The Journal of Membrane Biology

, Volume 247, Issue 4, pp 291–307 | Cite as

Transferrin Receptor-Mediated Endocytosis: A Useful Target for Cancer Therapy

  • Stephanie Tortorella
  • Tom C. Karagiannis
Topical Review


Current cancer management strategies fail to adequately treat malignancies with multivariable dose-restricting factors such as systemic toxicity and multi-drug resistance limiting therapeutic benefit, quality of life and complete long-term remission rates. The targeted delivery of a therapeutic compound aims to enhance its circulation and cellular uptake, decrease systemic toxicity and improve therapeutic benefit with disease specificity. The transferrin peptide, its receptor and their biological significance, has been widely characterised and vastly relevant when applied to targeting strategies. Utilising knowledge about the physiological function of the transferrin–transferrin receptor complex and the efficiency of its receptor-mediated endocytosis provides rationale to continue the development of transferrin-targeted anticancer modalities. Furthermore, multiple studies report an upregulation in expression of the transferrin receptor on metastatic and drug resistant tumours, highlighting its selectivity to cancer. Due to the increased expression of the transferrin receptor in brain glioma, the successful delivery of anticancer compounds to the tumour site and the ability to cross the blood brain barrier has shown to be an important discovery. Its significance in the development of cancer-specific therapies is shown to be important by direct conjugation and immunotoxin studies which use transferrin and anti-transferrin receptor antibodies as the targeting moiety. Such conjugates have demonstrated enhanced cellular uptake via transferrin-mediated mechanisms and increased selective cytotoxicity in a number of cancer cell lines and tumour xenograft animal models. In addition, incubation of chemotherapy-insensitive cancer cells with transferrin-targeted conjugates in vitro has resulted in a reversal of their drug resistance. Transferrin immunotoxins have also shown similar promise, with a diphtheria toxin mutant covalently bound to transferrin (Tf-CRM107) currently involved in human clinical trials for the treatment of glioblastoma. Despite this, the inability to translate preliminary research into a clinical setting has compelled research into novel targeting strategies including the use of nanoparticulate theory in the design of drug delivery systems. The main objective of this review is to evaluate the importance of the transferrin–transferrin receptor complex as a target for cancer therapy through extensive knowledge of both the physiological and pathological interactions between the complex and different cell types. In addition, this review serves as a summary to date of direct conjugation and immunotoxin studies, with an emphasis on transferrin as an important targeting moiety in the directed delivery of anticancer therapeutic compounds.


Transferrin Transferrin receptor Immunoconjugate Immunotargeting Cancer therapy 



The support of the Australian Institute of Nuclear Science and Engineering (AINSE) is acknowledged. TCK was the recipient of AINSE awards. TCK is supported by an Australian Research Council Future Fellowship and the Epigenomic Medicine Laboratory is supported by McCord Research. Supported in part by the Victorian Government’s Operational Infrastructure Support Program.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Epigenomic Medicine, Baker IDI Heart and Diabetes InstituteThe Alfred Medical Research and Education PrecinctMelbourneAustralia
  2. 2.Department of Agriculture and Food SystemsThe University of MelbourneParkvilleAustralia
  3. 3.Department of Chemical and Biomolecular EngineeringThe University of MelbourneParkvilleAustralia
  4. 4.Department of PathologyThe University of MelbourneParkvilleAustralia

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