{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T03:12:14Z","timestamp":1777518734858,"version":"3.51.4"},"reference-count":122,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T00:00:00Z","timestamp":1694044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union","award":["GINOP-2.3.2-15-2016-00043"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00043"]}]},{"name":"European Union","award":["TKP2021-EGA-20"],"award-info":[{"award-number":["TKP2021-EGA-20"]}]},{"name":"Ministry for Innovation and Technology in Hungary","award":["GINOP-2.3.2-15-2016-00043"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00043"]}]},{"name":"Ministry for Innovation and Technology in Hungary","award":["TKP2021-EGA-20"],"award-info":[{"award-number":["TKP2021-EGA-20"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Since angiogenesis\/neoangiogenesis has a major role in tumor development, progression and metastatic spread, the establishment of angiogenesis-targeting imaging and therapeutic vectors is of utmost significance. Aminopeptidase N (APN\/CD13) is a pivotal biomarker of angiogenic processes abundantly expressed on the cell surface of active vascular endothelial and various neoplastic cells, constituting a valuable target for cancer diagnostics and therapy. Since the asparagine\u2013glycine\u2013arginine (NGR) sequence has been shown to colocalize with APN\/CD13, the research interest in NGR-peptide-mediated vascular targeting is steadily growing. Earlier preclinical experiments have already demonstrated the imaging and therapeutic feasibility of NGR-based probes labeled with different positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radionuclides, including Gallium-68 (68Ga), Copper-64 (64Cu), Technetium-99m (99mTc), Lutetium-177 (177Lu), Rhenium-188 (188Re) or Bismuth-213 (213Bi). To improve the tumor binding affinity and the retention time of single-receptor targeting peptides, NGR motifs containing heterodimers have been introduced to identify multi-receptor overexpressing malignancies. Preclinical studies with various tumor-bearing experimental animals provide useful tools for the investigation of the in vivo imaging behavior of NGR-based heterobivalent ligands. Herein, we review the reported preclinical achievements on NGR heterodimers that could be highly relevant for the development of further target-specific multivalent compounds in diagnostic and therapeutic settings.<\/jats:p>","DOI":"10.3390\/cancers15184459","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T10:09:50Z","timestamp":1694081390000},"page":"4459","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Radiolabeled NGR-Based Heterodimers for Angiogenesis Imaging: A Review of Preclinical Studies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6456-6212","authenticated-orcid":false,"given":"Gy\u00f6rgy","family":"Trencs\u00e9nyi","sequence":"first","affiliation":[{"name":"Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00e1bor","family":"Halmos","sequence":"additional","affiliation":[{"name":"Department of Biopharmacy, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2889-8521","authenticated-orcid":false,"given":"Zita","family":"K\u00e9pes","sequence":"additional","affiliation":[{"name":"Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Vaz, S.C., Oliveira, F., Herrmann, K., and Veit-Haibach, P. (2020). Nuclear medicine and molecular imaging advances in the 21st century. Br. J. Radiol., 93.","DOI":"10.1259\/bjr.20200095"},{"key":"ref_2","first-page":"117","article-title":"Monoclonal antibodies to tumor antigens","volume":"11","author":"Brown","year":"1980","journal-title":"Contemp. Top. Immunobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1007\/s00726-010-0546-y","article-title":"Peptide heterodimers for molecular imaging","volume":"41","author":"Yan","year":"2011","journal-title":"Amino Acids"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/S0014-5793(99)00713-9","article-title":"Di-, tri- and tetrameric single chain Fv antibody fragments against human CD19: Effect of valency on cell binding","volume":"453","author":"Kipriyanov","year":"1999","journal-title":"FEBS. Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3545","DOI":"10.1200\/JCO.2002.02.126","article-title":"Radiolabeled anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoma","volume":"20","author":"Dillman","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/S0140-6736(95)92225-3","article-title":"Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas","volume":"346","author":"Press","year":"1995","journal-title":"Lancet"},{"key":"ref_7","first-page":"5144","article-title":"Micropharmacology of monoclonal antibodies in solid tumors: Direct experimental evidence for a binding site barrier","volume":"52","author":"Juweid","year":"1992","journal-title":"Cancer. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1002\/psp4.12224","article-title":"Pharmacokinetics of Monoclonal Antibodies","volume":"6","author":"Ryman","year":"2017","journal-title":"CPT. Pharmacomet. Syst. Pharmacol."},{"key":"ref_9","first-page":"109","article-title":"Pricing of monoclonal antibody therapies: Higher if used for cancer?","volume":"24","author":"Hernandez","year":"2018","journal-title":"Am. J. Manag. Care"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Vaisman-Mentesh, A., Rosenstein, S., Yavzori, M., Dror, Y., Fudim, E., Ungar, B., Kopylov, U., Picard, O., Kigel, A., and Ben-Horin, S. (2019). Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment With TNF\u03b1 Antagonists. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02921"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.2174\/1381612043383511","article-title":"Design, synthesis and preclinical evaluation of radiolabeled peptides for diagnosis and therapy","volume":"10","author":"Aloj","year":"2004","journal-title":"Curr. Pharm. Des."},{"key":"ref_12","first-page":"1704","article-title":"Peptide receptor imaging and therapy","volume":"41","author":"Kwekkeboom","year":"2000","journal-title":"J. Nucl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"780","DOI":"10.2174\/092986709787549307","article-title":"Peptides for tumour therapy and diagnosis: Current status and future directions","volume":"16","author":"Zaccaro","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1093\/annonc\/mdl105","article-title":"Rationale for the use of somatostatin analogs as antitumor agents","volume":"17","author":"Susini","year":"2006","journal-title":"Ann. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"453","DOI":"10.2967\/jnumed.107.048009","article-title":"18F-labeled BBN-RGD heterodimer for prostate cancer imaging","volume":"49","author":"Li","year":"2008","journal-title":"J. Nucl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2165\/00063030-200418050-00001","article-title":"Criteria for the design and biological characterization of radiolabeled peptide-based pharmaceuticals","volume":"18","author":"Benedetti","year":"2004","journal-title":"BioDrugs"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1002\/(SICI)1521-3773(19981102)37:20<2754::AID-ANIE2754>3.0.CO;2-3","article-title":"Polyvalent Interactions in Biological Systems: Implications for Design and Use of Multivalent Ligands and Inhibitors","volume":"37","author":"Mammen","year":"1998","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1007\/s00726-013-1469-1","article-title":"(99m)Tc-labeled monomeric and dimeric NGR peptides for SPECT imaging of CD13 receptor in tumor-bearing mice","volume":"44","author":"Ma","year":"2013","journal-title":"Amino Acids"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1056\/NEJMoa1113205","article-title":"Intratumor heterogeneity and branched evolution revealed by multiregion sequencing","volume":"366","author":"Gerlinger","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/bjc.2012.581","article-title":"Cancer heterogeneity: Implications for targeted therapeutics","volume":"108","author":"Fisher","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8999","DOI":"10.1073\/pnas.92.19.8999","article-title":"Targeting cancer micrometastases with monoclonal antibodies: A binding-site barrier","volume":"92","author":"Saga","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1021\/jm050947h","article-title":"Design, synthesis, and evaluation of near infrared fluorescent multimeric RGD peptides for targeting tumors","volume":"49","author":"Ye","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13715","DOI":"10.1073\/pnas.93.24.13715","article-title":"Melanotropic peptide-conjugated beads for microscopic visualization and characterization of melanoma melanotropin receptors","volume":"93","author":"Sharma","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1021\/bc010012p","article-title":"99mTc-labeling of a hydrazinonicotinamide-conjugated vitronectin receptor antagonist useful for imaging tumors","volume":"12","author":"Liu","year":"2001","journal-title":"Bioconjug. Chem."},{"key":"ref_25","first-page":"113","article-title":"Quantitative PET imaging of tumor integrin alphavbeta3 expression with 18F-FRGD2","volume":"47","author":"Zhang","year":"2006","journal-title":"J. Nucl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1162\/1535350041464892","article-title":"Micro-PET imaging of alphavbeta3-integrin expression with 18F-labeled dimeric RGD peptide","volume":"3","author":"Chen","year":"2004","journal-title":"Mol. Imaging"},{"key":"ref_27","first-page":"1707","article-title":"microPET imaging of glioma integrin {alpha}v{beta}3 expression using (64)Cu-labeled tetrameric RGD peptide","volume":"46","author":"Wu","year":"2005","journal-title":"J. Nucl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1007\/s00259-010-1615-x","article-title":"PET imaging of \u03b1v\u03b2\u2083 integrin expression in tumours with \u2076\u2078Ga-labelled mono-, di- and tetrameric RGD peptides","volume":"38","author":"Dijkgraaf","year":"2011","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/pat.1829","article-title":"Pro-apoptotic peptide-polymer conjugates to induce mitochondrial-dependent cell death","volume":"22","author":"Adar","year":"2011","journal-title":"Polym. Adv. Technol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1517\/14728222.8.6.565","article-title":"Hitting multiple targets with multimeric ligands","volume":"8","author":"Handl","year":"2004","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s00259-003-1184-3","article-title":"Concomitant expression of several peptide receptors in neuroendocrine tumours: Molecular basis for in vivo multireceptor tumour targeting","volume":"30","author":"Reubi","year":"2003","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.4155\/tde.12.99","article-title":"Multivalent ligand: Design principle for targeted therapeutic delivery approach","volume":"3","author":"Chittasupho","year":"2012","journal-title":"Ther. Deliv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1002\/cbic.200500112","article-title":"Probing lectin and sperm with carbohydrate-modified quantum dots","volume":"6","author":"Robinson","year":"2005","journal-title":"ChemBioChem"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1007\/s13346-021-01103-4","article-title":"Critical parameters for design and development of multivalent nanoconstructs: Recent trends","volume":"12","author":"Bakshi","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1021\/mp500115x","article-title":"Design and applications of bispecific heterodimers: Molecular imaging and beyond","volume":"11","author":"Luo","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1146\/annurev-bioeng-071812-152412","article-title":"Replacing antibodies: Engineering new binding proteins","volume":"15","author":"Banta","year":"2013","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1021\/acs.molpharmaceut.9b01134","article-title":"Evaluation of an Integrin \u03b1v\u03b23 and Aminopeptidase N Dual-Receptor Targeting Tracer for Breast Cancer Imaging","volume":"17","author":"Gai","year":"2020","journal-title":"Mol. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1007\/s00259-009-1123-z","article-title":"(68)Ga-Labeled NOTA-RGD-BBN Peptide for Dual Integrin and GRPR-Targeted Tumor Imaging","volume":"36","author":"Liu","year":"2009","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Judmann, B., Braun, D., W\u00e4ngler, B., Schirrmacher, R., Fricker, G., and W\u00e4ngler, C. (2020). Current State of Radiolabeled Heterobivalent Peptidic Ligands in Tumor Imaging and Therapy. Pharmaceutics, 3.","DOI":"10.3390\/ph13080173"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1021\/mp200661t","article-title":"99mTc-labeled RGD-BBN peptide for small-animal SPECT\/CT of lung carcinoma","volume":"9","author":"Liu","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_41","unstructured":"McMichael, A.J. (1987). Leukocyte Typing III, Proceedings of the Third International Workshop on Human Leukocyte Differentiation Antigens, Oxford, UK, 21\u201326 September 1986, Oxford University Press."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0167-5699(98)01398-X","article-title":"CD13--not just a marker in leukemia typing","volume":"20","author":"Riemann","year":"1999","journal-title":"Immunol. Today"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1096\/fasebj.7.2.8440407","article-title":"Aminopeptidases: Structure and function","volume":"7","author":"Taylor","year":"1993","journal-title":"FASEB J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1182\/blood.V82.4.1052.1052","article-title":"Hematopoietic differentiation antigens that are membrane-associated enzymes: Cutting is the key!","volume":"82","author":"Shipp","year":"1993","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/0268-960X(92)90020-Q","article-title":"The significance of aminopeptidases and haematopoietic cell differentiation","volume":"6","author":"Razak","year":"1992","journal-title":"Blood Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1136\/jcp.47.1.43","article-title":"Expression of aminopeptidase-n (CD 13) in normal tissues and malignant neoplasms of epithelial and lymphoid origin","volume":"47","author":"Dixon","year":"1994","journal-title":"J. Clin. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.4049\/jimmunol.157.6.2593","article-title":"p161, a murine membrane protein expressed on mast cells and some macrophages, is mouse CD13\/aminopeptidase N","volume":"157","author":"Chen","year":"1996","journal-title":"J. Immunol."},{"key":"ref_48","first-page":"697","article-title":"Classification of acute myeloid leukemias: A comparison of FAB and immunophenotyping","volume":"1","author":"Drexler","year":"1987","journal-title":"Leukemia"},{"key":"ref_49","first-page":"867","article-title":"Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia, and myeloid cells","volume":"62","author":"Curnis","year":"2002","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1182\/blood.V97.3.652","article-title":"CD13\/APN is activated by angiogenic signals and is essential for capillary tube formation","volume":"97","author":"Bhagwat","year":"2001","journal-title":"Blood"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s12032-011-9984-y","article-title":"Prognostic value of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and aminopeptidase N\/CD13 in breast cancer patients","volume":"29","author":"Ranogajec","year":"2012","journal-title":"Med. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1111\/j.1525-1438.2006.00657.x","article-title":"Expression of aminopeptidase N\/CD13 in human ovarian cancers","volume":"16","author":"Surowiak","year":"2006","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_53","first-page":"8500","article-title":"Biological significance of aminopeptidase N\/CD13 in thyroid carcinomas","volume":"63","author":"Kehlen","year":"2003","journal-title":"Cancer Res."},{"key":"ref_54","first-page":"1503","article-title":"Clinical significance of aminopeptidase N\/CD13 expression in human pancreatic carcinoma","volume":"9","author":"Ikeda","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1053\/gast.2002.31095","article-title":"Aminopeptidase N is involved in cell motility and angiogenesis: Its clinical significance in human colon cancer","volume":"122","author":"Hashida","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"223","DOI":"10.4103\/0973-1482.138007","article-title":"Expression and clinical significance of aminopeptidase N\/CD13 in non-small cell lung cancer","volume":"11","author":"Zhang","year":"2015","journal-title":"J. Cancer Res. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.3892\/or.2016.4611","article-title":"Ubenimex inhibits cell proliferation, migration and invasion by inhibiting the expression of APN and inducing autophagic cell death in prostate cancer cells","volume":"35","author":"Wang","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Otsuki, T., Nakashima, T., Hamada, H., Takayama, Y., Akita, S., Masuda, T., Horimasu, Y., Miyamoto, S., Iwamoto, H., and Fujitaka, K. (2018). Aminopeptidase N\/CD13 as a potential therapeutic target in malignant pleural mesothelioma. Eur. Respir. J., 51.","DOI":"10.1183\/13993003.01610-2017"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Barnieh, F.M., Loadman, P.M., and Falconer, R.A. (2021). Is tumour-expressed aminopeptidase N (APN\/CD13) structurally and functionally unique?. Biochim. Biophys. Acta Rev. Cancer, 1876.","DOI":"10.1016\/j.bbcan.2021.188641"},{"key":"ref_60","first-page":"722","article-title":"Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis","volume":"60","author":"Pasqualini","year":"2000","journal-title":"Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"639","DOI":"10.2174\/092986707780059571","article-title":"The structure and main functions of aminopeptidase N","volume":"14","author":"Luan","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"11999","DOI":"10.1016\/S0021-9258(18)99056-3","article-title":"Separate promoters control transcription of the human aminopeptidase N gene in myeloid and intestinal epithelial cells","volume":"266","author":"Shapiro","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.molmed.2008.06.003","article-title":"The moonlighting enzyme CD13: Old and new functions to target","volume":"14","year":"2008","journal-title":"Trends Mol. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1182\/blood-2008-04-150862","article-title":"The neovasculature homing motif NGR: More than meets the eye","volume":"112","author":"Corti","year":"2008","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Enyedi, K.N., T\u00f3th, S., Szak\u00e1cs, G., and Mez\u0151, G. (2017). NGR-peptide-drug conjugates with dual targeting properties. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178632"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1021\/bi971705p","article-title":"Characterization of Glu350 as a critical residue involved in the N-terminal amine binding site of aminopeptidase N (EC 3.4.11.2): Insights into its mechanism of action","volume":"37","author":"Luciani","year":"1998","journal-title":"Biochemistry"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"17966","DOI":"10.1073\/pnas.1210123109","article-title":"Structural basis for multifunctional roles of mammalian aminopeptidase N","volume":"109","author":"Chen","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1021\/co300055s","article-title":"NGR peptide ligands for targeting CD13\/APN identified through peptide array screening resemble fibronectin sequences","volume":"14","author":"Soudy","year":"2012","journal-title":"ACS Comb. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"47891","DOI":"10.1074\/jbc.M207500200","article-title":"Structure\u2212activity relationships of linear and cyclic peptides containing the NGR tumorhoming motif","volume":"277","author":"Colombo","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"9114","DOI":"10.1074\/jbc.M109.044297","article-title":"Critical Role of Flanking Residues in NGRto-isoDGR transition and CD13\/integrin receptor switching","volume":"285","author":"Curnis","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ejps.2015.01.002","article-title":"In vivo imaging of Aminopeptidase N (CD13) receptors in experimental renal tumors using the novel radiotracer (68)Ga-NOTA-c(NGR)","volume":"69","author":"Enyedi","year":"2015","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"9121","DOI":"10.1007\/s13277-016-4810-y","article-title":"Evaluation of (188)Re-labeled NGR-VEGI protein for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts","volume":"37","author":"Ma","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jpba.2018.01.052","article-title":"177Lu-labeled cyclic Asn-Gly-Arg peptide tagged carbon nanospheres as tumor targeting radio-nanoprobes","volume":"152","author":"Vats","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3938","DOI":"10.1021\/mp500354x","article-title":"MicroPET imaging of CD13 expression using a (64)Cu-labeled dimeric NGR peptide based on sarcophagine cage","volume":"11","author":"Li","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1039\/C7MD00006E","article-title":"68Ga-Chelation and comparative evaluation of N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) conjugated NGR and RGD peptides as tumor targeted molecular imaging probes","volume":"8","author":"Satpati","year":"2017","journal-title":"MedChemComm"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/jlcr.3522","article-title":"99m Tc-labeled NGR-chlorambucil conjugate, 99m Tc-HYNIC-CLB-c(NGR) for targeted chemotherapy and molecular imaging","volume":"60","author":"Vats","year":"2017","journal-title":"J. Labelled Comp. Radiopharm."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.2967\/jnumed.113.123810","article-title":"Promises of cyclotron-produced 44Sc as a diagnostic match for trivalent \u03b2--emitters: In vitro and in vivo study of a 44Sc-DOTA-folate conjugate","volume":"54","author":"Bunka","year":"2013","journal-title":"J. Nucl. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/cmmi.232","article-title":"68Ga-PET: A powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals","volume":"3","author":"Fani","year":"2008","journal-title":"Contrast. Media. Mol. Imaging"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.nucmedbio.2008.04.006","article-title":"Validation of (68)Ge\/(68)Ga generator processing by chemical purification for routine clinical application of (68)Ga-DOTATOC","volume":"35","author":"Asti","year":"2008","journal-title":"Nucl. Med. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4359","DOI":"10.7150\/thno.20586","article-title":"Clinical Translation and First In-Human Use of [44Sc]Sc-PSMA-617 for PET Imaging of Metastasized Castrate-Resistant Prostate Cancer","volume":"7","author":"Eppard","year":"2017","journal-title":"Theranostics"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.1021\/mp500343j","article-title":"44Sc: An Attractive Isotope for Peptide-Based PET Imaging","volume":"11","author":"Hernandez","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4593","DOI":"10.1016\/S0021-9258(20)64364-2","article-title":"Variable O-glycosylation of CD13 (aminopeptidase N)","volume":"266","author":"Gerkis","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Long, Y., Shao, F., Ji, H., Song, X., Lv, X., Xia, X., Liu, Q., Zhang, Y., Zeng, D., and Lan, X. (2022). Evaluation of a CD13 and Integrin \u03b1v\u03b23 Dual-Receptor Targeted Tracer 68Ga-NGR-RGD for Ovarian Tumor Imaging: Comparison With 18F-FDG. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.884554"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1126\/science.2821619","article-title":"New perspectives in cell adhesion: RGD and integrins","volume":"238","author":"Ruoslahti","year":"1987","journal-title":"Science"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1007\/s11307-022-01704-6","article-title":"Heterodimeric RGD-NGR PET Tracer for the Early Detection of Pancreatic Cancer","volume":"24","author":"Sun","year":"2022","journal-title":"Mol. Imaging Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S1535-6108(03)00309-X","article-title":"Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse","volume":"4","author":"Hingorani","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.ccr.2005.04.023","article-title":"Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice","volume":"7","author":"Hingorani","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ydbio.2011.11.010","article-title":"Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas","volume":"362","author":"Kopinke","year":"2012","journal-title":"Dev. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Li, X., Fu, H., Wang, J., Liu, W., Deng, H., Zhao, P., Liao, W., Yang, Y., Wei, H., and Yang, X. (2021). Multimodality labeling of NGR-functionalized hyaluronan for tumor targeting and radiotherapy. Eur. J. Pharm. Sci., 161.","DOI":"10.1016\/j.ejps.2021.105775"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/j.biomaterials.2011.10.009","article-title":"The CD44\/integrins interplay and the significance of receptor binding and re-presentation in the uptake of RGD-functionalized hyaluronic acid","volume":"33","author":"Ouasti","year":"2012","journal-title":"Biomaterials"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jconrel.2016.05.050","article-title":"Synergistic active targeting of dually integrin alphavbeta3\/CD44-targeted nanoparticles to B16F10 tumors located at different sites of mouse bodies","volume":"235","author":"Shi","year":"2016","journal-title":"J. Control Release"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1158\/0008-5472.CAN-06-3567","article-title":"Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth","volume":"67","author":"Laakkonen","year":"2007","journal-title":"Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF02387282","article-title":"Removal of fibroblasts from primary cultures of squamous cell carcinoma of the head and neck","volume":"15","author":"Chen","year":"1993","journal-title":"J. Tissue Cult. Methods"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.canlet.2005.11.051","article-title":"Aminopeptidase N (APN\/CD13) is selectively expressed in vascular endothelial cells and plays multiple roles in angiogenesis","volume":"243","author":"Fukasawa","year":"2006","journal-title":"Cancer Lett."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"150","DOI":"10.2174\/1874471008666150313115423","article-title":"Theranostic radiopharmaceuticals based on gold nanoparticles labeled with (177)Lu and conjugated to peptides","volume":"8","author":"AzorinVega","year":"2015","journal-title":"Curr. Radiopharm."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1166\/jbn.2014.1721","article-title":"Molecular targeting radiotherapy with cyclo-RGDFK(C) peptides conjugated to 177Lu-labeled gold nanoparticles in tumor-bearing mice","volume":"10","year":"2014","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1021\/acsami.6b13738","article-title":"Coadministration of Oligomeric Hyaluronic Acid-Modified Liposomes with Tumor-Penetrating Peptide-iRGD Enhances the Antitumor Efficacy of Doxorubicin against Melanoma","volume":"9","author":"Deng","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Miyagawa, T., Chen, Z.Y., Chang, C.Y., Chen, K.H., Wang, Y.K., Liu, G.S., and Tseng, C.L. (2020). Topical Application of Hyaluronic Acid-RGD Peptide-Coated Gelatin\/Epigallocatechin-3 Gallate (EGCG) Nanoparticles Inhibits Corneal Neovascularization Via Inhibition of VEGF Production. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12050404"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Yang, X., Wang, J., Ding, Z., Lin, Q., Zhuo, L., Liao, W., Zhao, Y., Feng, Y., Chen, Y., and Wei, H. (2020). Dual-radiolabelling of an injectable hyaluronan-tyramine-bisphosphonate hybrid gel for in vitro and in vivo tracking. Carbohydr. Polym., 231.","DOI":"10.1016\/j.carbpol.2019.115652"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"20290","DOI":"10.1021\/am505824d","article-title":"Hyaluronic acid oligosaccharide modified redox-responsive mesoporous silica nanoparticles for targeted drug delivery","volume":"6","author":"Zhao","year":"2014","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Trujillo-Nolasco, R.M., Morales-Avila, E., Ocampo-Garc\u00eda, B.E., Ferro-Flores, G., Gibbens-Bandala, B.V., Escudero-Castellanos, A., and Isaac-Olive, K. (2019). Preparation and in vitro evaluation of radiolabeled HA-PLGA nanoparticles as novel MTX delivery system for local treatment of rheumatoid arthritis. Mater. Sci. Eng. C Mater. Biol. Appl., 103.","DOI":"10.1016\/j.msec.2019.109766"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1021\/mp800024g","article-title":"Anticancer therapeutics: Targeting macromolecules and nanocarriers to hyaluronan or CD44, a hyaluronan receptor","volume":"5","author":"Platt","year":"2008","journal-title":"Mol. Pharm."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1126\/science.279.5349.377","article-title":"Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model","volume":"279","author":"Arap","year":"1998","journal-title":"Science"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/12469","article-title":"Anti-cancer activity of targeted pro-apoptotic peptides","volume":"5","author":"Ellerby","year":"1999","journal-title":"Nat. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1126\/science.1070200","article-title":"Tumor regression by targeted gene delivery to the neovasculature","volume":"296","author":"Hood","year":"2002","journal-title":"Science"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1158\/1078-0432.CCR-05-1147","article-title":"Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-alpha","volume":"12","author":"Sacchi","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1016\/j.molimm.2005.10.009","article-title":"Immunogenic and structural properties of the Asn-Gly-Arg (NGR) tumor neovasculature-homing motif","volume":"43","author":"Curnis","year":"2006","journal-title":"Mol. Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s10456-013-9391-4","article-title":"Non-invasive monitoring of tumor-vessel infarction by retargeted truncated tissue factor tTF-NGR using multi-modal imaging","volume":"17","author":"Persigehl","year":"2014","journal-title":"Angiogenesis"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"6317","DOI":"10.1158\/1078-0432.CCR-05-0389","article-title":"Inhibition of tumor growth by RGD peptide-directed delivery of truncated tissue factor to the tumor vasculature","volume":"11","author":"Kessler","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/157016308783769487","article-title":"Generation of fusion proteins for selective occlusion of tumor vessels","volume":"5","author":"Kessler","year":"2008","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5019","DOI":"10.1182\/blood-2008-04-150318","article-title":"Infarction of tumor vessels by NGR-peptide-directed targeting of tissue factor: Experimental results and first-in-man experience","volume":"113","author":"Bieker","year":"2009","journal-title":"Blood"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"S143","DOI":"10.1016\/S0049-3848(10)70033-5","article-title":"Tissue-factor fusion proteins induce occlusion of tumor vessels","volume":"125","author":"Kessler","year":"2010","journal-title":"Thromb. Res."},{"key":"ref_113","unstructured":"Ma, W., Wang, J., and Yang, W. (2013). Evaluation of direct rhenium-188-labeled NGR-VEGI for radiotherapy of murine breast tumor 4T1. J. Nucl. Med., 54."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1016\/j.apradiso.2009.02.003","article-title":"Preparation and bioevaluation of a 99mTclabeled chlorambucil analog as a tumor targeting agent","volume":"67","author":"Satpati","year":"2009","journal-title":"Appl. Radiat. Isot."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1002\/jlcr.3481","article-title":"Synthesis and preliminary biological evaluation of a 99m Tc-chlorambucil derivative as a potential tumor imaging agent","volume":"60","author":"Lin","year":"2017","journal-title":"J. Label. Comp. Radiopharm."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1002\/bip.22800","article-title":"Dual-drug RGD conjugates provide enhanced cytotoxicity to melanoma and non-small lung cancer cells","volume":"106","author":"Gilad","year":"2016","journal-title":"Biopolymers"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"96","DOI":"10.2174\/1381612825666190329151326","article-title":"A Uniquely Modified DKL-based Peptide Probe for Positron Emission Tomography Imaging","volume":"25","author":"Liu","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00005-014-0268-z","article-title":"D-K6L 9 peptide combination with IL-12 inhibits the recurrence of tumors in mice","volume":"62","author":"Smolarczyk","year":"2014","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_119","first-page":"29","article-title":"Potent anti-tumor activity of tumor vessel-targeted Bax modified for enhanced apoptosis-inducing activity in a cancer xenograft model","volume":"19","author":"Asoh","year":"2008","journal-title":"Ann. Oncol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1021\/nl052405t","article-title":"Peptide-labeled near-infrared quantum dots for imaging tumor vasculature in living subjects","volume":"6","author":"Cai","year":"2006","journal-title":"Nano. Lett."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nprot.2007.478","article-title":"Preparation of peptide-conjugated quantum dots for tumor vasculature-targeted imaging","volume":"3","author":"Cai","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"7676","DOI":"10.1158\/0008-5472.CAN-08-0689","article-title":"Quantitative molecular magnetic resonance imaging of tumor angiogenesis using cNGR-labeled paramagnetic quantum dots","volume":"68","author":"Oostendorp","year":"2008","journal-title":"Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/18\/4459\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:46:54Z","timestamp":1760129214000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/18\/4459"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,7]]},"references-count":122,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["cancers15184459"],"URL":"https:\/\/doi.org\/10.3390\/cancers15184459","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,7]]}}}