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

https://doi.org/10.1016/j.bbagen.2011.07.016Get rights and content

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.

Highlights

► Summary of delivery strategies targeting the transferrin receptor. ► Summary of complexes with targeting moiety directly conjugated to the therapeutic. ► Summary of approaches where targeted carriers are loaded with the therapeutic.

Introduction

The receptor for transferrin (Tf), referred to as TfR1 (also known as CD71), is ubiquitously expressed at low levels in most normal human tissues. A second member of the TfR family is TfR2, a protein that is homologous to TfR1 but whose expression is largely restricted to hepatocytes [1]. Serving as the main port of entry for iron bound Tf into cells, TfR1 is a type-II receptor that resides on the cell membrane and cycles into acidic endosomes into the cell in a clathrin/dynamin dependent manner [1], [2], [3], [4]. Iron is delivered into the cell and TfR1 is recycled back to the cell surface (Fig. 1, Fig. 2) [1], [5], [6]. Despite its ubiquitous expression, TfR1 is expressed on malignant cells at levels several fold higher than those on normal cells and its expression can be correlated with tumor stage or cancer progression [7], [8], [9], [10], [11], [12]. This high expression of the receptor on malignant cells, its ability to internalize, and the necessity of iron for cancer cell proliferation make this receptor a widely accessible portal for the delivery of drugs into malignant cells and thus, an attractive target for cancer therapy (Fig. 3).

Targeting of the TfR1 has occurred through the use of a variety of methods including strategies that utilize mostly its natural ligand Tf or monoclonal antibodies or their fragments (Fig. 3). However, short peptides have also been used as targeting moieties. In general, cytotoxicity of Tf conjugates can be blocked by native Tf. Therefore, high levels of circulating free Tf in the blood may interfere with the effects of these Tf conjugates leading to decreased therapeutic efficacy. As Tf conjugates have the potential to interact with both TfR1 and TfR2 (which is highly expressed in the liver), they may be particularly toxic in certain cases to liver cells in addition to the targeted malignant cells. Targeting the TfR1 through the use of monoclonal antibodies may help to circumvent this potential concern.

There are two ways to effectively exploit the TfR for cancer therapeutic purposes. One is through the use of molecules that are capable of antagonizing the normal function of the receptor. Work from our group and others have shown promising results for the treatment of a variety of cancers via cytotoxicity induced by the direct inhibition of TfR1 function by monoclonal antibodies. Among these are the monoclonal antibodies 42/6 [13], A24 [14], and ch128.1Av (also known as anti-hTfR1 IgG3-Av) [15], [16]. The second way of targeting the TfR is for the delivery of therapeutic agents into malignant cells. This allows the delivery of anticancer drugs to neoplastic cells by the association of the drugs to molecules with high affinity and specificity for the receptor. Even though the receptor is normally constitutively recycled, its use as a delivery vehicle is possible and has been clearly shown as discussed below. Delivery of therapeutic agents into the cytoplasm of cancer cells may be due to the alteration of the intracellular trafficking of the receptor, which can be caused by the targeting molecule or through the delivered cargo. Additionally, agents that increase vesicle pH can be used to ensure that the cargo is not degraded in low pH vesicles during intracellular trafficking. These agents can be part of the cargo itself or as additional agents that are used in combination with the targeted therapy. This review is focused on the specific targeting of TfR1 by antibodies or other ligands and how these vehicles can be employed for the delivery of a broad repertoire of anti-cancer agents (Fig. 3).

Section snippets

Delivery strategies

The literature on the use of TfR1 as a target for the delivery of small molecules, proteins, nucleic acids, and even nanoparticles and viruses into many types of malignant cells continues to grow. Delivery can be achieved by the direct linkage of the therapeutic to the targeting moiety or by loading of the therapeutic into carriers such as nanoparticles linked to the targeting molecule. A wide variety of therapeutic agents have been used for TfR-targeted cancer therapy (Fig. 3). They include

Tf–Doxorubicin/Adriamycin® conjugates

Doxorubicin or Adriamycin® (ADR), is an anthracycline, antineoplastic drug that has the ability to intercalate into DNA, generate free radicals, and inhibit certain enzymes such as topoisomerase II [22]. ADR is a widely used chemotherapy in treating many forms of cancer, but ultimately exhibits severe side effects, including cardiotoxicity, myelosuppression, nephrotoxicity, extravasation, and bone marrow depression due to quick diffusion throughout the body [22]. To circumvent the adverse

Polymeric micelles

Polymeric micelles are nanoscopic structures characterized by a core-shell structure and are the product of self-assembly of amphiphilic copolymers in aqueous media. These nano-structures tend to be smaller than 100 nm and have the capacity to hold hydrophobic drugs at their cores [124], [125]. The shell of the micelles is formed by the hydrophilic portion of the amphiphilic co-polymers, which favors the dispersion of the system in aqueous media [126] and the increase of circulation time in vivo

Conclusions

In summary, the TfR displays multiple desirable characteristics for use in the targeting of cytotoxic agents to cancer tissue. Although conventional chemotherapeutics are often successful in destroying cancer cells, their non-targeted nature renders them also toxic to normal cells, which can lead to the development of dangerous and often life-threatening side effects. Although the TfR has been explored for some time as a targeting molecule against a variety of malignancies, improvements in the

Acknowledgements

This work was supported in part by the NIH/NCI grants R01CA136841, R01CA107023, R01CA123495, R01CA57152, U01CA151815, K01CA138559, the Howard Hughes Medical Institute Gilliam Fellowship, and the Whitcome Fellowship of the Molecular Biology Institute at UCLA. GH and DAC are partially supported by the National Council for Scientific and Technological Research (CONICET), Argentina. EB is supported by the PFDT fellowship from the National Agency for Promotion of Science and Technology (

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