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Targeting CD13 with Asn-Gly-Arg (NGR) Peptide-Drug Conjugates

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Next-Generation Therapies and Technologies for Immune-Mediated Inflammatory Diseases

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

CD13/aminopeptidase N is a multifunctional cell surface metalloprotease expressed in myeloid and activated endothelial cells; in epithelial cells of the intestine, liver, and kidney; and in other cells. A growing body of evidence suggests that CD13 has an important role in inflammation and angiogenesis. Furthermore, a CD13 form selectively expressed by the angiogenic endothelium, but not in normal vessels, is recognized by peptides containing the Asn-Gly-Arg (NGR) motif. Because of this property, NGR peptides have been exploited as ligands for the selective delivery of a variety of therapeutic and imaging agents to angiogenic vessels. In this chapter, we discuss the structural and functional properties of NGR peptides and their potential applications as drug delivery systems in diseases with angiogenesis and inflammatory components. In addition, we discuss the experimental evidence suggesting that the asparagine residue of NGR can rapidly undergo deamidation, a spontaneous reaction that changes NGR to isoDGR (an integrin-binding motif), and the potential biological, pharmacological, and toxicological implications of this sequence transition in peptide-drug conjugates.

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References

  1. Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273–286

    Article  CAS  PubMed  Google Scholar 

  2. Italiano JE Jr, Richardson JL, Patel-Hett S et al (2008) Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 111:1227–1233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ribatti D (2009) Endogenous inhibitors of angiogenesis: a historical review. Leuk Res 33:638–644

    Article  CAS  PubMed  Google Scholar 

  4. Crippa L, Bianco M, Colombo B et al (2013) A new chromogranin A-dependent angiogenic switch activated by thrombin. Blood 121:392–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pasqualini R, Koivunen E, Kain R et al (2000) Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res 60:722–727

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Curnis F, Arrigoni G, Sacchi A et al (2002) Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia, and myeloid cells. Cancer Res 62:867–874

    CAS  PubMed  Google Scholar 

  7. Lahdenranta J, Sidman RL, Pasqualini R et al (2007) Treatment of hypoxia-induced retinopathy with targeted proapoptotic peptidomimetic in a mouse model of disease. FASEB J 21:3272–3278

    Article  CAS  PubMed  Google Scholar 

  8. Buehler A, van Zandvoort MA, Stelt BJ et al (2006) cNGR: a novel homing sequence for CD13/APN targeted molecular imaging of murine cardiac angiogenesis in vivo. Arterioscler Thromb Vasc Biol 26:2681–2687

    Article  CAS  PubMed  Google Scholar 

  9. Di Matteo P, Arrigoni GL, Alberici L et al (2011) Enhanced expression of CD13 in vessels of inflammatory and neoplastic tissues. J Histochem Cytochem 59:47–59

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Corti A, Curnis F (2011) Isoaspartate-dependent molecular switches for integrin-ligand recognition. J Cell Sci 124:515–522

    Article  CAS  PubMed  Google Scholar 

  12. Santos AN, Langner J, Herrmann M et al (2000) Aminopeptidase N/CD13 is directly linked to signal transduction pathways in monocytes. Cell Immunol 201:22–32

    Article  CAS  PubMed  Google Scholar 

  13. O’Connell PJ, Gerkis V, d’Apice AJ (1991) Variable O-glycosylation of CD13 (aminopeptidase N). J Biol Chem 266:4593–4597

    PubMed  Google Scholar 

  14. Chen L, Lin YL, Peng G et al (2012) Structural basis for multifunctional roles of mammalian aminopeptidase N. Proc Natl Acad Sci U S A 109:17966–17971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wong AH, Zhou D, Rini JM (2012) The X-ray crystal structure of human aminopeptidase N reveals a novel dimer and the basis for peptide processing. J Biol Chem 287:36804–36813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen H, Kinzer CA, Paul WE (1996) p161, a murine membrane protein expressed on mast cells and some macrophages, is mouse CD13/aminopeptidase N. J Immunol 157:2593–2600

    CAS  PubMed  Google Scholar 

  17. Riemann D, Kehlen A, Langner J (1999) CD13 – not just a marker in leukemia typing. Immunol Today 20:83–88

    Article  CAS  PubMed  Google Scholar 

  18. Mina-Osorio P (2008) The moonlighting enzyme CD13: old and new functions to target. Trends Mol Med 14:361–371

    Article  CAS  PubMed  Google Scholar 

  19. Taylor A (1993) Aminopeptidases: structure and function. FASEB J 7:290–298

    CAS  PubMed  Google Scholar 

  20. Dixon J, Kaklamanis L, Turley H et al (1994) Expression of aminopeptidase-n (CD 13) in normal tissues and malignant neoplasms of epithelial and lymphoid origin. J Clin Pathol 47:43–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dan H, Tani K, Hase K et al (2003) CD13/aminopeptidase N in collagen vascular diseases. Rheumatol Int 23:271–276

    Article  CAS  PubMed  Google Scholar 

  22. Shimizu T, Tani K, Hase K et al (2002) CD13/aminopeptidase N-induced lymphocyte involvement in inflamed joints of patients with rheumatoid arthritis. Arthritis Rheum 46:2330–2338

    Article  CAS  PubMed  Google Scholar 

  23. Pereira FE, Cronin C, Ghosh M et al (2013) CD13 is essential for inflammatory trafficking and infarct healing following permanent coronary artery occlusion in mice. Cardiovasc Res 100:74–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wickstrom M, Larsson R, Nygren P et al (2011) Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci 102:501–508

    Article  PubMed  CAS  Google Scholar 

  25. Oostendorp M, Douma K, Wagenaar A et al (2010) Molecular magnetic resonance imaging of myocardial angiogenesis after acute myocardial infarction. Circulation 121:775–783

    Article  CAS  PubMed  Google Scholar 

  26. Luan Y, Xu W (2007) The structure and main functions of aminopeptidase N. Curr Med Chem 14:639–647

    Article  CAS  PubMed  Google Scholar 

  27. Bhagwat SV, Lahdenranta J, Giordano R et al (2001) CD13/APN is activated by angiogenic signals and is essential for capillary tube formation. Blood 97:652–659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Razak K, Newland AC (1992) The significance of aminopeptidases and haematopoietic cell differentiation. Blood Rev 6:243–250

    Article  CAS  PubMed  Google Scholar 

  29. Razak K, Newland AC (1992) Induction of CD13 expression on fresh myeloid leukaemia: correlation of CD13 expression with aminopeptidase-N activity. Leuk Res 16:625–630

    Article  CAS  PubMed  Google Scholar 

  30. Wulfaenger J, Niedling S, Riemann D et al (2008) Aminopeptidase N (APN)/CD13-dependent CXCR4 downregulation is associated with diminished cell migration, proliferation and invasion. Mol Membr Biol 25:72–82

    Article  CAS  PubMed  Google Scholar 

  31. Mina-Osorio P, Winnicka B, O’Conor C et al (2008) CD13 is a novel mediator of monocytic/endothelial cell adhesion. J Leukoc Biol 84:448–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mina-Osorio P, Ortega E (2005) Aminopeptidase N (CD13) functionally interacts with FcgammaRs in human monocytes. J Leukoc Biol 77:1008–1017

    Article  CAS  PubMed  Google Scholar 

  33. Bauvois B (2004) Transmembrane proteases in cell growth and invasion: new contributors to angiogenesis? Oncogene 23:317–329

    Article  CAS  PubMed  Google Scholar 

  34. Bauvois B, Dauzonne D (2006) Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: chemistry, biological evaluations, and therapeutic prospects. Med Res Rev 26:88–130

    Article  CAS  PubMed  Google Scholar 

  35. Fukasawa K, Fujii H, Saitoh Y et al (2006) Aminopeptidase N (APN/CD13) is selectively expressed in vascular endothelial cells and plays multiple roles in angiogenesis. Cancer Lett 243:135–143

    Article  CAS  PubMed  Google Scholar 

  36. Mahoney KM, Petrovic N, Schacke W et al (2007) CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element. Gene 403:178–187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang E, Shim JS, Woo HJ et al (2007) Aminopeptidase N/CD13 induces angiogenesis through interaction with a pro-angiogenic protein, galectin-3. Biochem Biophys Res Commun 363:336–341

    Article  CAS  PubMed  Google Scholar 

  38. Petrovic N, Schacke W, Gahagan JR et al (2007) CD13/APN regulates endothelial invasion and filopodia formation. Blood 110:142–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rangel R, Sun Y, Guzman-Rojas L et al (2007) Impaired angiogenesis in aminopeptidase N-null mice. Proc Natl Acad Sci U S A 104:4588–4593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dondossola E, Corti A, Sidman RL et al (2014) Bone marrow-derived CD13 cells sustain tumor progression: a potential non-malignant target for anticancer therapy. Oncoimmunology 3:e27716

    Article  PubMed  PubMed Central  Google Scholar 

  41. Curnis F, Sacchi A, Borgna L et al (2000) Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat Biotechnol 18:1185–1190

    Article  CAS  PubMed  Google Scholar 

  42. Oostendorp M, Douma K, Hackeng TM et al (2008) Quantitative molecular magnetic resonance imaging of tumor angiogenesis using cNGR-labeled paramagnetic quantum dots. Cancer Res 68:7676–7683

    Article  CAS  PubMed  Google Scholar 

  43. Liu C, Yang Y, Chen L et al (2014) A unified mechanism for aminopeptidase N-based tumor cell motility and tumor-homing therapy. J Biol Chem 289:34520–34529

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Bieker R, Kessler T, Schwoppe C et al (2009) Infarction of tumor vessels by NGR-peptide-directed targeting of tissue factor: experimental results and first-in-man experience. Blood 113:5019–5027

    Article  CAS  PubMed  Google Scholar 

  45. Dreischaluck J, Schwoppe C, Spieker T et al (2010) Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: activity and toxicity profile. Int J Oncol 37:1389–1397

    PubMed  Google Scholar 

  46. Schwoppe C, Kessler T, Persigehl T et al (2010) Tissue-factor fusion proteins induce occlusion of tumor vessels. Thromb Res 125(Suppl 2):S143–S150

    Article  PubMed  Google Scholar 

  47. Corti A, Curnis F, Rossoni G et al (2013) Peptide-mediated targeting of cytokines to tumor vasculature: the NGR-hTNF example. BioDrugs 27:591–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Curnis F, Sacchi A, Corti A (2002) Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J Clin Investig 110:475–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sacchi A, Gasparri A, Gallo-Stampino C et al (2006) Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-alpha. Clin Cancer Res 12:175–182

    Article  CAS  PubMed  Google Scholar 

  50. Calcinotto A, Grioni M, Jachetti E et al (2012) Targeting TNF-alpha to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy. J Immunol 188:2687–2694

    Article  CAS  PubMed  Google Scholar 

  51. Gregorc V, Zucali PA, Santoro A et al (2010) Phase II study of asparagine-glycine-arginine-human tumor necrosis factor alpha, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma. J Clin Oncol: Off J Am Soc Clin Oncol 28:2604–2611

    Article  CAS  Google Scholar 

  52. Zucali PA, Simonelli M, De Vincenzo F et al (2013) Phase I and pharmacodynamic study of high- dose NGR-hTNF in patients with refractory solid tumours. Br J Cancer 108:58–63

    Article  CAS  PubMed  Google Scholar 

  53. Lorusso D, Scambia G, Amadio G et al (2012) Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients. Br J Cancer 107:37–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gregorc V, De Braud FG, De Pas TM et al (2011) Phase I study of NGR-hTNF, a selective vascular targeting agent, in combination with cisplatin in refractory solid tumors. Clin Cancer Res 17:1964–1972

    Article  CAS  PubMed  Google Scholar 

  55. Gupta M, Chashoo G, Sharma PR et al (2014) Dual targeted polymeric nanoparticles based on tumor endothelium and tumor cells for enhanced antitumor drug delivery. Mol Pharm 11:697–715

    Article  CAS  PubMed  Google Scholar 

  56. Zhang Z, Harada H, Tanabe K et al (2005) Aminopeptidase N/CD13 targeting fluorescent probes: synthesis and application to tumor cell imaging. Peptides 26:2182–2187

    Article  CAS  PubMed  Google Scholar 

  57. Zhang Z, Hatta H, Tanabe K et al (2005) A new class of 5-fluoro-2′-deoxyuridine prodrugs conjugated with a tumor-homing cyclic peptide CNGRC by ester linkers: synthesis, reactivity, and tumor-cell-selective cytotoxicity. Pharm Res 22:381–389

    Article  CAS  PubMed  Google Scholar 

  58. Ndinguri MW, Solipuram R, Gambrell RP et al (2009) Peptide targeting of platinum anti-cancer drugs. Bioconjug Chem 20:1869–1878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mammoliti S, Andretta V, Bennicelli E et al (2011) Two doses of NGR-hTNF in combination with capecitabine plus oxaliplatin in colorectal cancer patients failing standard therapies. Ann Oncol 22:973–978

    Article  CAS  PubMed  Google Scholar 

  60. Santoro A, Citterio G, Rimassa L et al. (2009) Phase II trial of NGR-hTNF, a selective vascular targeting agent (VTA), administered at low dose in pre-treated patients with hepatocellular carcinoma (HCC). ASCO 2009 Annual Meeting, Abstract 247

    Google Scholar 

  61. Santoro A, Rimassa L, Sobrero AF et al (2010) Phase II study of NGR-hTNF, a selective vascular targeting agent, in patients with metastatic colorectal cancer after failure of standard therapy. Eur J Cancer 46:2746–2752

    Article  CAS  PubMed  Google Scholar 

  62. Gregorc V, Ceresoli G, Zucali PA et al (2009) Phase II study of NGR-hTNF, a selective vascular targeting agent (VTA), in previously treated patients with malignant pleural mesothelioma MPM). J Clin Oncol 27:15s, suppl; abstr 7582

    Article  Google Scholar 

  63. Rimassa L, Sobrero A, Santoro A et al (2009) Phase II study of NGR-hTNF, a selective vascular targeting agent (VTA), administered as single agent in patients (pts) with colorectal cancer (CRC) refractory to standard regimens. J Clin Oncol 27:15s, suppl; abstr 4088

    Article  Google Scholar 

  64. Gregorc V, Santoro A, Bennicelli E et al (2009) Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours. Br J Cancer 101:219–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Citterio G, De Braud F, Gregorc V et al (2009) Phase Ib study of NGR-hTNF, a selective vascular targeting agent (VTA), in combination with cisplatin in patients with refractory solid tumors. J Clin Oncol 27:15s, suppl; abstr 3570

    Article  Google Scholar 

  66. Desar IM, van Herpen CM, van Asten JJ et al (2011) Factors affecting the unexpected failure of DCE-MRI to determine the optimal biological dose of the vascular targeting agent NGR-hTNF in solid cancer patients. Eur J Radiol 80:655–661

    Article  PubMed  Google Scholar 

  67. Gregorc V, Citterio G, Vitali G et al (2010) Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours. Eur J Cancer 46:198–206

    Article  CAS  PubMed  Google Scholar 

  68. Santoro A, Pressiani T, Citterio G et al (2010) Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma. Br J Cancer 103:837–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Li B, Zheng YB, Li DD et al (2014) Preparation and evaluation of a CD13/APN-targeting and hydrolase-resistant conjugate that comprises pingyangmycin and NGR motif-integrated apoprotein. J Pharm Sci 103:1204–1213

    Article  CAS  PubMed  Google Scholar 

  70. Liu C, Yu W, Chen Z et al (2011) Enhanced gene transfection efficiency in CD13-positive vascular endothelial cells with targeted poly(lactic acid)-poly(ethylene glycol) nanoparticles through caveolae-mediated endocytosis. J Control Release 151:162–175

    Article  CAS  PubMed  Google Scholar 

  71. von Wallbrunn A, Waldeck J, Holtke C et al (2008) In vivo optical imaging of CD13/APN- expression in tumor xenografts. J Biomed Opt 13:011007

    Article  CAS  Google Scholar 

  72. Ellerby HM, Arap W, Ellerby LM et al (1999) Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med 5:1032–1038

    Article  CAS  PubMed  Google Scholar 

  73. Jiang W, Jin G, Ma D et al (2012) Modification of cyclic NGR tumor neovasculature-homing motif sequence to human plasminogen kringle 5 improves inhibition of tumor growth. PLoS One 7:e37132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lei H, Cao P, Miao G et al (2010) Expression and functional characterization of tumor-targeted fusion protein composed of NGR peptide and 15-kDa actin fragment. Appl Biochem Biotechnol 162:988–995

    Article  CAS  PubMed  Google Scholar 

  75. Hu Z, Yang W, Ma X et al (2013) Cerenkov luminescence tomography of aminopeptidase N (APN/CD13) expression in mice bearing HT1080 tumors. Mol Imaging 12:173–181

    CAS  PubMed  Google Scholar 

  76. Ma W, Wang Z, Yang W et al (2014) Biodistribution and SPECT imaging study of (99m)Tc labeling NGR peptide in nude mice bearing human HepG2 hepatoma. Biomed Res Int 2014:618096

    PubMed  PubMed Central  Google Scholar 

  77. Tillmanns J, Schneider M, Fraccarollo D et al (2015) PET imaging of cardiac wound healing using a novel [68Ga]-labeled NGR probe in rat myocardial infarction. Mol Imaging Biol 17:76–86

    Article  CAS  PubMed  Google Scholar 

  78. Wolters M, Oostendorp M, Coolen BF et al (2012) Efficacy of positive contrast imaging techniques for molecular MRI of tumor angiogenesis. Contrast Media Mol Imaging 7:130–139

    Article  CAS  PubMed  Google Scholar 

  79. Hendrikx G, De Saint-Hubert M, Dijkgraaf I et al (2015) Molecular imaging of angiogenesis after myocardial infarction by (111)In-DTPA-cNGR and (99m)Tc-sestamibi dual-isotope myocardial SPECT. EJNMMI Res 5:2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Dirksen A, Langereis S, de Waal BF et al (2004) Design and synthesis of a bimodal target-specific contrast agent for angiogenesis. Org Lett 6:4857–4860

    Article  CAS  PubMed  Google Scholar 

  81. Ma W, Li G, Wang J et al (2014) In vivo NIRF imaging-guided delivery of a novel NGR-VEGI fusion protein for targeting tumor vasculature. Amino Acids 46:2721–2732

    Article  CAS  PubMed  Google Scholar 

  82. Jullienne B, Vigant F, Muth E et al (2009) Efficient delivery of angiostatin K1-5 into tumors following insertion of an NGR peptide into adenovirus capsid. Gene Ther 16:1405–1415

    Article  CAS  PubMed  Google Scholar 

  83. Curnis F, Sacchi A, Gasparri A et al (2008) Isoaspartate-glycine-arginine: a new tumor vasculature- targeting motif. Cancer Res 68:7073–7082

    Article  CAS  PubMed  Google Scholar 

  84. Sheng W, Shang Y, Li L et al (2014) An EGFR/CD13 bispecific fusion protein and its enediyne- energized analog show potent antitumor activity. Anticancer Drugs 25:82–91

    Article  CAS  PubMed  Google Scholar 

  85. Majhen D, Gabrilovac J, Eloit M et al (2006) Disulfide bond formation in NGR fiber-modified adenovirus is essential for retargeting to aminopeptidase N. Biochem Biophys Res Commun 348:278–287

    Article  CAS  PubMed  Google Scholar 

  86. Alberici L, Roth L, Sugahara KN et al (2013) De novo design of a tumor-penetrating peptide. Cancer Res 73:804–812

    Article  CAS  PubMed  Google Scholar 

  87. Curnis F, Gasparri A, Sacchi A et al (2005) Targeted delivery of IFNgamma to tumor vessels uncouples antitumor from counterregulatory mechanisms. Cancer Res 65:2906–2913

    Article  CAS  PubMed  Google Scholar 

  88. Liu F, Li M, Liu C et al (2014) Tumor-specific delivery and therapy by double-targeted DTX- CMCS-PEG-NGR conjugates. Pharm Res 31:475–488

    Article  CAS  PubMed  Google Scholar 

  89. Wang X, Wang Y, Chen X et al (2009) NGR-modified micelles enhance their interaction with CD13-overexpressing tumor and endothelial cells. J Control Release: Off J Control Release Soc 139:56–62

    Article  CAS  Google Scholar 

  90. Chen K, Ma W, Li G et al (2013) Synthesis and evaluation of 64Cu-labeled monomeric and dimeric NGR peptides for MicroPET imaging of CD13 receptor expression. Mol Pharm 10:417–427

    Article  CAS  PubMed  Google Scholar 

  91. Li G, Xing Y, Wang J et al (2014) Near-infrared fluorescence imaging of CD13 receptor expression using a novel Cy5.5-labeled dimeric NGR peptide. Amino Acids 46:1547–1556

    Article  CAS  PubMed  Google Scholar 

  92. Negussie AH, Miller JL, Reddy G et al (2010) Synthesis and in vitro evaluation of cyclic NGR peptide targeted thermally sensitive liposome. J Control Release 143:265–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Mate G, Kertesz I, Enyedi KN et al (2015) In vivo imaging of Aminopeptidase N (CD13) receptors in experimental renal tumors using the novel radiotracer (68)Ga-NOTA-c(NGR). Eur J Pharm Sci 69:61–71

    Article  CAS  PubMed  Google Scholar 

  94. Faintuch BL, Oliveira EA, Targino RC et al (2014) Radiolabeled NGR phage display peptide sequence for tumor targeting. Appl Radiat Isot 86:41–45

    Article  CAS  PubMed  Google Scholar 

  95. Yokoyama Y, Ramakrishnan S (2005) Addition of an aminopeptidase N-binding sequence to human endostatin improves inhibition of ovarian carcinoma growth. Cancer 104:321–331

    Article  CAS  PubMed  Google Scholar 

  96. Mukhopadhyay S, Barnes CM, Haskel A et al (2007) Conjugated platinum(IV)-peptide complexes for targeting angiogenic tumor vasculature. Bioconjug Chem 19:39–49

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Colombo G, Curnis F, De Mori GM et al (2002) Structure-activity relationships of linear and cyclic peptides containing the NGR tumor-homing motif. J Biol Chem 277:47891–47897

    Article  CAS  PubMed  Google Scholar 

  98. Dunne M, Zheng J, Rosenblat J et al (2011) APN/CD13-targeting as a strategy to alter the tumor accumulation of liposomes. J Control Release 154:298–305

    Article  CAS  PubMed  Google Scholar 

  99. Takara K, Hatakeyama H, Kibria G et al (2012) Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy. J Control Release 162:225–232

    Article  CAS  PubMed  Google Scholar 

  100. Ma W, Kang F, Wang Z et al (2013) (99m)Tc-labeled monomeric and dimeric NGR peptides for SPECT imaging of CD13 receptor in tumor-bearing mice. Amino Acids 44:1337–1345

    Article  CAS  PubMed  Google Scholar 

  101. Pastorino F, Brignole C, Marimpietri D et al (2003) Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy. Cancer Res 63:7400–7409

    CAS  PubMed  Google Scholar 

  102. Garde SV, Forte AJ, Ge M et al (2007) Binding and internalization of NGR-peptide-targeted liposomal doxorubicin (TVT-DOX) in CD13-expressing cells and its antitumor effects. Anticancer Drugs 18:1189–1200

    Article  CAS  PubMed  Google Scholar 

  103. Chen Y, Wu JJ, Huang L (2010) Nanoparticles targeted with NGR motif deliver c-myc siRNA and doxorubicin for anticancer therapy. Mol Ther 18:828–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Persigehl T, Ring J, Bremer C et al (2014) Non-invasive monitoring of tumor-vessel infarction by retargeted truncated tissue factor tTF-NGR using multi-modal imaging. Angiogenesis 17:235–246

    Article  CAS  PubMed  Google Scholar 

  105. Meng J, Ma N, Yan Z et al (2006) NGR enhanced the anti-angiogenic activity of tum-5. J Biochem 140:299–304

    Article  CAS  PubMed  Google Scholar 

  106. Meng J, Yan Z, Wu J et al (2007) High-yield expression, purification and characterization of tumor- targeted IFN-alpha2a. Cytotherapy 9:60–68

    Article  CAS  PubMed  Google Scholar 

  107. Zhang B, Gao B, Dong S et al (2011) Anti-tumor efficacy and pre-clinical immunogenicity of IFNalpha2a-NGR. Regul Toxicol Pharm 60:73–78

    Article  CAS  Google Scholar 

  108. Grifman M, Trepel M, Speece P et al (2001) Incorporation of tumor-targeting peptides into recombinant adeno-associated virus capsids. Mol Ther 3:964–975

    Article  CAS  PubMed  Google Scholar 

  109. Liu L, Anderson WF, Beart RW et al (2000) Incorporation of tumor vasculature targeting motifs into moloney murine leukemia virus env escort proteins enhances retrovirus binding and transduction of human endothelial cells. J Virol 74:5320–5328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Simnick AJ, Amiram M, Liu W et al (2011) In vivo tumor targeting by a NGR-decorated micelle of a recombinant diblock copolypeptide. J Control Release 155:144–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Luan Y, Jing F, Zhang J et al (2012) Design, synthesis, and activity evaluation of a new 5- fluorouracil prodrug containing an Asn-Gly-Arg(NO2)COOCH3 tripeptide. Protein Pept Lett 19:1122–1131

    Article  CAS  PubMed  Google Scholar 

  112. Teesalu T, Sugahara KN, Ruoslahti E (2013) Tumor-penetrating peptides. Front Oncol 3:216

    Article  PubMed  PubMed Central  Google Scholar 

  113. Wythe SE, DiCara D, Taher TE et al (2013) Targeted delivery of cytokine therapy to rheumatoid tissue by a synovial targeting peptide. Ann Rheum Dis 72:129–135

    Article  CAS  PubMed  Google Scholar 

  114. Di Matteo P, Curnis F, Longhi R et al (2006) Immunogenic and structural properties of the Asn-Gly- Arg (NGR) tumor neovasculature-homing motif. Mol Immunol 43:1509–1518

    Article  PubMed  CAS  Google Scholar 

  115. Curnis F, Longhi R, Crippa L et al (2006) Spontaneous formation of L-isoaspartate and gain of function in fibronectin. J Biol Chem 281:36466–36476

    Article  CAS  PubMed  Google Scholar 

  116. Robinson AB (1979) Molecular clocks, molecular profiles, and optimum diets: three approaches to the problem of aging. Mech Ageing Dev 9:225–236

    Article  CAS  PubMed  Google Scholar 

  117. Robinson NE (2002) Protein deamidation. Proc Natl Acad Sci U S A 99:5283–5288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Robinson NE, Robinson AB (2001) Molecular clocks. Proc Natl Acad Sci U S A 98:944–949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Curnis F, Cattaneo A, Longhi R et al (2010) Critical role of flanking residues in NGR-to-isoDGR transition and CD13/integrin receptor switching. J Biol Chem 285:9114–9123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Barbariga M, Curnis F, Spitaleri A et al (2014) Oxidation-induced structural changes of ceruloplasmin foster NGR motif deamidation that promotes integrin binding and signaling. J Biol Chem 289:3736–3748

    Article  CAS  PubMed  Google Scholar 

  121. Spitaleri A, Ghitti M, Mari S et al (2011) Use of metadynamics in the design of isoDGR-based alphavbeta3 antagonists to fine-tune the conformational ensemble. Angew Chem 50:1832–1836

    Article  CAS  Google Scholar 

  122. Spitaleri A, Mari S, Curnis F et al (2008) Structural basis for the interaction of isoDGR with the RGD-binding site of alphavbeta3 integrin. J Biol Chem 283:19757–19768

    Article  CAS  PubMed  Google Scholar 

  123. Curnis F, Sacchi A, Longhi R et al (2013) IsoDGR-tagged albumin: a new alphavbeta3 selective carrier for nanodrug delivery to tumors. Small 9:673–678

    Article  CAS  PubMed  Google Scholar 

  124. Brooks PC, Stromblad S, Klemke R et al (1995) Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 96:1815–1822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Eliceiri BP, Cheresh DA (2000) Role of alpha v integrins during angiogenesis. Cancer J 6(Suppl 3):S245–S249

    PubMed  Google Scholar 

  126. Friedlander M, Brooks PC, Shaffer RW et al (1995) Definition of two angiogenic pathways by distinct alpha v integrins. Science 270:1500–1502

    Article  CAS  PubMed  Google Scholar 

  127. Friedlander M, Theesfeld CL, Sugita M et al (1996) Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases. Proc Natl Acad Sci U S A 93:9764–9769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Neubauer S, Rechenmacher F, Beer AJ et al (2013) Selective imaging of the angiogenic relevant integrins alpha5beta1 and alphavbeta3. Angew Chem Int Ed Engl 52:11656–11659

    Article  CAS  PubMed  Google Scholar 

  129. Kumar CC (2003) Integrin alpha v beta 3 as a therapeutic target for blocking tumor-induced angiogenesis. Curr Drug Targets 4:123–131

    Article  CAS  PubMed  Google Scholar 

  130. Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10:9–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ruoslahti E, Bhatia SN, Sailor MJ (2010) Targeting of drugs and nanoparticles to tumors. J Cell Biol 188:759–768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Liu Z, Wang F, Chen X (2008) Integrin alpha(v)beta(3)-targeted cancer therapy. Drug Dev Res 69:329–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants from the Associazione Italiana Ricerca sul Cancro (AIRC IG-14338 and 9965), Worldwide Cancer Research (formerly known as AICR, 14-0066), and Ministero della Salute of Italy (RF-2011-02350836).

Conflict of Interest

A. Corti and F. Curnis are the inventors of various patents on the use of NGR peptides for drug delivery. M. Fiocchi declares no conflict of interests.

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Authors and Affiliations

  1. Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Angelo Corti

  2. Vita-Salute San Raffaele University, Milan, Italy

    Angelo Corti

  3. Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Martina Fiocchi & Flavio Curnis

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  1. Angelo Corti
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  2. Martina Fiocchi
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  3. Flavio Curnis
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Correspondence to Angelo Corti or Flavio Curnis .

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Editors and Affiliations

  1. US Medical Division, Eli Lilly & Company, New York, New York, USA

    Paola Mina-Osorio

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Corti, A., Fiocchi, M., Curnis, F. (2017). Targeting CD13 with Asn-Gly-Arg (NGR) Peptide-Drug Conjugates. In: Mina-Osorio, P. (eds) Next-Generation Therapies and Technologies for Immune-Mediated Inflammatory Diseases. Progress in Inflammation Research. Springer, Cham. https://doi.org/10.1007/978-3-319-42252-7_6

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