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

Abstract

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.

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

“…207 It is reported that the mRNA level of TfR1 is upregulated in human HCC but that of TfR2 is downregulated. 208 Consistent conclusion has been drawn in a similar study on a rat model of HCC.…”

Nanocarrier drugs in the treatment of brain tumors

“…During RMT, macromolecules move across the endothelial cells into the brain, due to the expression of several peptidespecific receptors, e.g. neonatal Fc receptor, [55] lowdensity lipoprotein receptor-related protein receptor, transferrin receptor, [56] lactoferrin receptor, [57] and insulin receptor.…”

Transferrin-functionalized nanographene oxide for delivery of platinum complexes to enhance cancer-cell selectivity and apoptosis-inducing efficacy

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