title: An NGR-integrated and enediyne-energized apoprotein shows CD13-targeting antitumor activity.
abstract: Targeting and inhibiting angiogenesis is a promising strategy for treatment of cancer. NGR peptide motif is a tumor-homing peptide, which could bind with CD13 expressed on tumor blood vessels. Lidamycin is a highly potent antitumor antibiotic, which is composed of an apoprotein (LDP) and an active enediyne chromophore (AE). Here, an NGR-integrated and enediyne-energized apoprotein composed of cyclic NGR peptide and lidamycin was developed by a two-step procedure. Firstly, we prepared the fusion protein composed of NGR peptide and LDP by recombinant DNA technology. Then, AE was reloaded to the fusion protein to get NGR-LDP-AE. Our experiments showed that NGR-LDP could bind to CD13-expressing HT-1080 cells, whereas the recombinant LDP (rLDP) showed weak binding. NGR-LDP-AE exerted highly potent cytotoxicity to cultured tumor cells in vitro. In vivo antitumor activity was evaluated in murine hepatoma 22 (H22) model and human fibrosarcoma HT-1080 model. At the tolerable dose, NGR-LDP-AE and lidamycin inhibited H22 tumor growth by 94.8 and 66.9%, and the median survival time of the mice was 62 and 37 days, respectively. In the HT-1080 model, NGR-LDP-AE inhibited tumor growth by 88.6%, which was statistically different from that of lidamycin (74.5%). Immunohistochemical study showed that NGR-LDP could bind to tumor blood vessels. Conclusively, these results demonstrate that fusion of LDP with CNGRC peptide delivers AE to tumor blood vessels and improves its antitumor activity.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. zhengyb2001@sina.com
authors.forename: Yan-Bo
authors.initials: YB
authors.lastname: Zheng
authors.forename: Bo-Yang
authors.initials: BY
authors.lastname: Shang
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Yong-Su
authors.initials: YS
authors.lastname: Zhen
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001059:Apoproteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D018826:CD13 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D053281:Enediynes / Q000494:pharmacology*; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy; D056945:Hep G2 Cells; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000617:Aminoglycosides; D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D001059:Apoproteins; D053281:Enediynes; C526428:NGR peptide; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; C058024:C 1027; D018826:CD13 Antigens