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.