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Published on: December 29, 2012
An NGR-integrated and enediyne-energized apoprotein shows CD13-targeting antitumor activity
Yan-Bo Zheng1, Bo-Yang Shang, Yi Li
1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. zhengyb2001@sina.com
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.
Insights
Researchers developed a novel NGR-integrated apoprotein (NGR-LDP-AE) by fusing a tumor-homing peptide (NGR) with lidamycin. This new conjugate significantly enhances antitumor activity and targets tumor blood vessels, offering a promising cancer treatment strategy.
Area of Science:
- Biotechnology
- Pharmacology
- Oncology
Background:
- Targeting tumor angiogenesis is a key cancer treatment strategy.
- The NGR peptide motif targets CD13 on tumor vasculature.
- Lidamycin is a potent antitumor antibiotic with an apoprotein (LDP) and enediyne chromophore (AE).
Purpose of the Study:
- To develop an NGR-integrated, enediyne-energized apoprotein for enhanced cancer therapy.
- To evaluate the tumor-homing and cytotoxic properties of the novel conjugate.
Main Methods:
- Constructed a fusion protein (NGR-LDP) using recombinant DNA technology.
- Reconstituted the fusion protein with the enediyne chromophore (AE) to create NGR-LDP-AE.
- Assessed binding affinity to CD13-expressing cells and in vitro cytotoxicity.
- Evaluated in vivo antitumor efficacy in murine hepatoma (H22) and human fibrosarcoma (HT-1080) models.
Main Results:
- NGR-LDP demonstrated specific binding to CD13-expressing cells, unlike rLDP.
- NGR-LDP-AE exhibited potent in vitro cytotoxicity against tumor cells.
- In vivo, NGR-LDP-AE significantly inhibited H22 tumor growth (94.8%) and prolonged survival (62 days) compared to lidamycin.
- NGR-LDP-AE also showed superior tumor growth inhibition in the HT-1080 model (88.6%) versus lidamycin (74.5%).
Conclusions:
- Fusion of LDP with the CNGRC peptide facilitates targeted delivery of AE to tumor vasculature.
- The NGR-LDP-AE conjugate demonstrates improved antitumor activity and targeted delivery, highlighting its therapeutic potential.
