Skip to main content
SpringerLink
Log in

Modularly designed peptide-based nanomedicine inhibits angiogenesis to enhance chemotherapy for post-surgical recurrence of esophageal squamous cell carcinomas

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

An Erratum to this article was published on 13 April 2023

This article has been updated

Abstract

Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas (ESCC), and postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis. Since surgical resection promotes the local angiogenesis at the tumor site, further exacerbating the proliferation and invasion of residual tumor cells, it is urgent to inhibit angiogenesis after surgery. Here, a functional peptide-based nanomedicine was obtained from peptide—drug conjugates, which are composed of a hydrophilic targeting motif (vascular endothelial growth factor family and their receptors (VEGFR) targeting peptide for anti-angiogenesis), and an ester-linked hydrophobic oridonin (ORI). The nanomedicine exhibits esterase-catalyzed disassembly and drug release, and significantly enhanced the anti-tumor efficacy of chemotherapeutics in a postoperative tumor recurrence model through synergistic anti-angiogenic strategies. This study provides an integrated solution for anti-angiogenesis-augmented chemotherapy and demonstrates the encouraging potential for postoperative treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Change history

References

  1. Kamangar, F.; Dores, G. M.; Anderson, W. F. Patterns of cancer incidence, mortality, and prevalence across five continents: Defining priorities to reduce cancer disparities in different geographic regions of the world. J. Clin. Oncol. 2006, 24, 2137–2150.

    Article  Google Scholar 

  2. Ohashi, S.; Miyamoto, S.; Kikuchi, O.; Goto, T.; Amanuma, Y.; Muto, M. Recent advances from basic and clinical studies of esophageal squamous cell carcinoma. Gastroenterology 2015, 149, 1700–1715.

    Article  Google Scholar 

  3. Abnet, C. C.; Arnold, M.; Wei, W. Q. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology 2018, 154, 360–373.

    Article  Google Scholar 

  4. Poon, R. T. P.; Fan, S. T.; Wong, J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann. Surg. 2000, 232, 10–24.

    Article  Google Scholar 

  5. Sasaki, K.; Matsuda, M.; Ohkura, Y.; Kawamura, Y.; Hashimoto, M.; Ikeda, K.; Kumada, H.; Watanabe, G. Minimum resection margin should be based on tumor size in hepatectomy for hepatocellular carcinoma in hepatoviral infection patients. Hepatol. Res. 2013, 43, 1295–1303.

    Article  Google Scholar 

  6. Zhang, Z. Y.; Kuang, G. Z.; Zong, S.; Liu, S.; Xiao, H. H.; Chen, X. S.; Zhou, D. F.; Huang, Y. B. Sandwich-like fibers/sponge composite combining chemotherapy and hemostasis for efficient postoperative prevention of tumor recurrence and metastasis. Adv. Mater. 2018, 30, 1803217.

    Article  Google Scholar 

  7. Ceelen, W.; Pattyn, P.; Mareel, M. Surgery, wound healing, and metastasis: Recent insights and clinical implications. Crit. Rev. Oncol. Hematol. 2014, 89, 16–26.

    Article  Google Scholar 

  8. Goldstein, M. R.; Mascitelli, L. Surgery and cancer promotion: Are we trading beauty for cancer? QJM An Int. J. Med. 2011, 104, 811–815.

    Article  CAS  Google Scholar 

  9. Maniwa, Y.; Okada, M.; Ishii, N.; Kiyooka, K. Vascular endothelial growth factor increased by pulmonary surgery accelerates the growth of micrometastases in metastatic lung cancer. Chest 1998, 114, 1668–1675.

    Article  CAS  Google Scholar 

  10. Heidemann, J.; Binion, D. G.; Domschke, W.; Kucharzik, T. Antiangiogenic therapy in human gastrointestinal malignancies. Gut 2006, 55, 1497–1511.

    Article  CAS  Google Scholar 

  11. Jayson, G. C.; Kerbel, R.; Ellis, L. M.; Harris, A. L. Antiangiogenic therapy in oncology: Current status and future directions. Lancet 2016, 388, 518–529.

    Article  CAS  Google Scholar 

  12. Jain, R. K. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 2005, 307, 58–62.

    Article  CAS  Google Scholar 

  13. Ferrara, N.; Kerbel, R. S. Angiogenesis as a therapeutic target. Nature 2005, 438, 967–974.

    Article  CAS  Google Scholar 

  14. Kerbel, R. S. Tumor angiogenesis. N. Engl. J. Med. 2008, 358, 2039–2049.

    Article  CAS  Google Scholar 

  15. Bailey, C. E.; Parikh, A. A. Assessment of the risk of antiangiogenic agents before and after surgery. Cancer Treat. Rev. 2018, 68, 38–46.

    Article  CAS  Google Scholar 

  16. Ferrara, N.; Gerber, H. P.; LeCouter, J. The biology of VEGF and its receptors. Nat. Med. 2003, 9, 669–676.

    Article  CAS  Google Scholar 

  17. Olsson, A. K.; Dimberg, A.; Kreuger, J.; Claesson-Welsh, L. VEGF receptor signalling - in control of vascular function. Nat. Rev. Mol. Cell Biol. 2006, 7, 359–371.

    Article  CAS  Google Scholar 

  18. Min, H.; Wang, J.; Qi, Y. Q.; Zhang, Y. L.; Han, X. X.; Xu, Y.; Xu, J. C.; Li, Y.; Chen, L.; Cheng, K. M. et al. Biomimetic metal-organic framework nanoparticles for cooperative combination of antiangiogenesis and photodynamic therapy for enhanced efficacy. Adv. Mater. 2019, 31, 1808200.

    Article  Google Scholar 

  19. Qin, S.; Li, A. P.; Yi, M.; Yu, S. N.; Zhang, M. S.; Wu, K. M. Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J. Hematol. Oncol. 2019, 12, 27.

    Article  Google Scholar 

  20. Sadremomtaz, A.; Mansouri, K.; Alemzadeh, G.; Safa, M.; Rastaghi, A. E.; Asghari, S. M. Dual blockade of VEGFR1 and VEGFR2 by a novel peptide abrogates VEGF-driven angiogenesis, tumor growth, and metastasis through PI3K/AKT and MAPK/ERK1/2 pathway. Biochim. Biophys. Acta Gen Subj. 2018, 1862, 2688–2700.

    Article  CAS  Google Scholar 

  21. Fallah, A.; Sadeghinia, A.; Kahroba, H.; Samadi, A.; Heidari, H. R.; Bradaran, B.; Zeinali, S.; Molavi, O. Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependent diseases. Biomed. Pharmacother. 2019, 110, 775–785.

    Article  CAS  Google Scholar 

  22. Zanjanchi, P.; Asghari, S. M.; Mohabatkar, H.; Shourian, M.; Ardestani, M. S. Conjugation of VEGFR1/R2-targeting peptide with gold nanoparticles to enhance antiangiogenic and antitumoral activity. J. Nanobiotechnol. 2022, 20, 7.

    Article  CAS  Google Scholar 

  23. Moserle, L.; Jiménez-Valerio, G.; Casanovas, O. Antiangiogenic therapies: Going beyond their limits. Cancer Discov. 2014, 4, 31–41.

    Article  CAS  Google Scholar 

  24. Zubair, H.; Khan, M. A.; Anand, S.; Srivastava, S. K.; Singh, S.; Singh, A. P. Modulation of the tumor microenvironment by natural agents: Implications for cancer prevention and therapy. Semin. Cancer Biol. 2022, 80, 237–255.

    Article  CAS  Google Scholar 

  25. Deng, L. J.; Qi, M.; Li, N.; Lei, Y. H.; Zhang, D. M.; Chen, J. X. Natural products and their derivatives: Promising modulators of tumor immunotherapy. J. Leukoc. Biol. 2020, 108, 493–508.

    Article  CAS  Google Scholar 

  26. Azab, A.; Nassar, A.; Azab, A. N. Anti-inflammatory activity of natural products. Molecules 2016, 21, 1321.

    Article  Google Scholar 

  27. Efferth, T. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin. Cancer Biol. 2017, 46, 65–83.

    Article  CAS  Google Scholar 

  28. Ma, N.; Zhang, Z. Y.; Liao, F. L.; Jiang, T. L.; Tu, Y. Y. The birth of artemisinin. Pharmacol. Ther. 2020, 216, 107658.

    Article  CAS  Google Scholar 

  29. Ding, Y.; Ding, C. Y.; Ye, N.; Liu, Z. Q.; Wold, E. A.; Chen, H. Y.; Wild, C.; Shen, Q.; Zhou, J. Discovery and development of natural product oridonin-inspired anticancer agents. Eur. J. Med. Chem. 2016, 122, 102–117.

    Article  CAS  Google Scholar 

  30. Liu, X.; Xu, J. M.; Zhou, J.; Shen, Q. Oridonin and its derivatives for cancer treatment and overcoming therapeutic resistance. Genes Dis. 2021, 8, 448–462.

    Article  CAS  Google Scholar 

  31. Wang, Y.; Cheetham, A. G.; Angacian, G.; Su, H.; Xie, L. S.; Cui, H. G. Peptide-drug conjugates as effective prodrug strategies for targeted delivery. Adv. Drug Deliv. Rev. 2017, 110–111, 112–126.

    Article  Google Scholar 

  32. Cooper, B. M.; Iegre, J.; O’Donovan, D.; Halvarsson, M. Ö.; Spring, D. R. Peptides as a platform for targeted therapeutics for cancer: Peptide-drug conjugates (PDCs). Chem. Soc. Rev. 2021, 50, 1480–1494.

    Article  CAS  Google Scholar 

  33. Ji, T. J.; Ding, Y. P.; Zhao, Y.; Wang, J.; Qin, H.; Liu, X. M.; Lang, J. Y.; Zhao, R. F.; Zhang, Y. L.; Shi, J. et al. Peptide assembly integration of fibroblast-targeting and cell-penetration features for enhanced antitumor drug delivery. Adv. Mater. 2015, 27, 1865–1873.

    Article  CAS  Google Scholar 

  34. Han, X. X.; Cheng, K. M.; Xu, Y.; Wang, Y. Z.; Min, H.; Zhang, Y. L.; Zhao, X.; Zhao, R. F.; Anderson, G. J.; Ren, L. et al. Modularly designed peptide nanoprodrug augments antitumor immunity of PD-L1 checkpoint blockade by targeting indoleamine 2, 3-dioxygenase. J. Am. Chem. Soc. 2020, 142, 2490–2496.

    Article  CAS  Google Scholar 

  35. Zhang, H. J.; He, Q. Q.; Wang, J. J.; Wang, Y. P.; Xuan, X. Y.; Sui, M.; Zhang, Z. Z.; Hou, L. Biomimetic micelles to accurately regulate the inflammatory microenvironment for glomerulonephritis treatment. Pharmacol. Res. 2022, 181, 106263.

    Article  CAS  Google Scholar 

  36. Zhou, G. B.; Kang, H.; Wang, L.; Gao, L.; Liu, P.; Xie, J.; Zhang, F. X.; Weng, X. Q.; Shen, Z. X.; Chen, J. et al. Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. Blood 2007, 109, 3441–3450.

    Article  CAS  Google Scholar 

  37. Kang, N.; Zhang, J. H.; Qiu, F.; Tashiro, S. I.; Onodera, S.; Ikejima, T. Inhibition of EGFR signaling augments oridonin-induced apoptosis in human laryngeal cancer cells via enhancing oxidative stress coincident with activation of both the intrinsic and extrinsic apoptotic pathways. Cancer Lett. 2010, 294, 147–158.

    Article  CAS  Google Scholar 

  38. Jun, J. H.; Oh, J. E.; Shim, J. K.; Kwak, Y. L.; Cho, J. S. Effects of bisphenol A on the proliferation, migration, and tumor growth of colon cancer cells: In vitro and in vivo evaluation with mechanistic insights related to ERK and 5-HT3. Food Chem. Toxicol. 2021, 158, 112662.

    Article  CAS  Google Scholar 

  39. Blanco, E.; Shen, H. F.; Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 2015, 33, 941–951.

    Article  CAS  Google Scholar 

  40. Zhang, C.; Qu, G. W.; Sun, Y. J.; Wu, X. L.; Yao, Z.; Guo, Q. L.; Ding, Q. L.; Yuan, S. T.; Shen, Z. L.; Ping, Q. N. et al. Pharmacokinetics, biodistribution, efficacy and safety of N-octyl-O-sulfate chitosan micelles loaded with paclitaxel. Biomaterials 2008, 29, 1233–1241.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 32000998 and U2004123), the Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology (No. 2022HYTP046), and the China Postdoctoral Science Foundation (Nos. 2019TQ0285, 2019M662513, 2021TQ0298, and 2022TQ0296). The authors thank Lijing Zhang and Prof. Fazhan Wang (the First Affiliated Hospital, Zhengzhou University) for assistance with the in vivo fluorescence imaging. The authors would like to acknowledge the use of resources at Center of Advanced Analysis&Gene Sequencing, Zhengzhou University and National Center for Nanoscience and Technology, and acknowledge professor Bing Jiang and Ying Zhao for helpful discussions.

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China

    Yingqiu Qi, Jinxiu Shen, Chen Liu, Anni Du, Mengdie Chen, Xiaocao Meng, Hui Wang, Saiyang Zhang, Lirong Zhang & Yale Yue

  2. Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, China

    Chen Liu, Anni Du, Xiaocao Meng & Huan Min

  3. State Key Laboratory of Esophageal Cancer Prevention &Treatment, Zhengzhou, 450001, China

    Lirong Zhang

  4. College of Chemistry, Institute of Green Catalysis, Zhengzhou University, Henan, 450001, China

    Zhongjun Li & Yike Li

Authors
  1. Yingqiu Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinxiu Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anni Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mengdie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaocao Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Saiyang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lirong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhongjun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yike Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yale Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Huan Min
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yike Li, Yale Yue or Huan Min.

Electronic Supplementary Material

12274_2023_5396_MOESM1_ESM.pdf

Modularly designed peptide-based nanomedicine inhibits angiogenesis to enhance chemotherapy for post-surgical recurrence of esophageal squamous cell carcinomas

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qi, Y., Shen, J., Liu, C. et al. Modularly designed peptide-based nanomedicine inhibits angiogenesis to enhance chemotherapy for post-surgical recurrence of esophageal squamous cell carcinomas. Nano Res. 16, 7347–7354 (2023). https://doi.org/10.1007/s12274-023-5396-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-023-5396-5

Keywords

Search

Navigation