholar
  286. 286.
    Guin S, Ma Q, Padhye S, Zhou YQ, Yao HP, Wang MH (2011) Targeting acute hypoxic cancer cells by doxorubicin-immunoliposomes directed by monoclonal antibodies specific to RON receptor tyrosine kinase. Cancer Chemother Pharmacol 67:1073–1083. doi: 10.1007/s00280-010-1408-8 PubMedGoogle Scholar
  287. 287.
    Mortensen JH, Jeppesen M, Pilgaard L, Agger R, Duroux M, Zachar V, Moos T (2013) Targeted antiepidermal growth factor receptor (cetuximab) immunoliposomes enhance cellular uptake in vitro and exhibit increased accumulation in an intracranial model of glioblastoma multiforme. J Drug Deliv 2013:209205. doi: 10.1155/2013/209205 PubMedCentralPubMedGoogle Scholar
  288. 288.
    Lehtinen J, Raki M, Bergstrom KA, Uutela P, Lehtinen K, Hiltunen A, Pikkarainen J, Liang H, Pitkanen S, Maatta AM, Ketola RA, Yliperttula M, Wirth T, Urtti A (2012) Pre-targeting and direct immunotargeting of liposomal drug carriers to ovarian carcinoma. PLoS One 7:e41410. doi: 10.1371/journal.pone.0041410 PubMedCentralPubMedGoogle Scholar
  289. 289.
    Hantel C, Lewrick F, Schneider S, Zwermann O, Perren A, Reincke M, Suss R, Beuschlein F (2010) Anti insulin-like growth factor I receptor immunoliposomes: a single formulation combining two anticancer treatments with enhanced therapeutic efficiency. J Clin Endocrinol Metab 95:943–952. doi: 10.1210/jc.2009-1980 PubMedGoogle Scholar
  290. 290.
    Koren E, Apte A, Jani A, Torchilin VP (2012) Multifunctional PEGylated 2C5-immunoliposomes containing pH-sensitive bonds and TAT peptide for enhanced tumor cell internalization and cytotoxicity. J Control Release 160:264–273. doi: 10.1016/j.jconrel.2011.12.002 PubMedCentralPubMedGoogle Scholar
  291. 291.
    Kullberg M, Mann K, Anchordoquy TJ (2012) Targeting Her-2+ breast cancer cells with bleomycin immunoliposomes linked to LLO. Mol Pharm 9:2000–2008. doi: 10.1021/mp300049n PubMedGoogle Scholar
  292. 292.
    Catania A, Barrajon-Catalan E, Nicolosi S, Cicirata F, Micol V (2013) Immunoliposome encapsulation increases cytotoxic activity and selectivity of curcumin and resveratrol against HER2 overexpressing human breast cancer cells. Breast Cancer Res Treat 141:55–65. doi: 10.1007/s10549-013-2667-y PubMedGoogle Scholar
  293. 293.
    Yamamoto Y, Yoshida M, Sato M, Sato K, Kikuchi S, Sugishita H, Kuwabara J, Matsuno Y, Kojima Y, Morimoto M, Horiuchi A, Watanabe Y (2011) Feasibility of tailored, selective and effective anticancer chemotherapy by direct injection of docetaxel-loaded immunoliposomes into Her2/neu positive gastric tumor xenografts. Int J Oncol 38:33–39, PMID: 21109923PubMedGoogle Scholar
  294. 294.
    Srivastava A, O’Connor IB, Pandit A, Gerard Wall J (2014) Polymer-antibody fragment conjugates for biomedical applications. Prog Polym Sci 39:308–329. doi: 10.1016/j.progpolymsci.2013.09.003 Google Scholar
  295. 295.
    Hagemeyer CE, von Zur MC, von Elverfeldt D, Peter K (2009) Single-chain antibodies as diagnostic tools and therapeutic agents. Thromb Haemost 101:1012–1019, PMID: 19492141PubMedGoogle Scholar
  296. 296.
    Hu X, Spada S, White S, Hudson S, Magner E, Wall JG (2006) Adsorption and activity of a domoic acid binding antibody fragment on mesoporous silicates. J Phys Chem B 110:18703–18709. doi: 10.1021/jp062423e PubMedGoogle Scholar
  297. 297.
    Albrecht H, Denardo GL, Denardo SJ (2006) Monospecific bivalent scFv-SH: effects of linker length and location of an engineered cysteine on production, antigen binding activity and free SH accessibility. J Immunol Methods 310:100–116. doi: 10.1016/j.jim.2005.12.012 PubMedGoogle Scholar
  298. 298.
    Weisser NE, Hall JC (2009) Applications of single-chain variable fragment antibodies in therapeutics and diagnostics. Biotechnol Adv 27:502–520. doi: 10.1016/j.biotechadv.2009.04.004 PubMedGoogle Scholar
  299. 299.
    Yang K, Basu A, Wang M, Chintala R, Hsieh MC, Liu S, Hua J, Zhang Z, Zhou J, Li M, Phyu H, Petti G, Mendez M, Janjua H, Peng P, Longley C, Borowski V, Mehlig M, Filpula D (2003) Tailoring structure-function and pharmacokinetic properties of single-chain Fv proteins by site-specific PEGylation. Protein Eng 16:761–770. doi: 10.1093/protein/gzg093 PubMedGoogle Scholar
  300. 300.
    Kim SH, Lee YS, Hwang SY, Bae GW, Nho K, Kang SW, Kwak YG, Moon CS, Han YS, Kim TY, Kho WG (2007) Effects of PEGylated scFv antibodies against Plasmodium vivax duffy binding protein on the biological activity and stability in vitro. J Microbiol Biotechnol 17:1670–1674, PMID: 18156783PubMedGoogle Scholar
  301. 301.
    Kitamura K, Takahashi T, Takashina K, Yamaguchi T, Noguchi A, Tsurumi H, Toyokuni T, Hakomori S (1990) Polyethylene glycol modification of the monoclonal antibody A7 enhances its tumor localization. Biochem Biophys Res Commun 171:1387–1394. doi: 10.1016/0006-291X(90)90839-F PubMedGoogle Scholar
  302. 302.
    Delgado C, Pedley RB, Herraez A, Boden R, Boden JA, Keep PA, Chester KA, Fisher D, Begent RH, Francis GE (1996) Enhanced tumour specificity of an anti-carcinoembryonic antigen Fab′ fragment by poly(ethylene glycol) (PEG) modification. Br J Cancer 73:175–182. doi: 10.1038/bjc.1996.32 PubMedCentralPubMedGoogle Scholar
  303. 303.
    Casey J, Pedley R, King D, Boden R, Chapman A, Yarranton G, Begent R (1999) Improved tumour targeting of di-Fab′ fragments modified with polyethylene glycol. Tumor Target 4:235–244, Scholar
  304. 304.
    Li L, Yazaki PJ, Anderson AL, Crow D, Colcher D, Wu AM, Williams LE, Wong JY, Raubitschek A, Shively JE (2006) Improved biodistribution and radioimmunoimaging with poly(ethylene glycol)-DOTA-conjugated anti-CEA diabody. Bioconjug Chem 17:68–76. doi: 10.1021/bc0502614 PubMedGoogle Scholar
  305. 305.
    Lu ZR, Kopeckova P, Kopecek J (1999) Polymerizable Fab′ antibody fragments for targeting of anticancer drugs. Nat Biotechnol 17:1101–1104. doi: 10.1038/15085 PubMedGoogle Scholar
  306. 306.
    Seymour LW, Ferry DR, Anderson D, Hesslewood S, Julyan PJ, Poyner R, Doran J, Young AM, Burtles S, Kerr DJ, Cancer Research Campaign Phase IIICTc (2002) Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. J Clin Oncol 20:1668–1676, PMID: 11896118PubMedGoogle Scholar
  307. 307.
    Hovorka O, St’astny M, Etrych T, Subr V, Strohalm J, Ulbrich K, Rihova B (2002) Differences in the intracellular fate of free and polymer-bound doxorubicin. J Control Release 80:101–117. doi: 10.1016/S0168-3659(02)00016-0 PubMedGoogle Scholar
  308. 308.
    Satchi R, Connors TA, Duncan R (2001) PDEPT: polymer-directed enzyme prodrug therapy. I. HPMA copolymer-cathepsin B and PK1 as a model combination. Br J Cancer 85:1070–1076PubMedCentralPubMedGoogle Scholar
  309. 309.
    Etrych T, Strohalm J, Kovar L, Kabesova M, Rihova B, Ulbrich K (2009) HPMA copolymer conjugates with reduced anti-CD20 antibody for cell-specific drug targeting. I. Synthesis and in vitro evaluation of binding efficacy and cytostatic activity. J Control Release 140:18–26PubMedGoogle Scholar
  310. 310.
    Gao J, Xia Y, Chen H, Yu Y, Song J, Li W, Qian W, Wang H, Dai J, Guo Y (2014) Polymer-lipid hybrid nanoparticles conjugated with anti-EGF receptor antibody for targeted drug delivery to hepatocellular carcinoma. Nanomedicine (Lond) 9:279–293. doi: 10.2217/nnm.13.20 Google Scholar
  311. 311.
    Khaw BA, Gada KS, Patil V, Panwar R, Mandapati S, Hatefi A, Majewski S, Weisenberger A (2014) Bispecific antibody complex pre-targeting and targeted delivery of polymer drug conjugates for imaging and therapy in dual human mammary cancer xenografts : targeted polymer drug conjugates for cancer diagnosis and therapy. Eur J Nucl Med Mol Imaging 41(8):1603–1616. doi: 10.1007/s00259-014-2738-2 PubMedGoogle Scholar
  312. 312.
    Liu J, Kopeckova P, Buhler P, Wolf P, Pan H, Bauer H, Elsasser-Beile U, Kopecek J (2009) Biorecognition and subcellular trafficking of HPMA copolymer-anti-PSMA antibody conjugates by prostate cancer cells. Mol Pharm 6:959–970. doi: 10.1021/mp8002682 PubMedCentralPubMedGoogle Scholar
  313. 313.
    Satchi-Fainaro R, Wrasidlo W, Lode HN, Shabat D (2002) Synthesis and characterization of a catalytic antibody-HPMA copolymer-conjugate as a tool for tumor selective prodrug activation. Bioorg Med Chem 10:3023–3029. doi: 10.1016/s0968-0896(02)00156-6 PubMedGoogle Scholar
  314. 314.
    Berguig GY, Convertine AJ, Shi J, Palanca-Wessels MC, Duvall CL, Pun SH, Press OW, Stayton PS (2012) Intracellular delivery and trafficking dynamics of a lymphoma-targeting antibody-polymer conjugate. Mol Pharm 9:3506–3514. doi: 10.1021/mp300338s PubMedCentralPubMedGoogle Scholar
  315. 315.
    Tappertzhofen K, Metz VV, Hubo M, Barz M, Postina R, Jonuleit H, Zentel R (2013) Synthesis of maleimide-functionalyzed HPMA-copolymers and in vitro characterization of the aRAGE- and human immunoglobulin (huIgG)-polymer conjugates. Macromol Biosci 13:203–214. doi: 10.1002/mabi.201200344 PubMedGoogle Scholar
  316. 316.
    Rihova B, Kopeckova P, Strohalm J, Rossmann P, Vetvicka V, Kopecek J (1988) Antibody-directed affinity therapy applied to the immune system: in vivo effectiveness and limited toxicity of daunomycin conjugated to HPMA copolymers and targeting antibody. Clin Immunol Immunopathol 46:100–114. doi: 10.1016/0090-1229(88)90010-4 PubMedGoogle Scholar
  317. 317.
    Merdan T, Callahan J, Petersen H, Kunath K, Bakowsky U, Kopeckova P, Kissel T, Kopecek J (2003) Pegylated polyethylenimine-Fab' antibody fragment conjugates for targeted gene delivery to human ovarian carcinoma cells. Bioconjug Chem 14:989–996. doi: 10.1021/bc0340767 PubMedGoogle Scholar
  318. 318.
    Pechar M, Ulbrich K, Jelínková M, Říhová B (2003) Conjugates of antibody-targeted PEG multiblock polymers with doxorubicin in cancer therapy. Macromol Biosci 3:364–372. doi: 10.1002/mabi.200350004 Google Scholar
  319. 319.
    Patel NR, Pattni BS, Abouzeid AH, Torchilin VP (2013) Nanopreparations to overcome multidrug resistance in cancer. Adv Drug Deliv Rev 65:1748–1762. doi: 10.1016/j.addr.2013.08.004 PubMedGoogle Scholar
  320. 320.
    Kirtane AR, Kalscheuer SM, Panyam J (2013) Exploiting nanotechnology to overcome tumor drug resistance: challenges and opportunities. Adv Drug Deliv Rev 65:1731–1747. doi: 10.1016/j.addr.2013.09.001 PubMedGoogle Scholar
  321. 321.
    Yan Y, Bjornmalm M, Caruso F (2013) Particle carriers for combating multidrug-resistant cancer. ACS Nano 7:9512–9517. doi: 10.1021/nn405632s PubMedGoogle Scholar
  322. 322.
    Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC (2014) Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev 66C:2–25. doi: 10.1016/j.addr.2013.11.009 Google Scholar

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© Controlled Release Society 2015

Authors and Affiliations

  1. 1.Centre for Pharmaceutical Nanotechnology, Department of PharmaceuticsNational Institute of Pharmaceutical Education and Research (NIPER)MohaliIndia

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