The transferrin receptor and the targeted delivery of therapeutic agents against cancer

Abstract

Background: Traditional cancer therapy can be successful in destroying tumors, but can also cause dangerous side effects. Therefore, many targeted therapies are in development. The transferrin receptor (TfR) functions in cellular iron uptake through its interaction with transferrin. This receptor is an attractive molecule for the targeted therapy of cancer since it is upregulated on the surface of many cancer types and is efficiently internalized. This receptor can be targeted in two ways: 1) for the delivery of therapeutic molecules into malignant cells or 2) to block the natural function of the receptor leading directly to cancer cell death.

Scope of review: In the present article we discuss the strategies used to target the TfR for the delivery of therapeutic agents into cancer cells. We provide a summary of the vast types of anti-cancer drugs that have been delivered into cancer cells employing a variety of receptor binding molecules including Tf, anti-TfR antibodies, or TfR-binding peptides alone or in combination with carrier molecules including nanoparticles and viruses.

Major conclusions: Targeting the TfR has been shown to be effective in delivering many different therapeutic agents and causing cytotoxic effects in cancer cells in vitro and in vivo.

General significance: The extensive use of TfR for targeted therapy attests to the versatility of targeting this receptor for therapeutic purposes against malignant cells. More advances in this area are expected to further improve the therapeutic potential of targeting the TfR for cancer therapy leading to an increase in the number of clinical trials of molecules targeting this receptor. This article is part of a Special Issue entitled Transferrins: molecular mechanisms of iron transport and disorders.

Figure 1. Schematic representation of the TfR1 and cellular uptake of iron through the Tf system via receptor-mediated endocytosis

(A) TfR1 is found on the cell surface as a homodimer consisting of two monomers linked by disulfide bridges at cysteines 89 and 98 (■). The TfR contains an intracellular domain, a transmembrane domain, and a large extracellular domain. There is an O-linked glycosylation site at threonine 104 (◆) and three N-linked glycosylation sites on arginine residues 251, 317 and 727 (●). The extracellular domain of the TfR consists of three subdomains: apical (A), helical (H) and protease-like domain (P). (B) Each receptor monomer binds one Tf molecule that consists of two lobes (the N and C lobes). Each lobe of Tf binds one iron molecule and thus two diferric Tf molecules bind to the receptor with high affinity. (C) Endocytosis of the diferric Tf/TfR complex occurs via clathrin-coated pits and the complex is delivered into endosomes. Protons are pumped into the endosome resulting in a decrease in pH that stimulates a conformational change in Tf and its subsequent release of iron. The iron is then transported out of the endosome into the cytosol by the DMT1. Apotransferrin remains bound to the TfR while in the endosome and is only released once the complex reaches the cell surface. Figure is reprinted from [1] with permission from Elsevier.

Figure 2. Internalization of Tf by TfR1

Side and top views of the TfR alone (1) or bound to Tf (2). Numbers in the figure correspond to the numbers and explanations listed on the right side of the figure.

Figure 3. Strategies for targeting therapeutic agents via TfR to malignant cells

Targeting can be mediated by its natural ligand Tf, a specific peptide, monoclonal antibodies or single chain antibody fragments specific for the extracellular domain of the TfR. The therapeutic agent can be delivered conjugated to the compound or enclosed in a carrier. Targeting the TfR has been an option to deliver chemotherapeutic drugs, therapeutic proteins, genes in vectors, oligonucleotides or radionucleides.

Figure 4. Carriers for direct targeting of therapeutic agents via TfR to malignant cells

The various carriers can be targeted to the TfR using antibodies or their fragments, the natural ligand, or specific peptides. These carries can deliver a broad spectrum of therapeutic agents, including chemotherapeutic drugs, toxic proteins, or nucleic acids into targeted cells.

Figure 5. Schematic drawing of Polycefin molecule, a customized drug prepared to treat malignant tissue

Polymalic acid-trileucine copolymer is the platform carrying the other covalently bound functional groups and trileucine that mediates pH-dependent delivery through endodomal membrane into recipient cell cytoplasm. Functional (optional) groups: multiple same or different antisense oligos or siRNA (arrows, cleavage from the platform by action of glutathione in the cytoplasm), multiple same or different chemotherapeutic drugs (linked through glutathione or pH-responsive spacers for cleavage from the platform), same or different mAb or other proteins/peptides for specific tumor and/or recipient cell targeting, same or different tracking fluorescent dyes, protecting PEG (dispensible depending on the composition of the cargo).