Vol. 54, Issue 4, 561-588, December 2002

Targeted Drug Delivery via the Transferrin Receptor-Mediated Endocytosis Pathway

Zhong Ming Qian, Hongyan Li, Hongzhe Sun and Kwokping Ho

Laboratory of Iron Metabolism, Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Kowloon, Hong Kong (Z.M.Q., H.L., K.H.); and Department of Chemistry, University of Hong Kong, Hong Kong (H.S.)

I. Introduction
II. Transferrins
    A. Occurrence and Biological Function
    B. General Structural Features
III. The Transferrin Receptors
    A. Structure of the Transferrin Receptor 1
    B. Regulation of Transferrin Receptor 1 Expression
    C. Association of Transferrin Receptor 1 with the Hemochromatosis Protein HFE
    D. Second Transferrin-Binding Protein: Transferrin Receptor 2
IV. Transferrin Receptor-Mediated Iron Uptake
    A. Transferrin-Bound Iron Uptake by Cells
    B. Iron Transport Across the Blood-Brain Barrier
V. Transferrin As a Metallodrug Mediator
    A. Complexation of Metal-Based Drugs with Transferrin
    B. Structural Studies of the Complexes of Therapeutic Metal Ions with Transferrin
    C. Cellular Uptake of Therapeutic Metal Ions via Transferrin Receptor-Mediated Endocytosis
        1. Ga³⁺ and In³⁺.
        2. Bi³⁺, Ti³⁺ and Ru³⁺.
VI. Transferrin Conjugates in Site-Specific Drug Delivery
    A. General Methods of Preparation of the Conjugates
        1. Chemical Linkage.
        2. Protein Engineering.
    B. Cellular Uptake and Efficacy of the Conjugates
        1. Transferrin-Doxorubicin.
        2. Transferrin-CRM107.
        3. Others.
VII. Transferrin in Gene Delivery
    A. Transferrin-Polylysine-DNA Conjugates
        1. General Methods of Preparation.
        2. Uptake of DNA Particles.
        3. Problems Associated with Transferrin-Polylysine-Based Gene Delivery.
    B. Transferrin-Lipoplexes
    C. Other Vectors Using Transferrin as a Targeting Ligand
VIII. Transferrin and Transferrin Receptor in Drug and Gene Delivery across the Blood-Brain Barrier
    A. OX26 As an Efficient Brain Drug Transport Vehicle
    B. Preparation of OX26 Drug Conjugates
    C. Delivery of Therapeutics to the Brain
IX. Summary
Acknowledgments
References

The membrane transferrin receptor-mediated endocytosis or internalization of the complex of transferrin bound iron and the transferrin receptor is the major route of cellular iron uptake. This efficient cellular uptake pathway has been exploited for the site-specific delivery not only of anticancer drugs and proteins, but also of therapeutic genes into proliferating malignant cells that overexpress the transferrin receptors. This is achieved either chemically by conjugation of transferrin with therapeutic drugs, proteins, or genetically by infusion of therapeutic peptides or proteins into the structure of transferrin. The resulting conjugates significantly improve the cytotoxicity and selectivity of the drugs. The coupling of DNA to transferrin via a polycation or liposome serves as a potential alternative to viral vector for gene therapy. Moreover, the OX26 monoclonal antibody against the rat transferrin receptor offers great promise in the delivery of therapeutic agents across the blood-brain barrier to the brain.