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

  • Topical Review
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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.

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References

  • Aisen P, Leibman A, Zweier J (1978) Stoichiometric and site characteristics of the binding of iron to human transferrin. J Biol Chem 253(6):1930–1937

    CAS  PubMed  Google Scholar 

  • Batra JK, Jinno Y, Chaudhary VK, Kondo T, Willingham MC, FitzGerald DJ, Pastan I (1989) Antitumor activity in mice of an immunotoxin made with anti-transferrin receptor and a recombinant form of Pseudomonas exotoxin. Proc Natl Acad Sci USA 86(21):8545–8549

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Batra JK, Fitzgerald DJ, Chaudhary VK, Pastan I (1991) Single-chain immunotoxins directed at the human transferrin receptor containing Pseudomonas exotoxin A or diphtheria toxin: anti-TFR(Fv)-PE40 and DT388-anti-TFR(Fv). Mol Cell Biol 11(4):2200–2205

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bejaoui N, Page M, Noel C (1991) Cytotoxicity of transferrin–daunorubicin conjugates on small cell carcinoma of the lung (SCCL) cell line NCI-H69. Anticancer Res 11(6):2211–2213

    CAS  PubMed  Google Scholar 

  • Berczi A, Barabas K, Sizensky JA, Faulk WP (1993) Adriamycin conjugates of human transferrin bind transferrin receptors and kill K562 and HL60 cells. Arch Biochem Biophys 300(1):356–363

    Article  CAS  PubMed  Google Scholar 

  • Bergamaschi G, Cazzola M, Dezza L, Savino E, Consonni L, Lappi D (1988) Killing of K562 cells with conjugates between human transferrin and a ribosome-inactivating protein (SO-6). Br J Haematol 68(3):379–384

    Article  CAS  PubMed  Google Scholar 

  • Bleil JD, Bretscher MS (1982) Transferrin receptor and its recycling in HeLa cells. EMBO J 1(3):351–355

    PubMed Central  CAS  PubMed  Google Scholar 

  • Brandsma M, Jevnikar A, Ma S (2011) Recombinant human transferrin: beyond iron binding and transport. Biotechnol Adv 29(2):230–238

    Article  CAS  PubMed  Google Scholar 

  • Bridges KR, Cudkowicz A (1984) Effect of iron chelators on the transferrin receptor in K562 cells. J Biol Chem 259(21):12970–12977

    CAS  PubMed  Google Scholar 

  • Brigger I, Dubernet C, Couvreur P (2002) Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev 54(5):631–651

    Article  CAS  PubMed  Google Scholar 

  • Burdo JR, Antonetti DA, Wolpert EB, Connor JR (2003) Mechanisms and regulation of transferrin and iron transport in a model blood–brain barrier system. Neuroscience 121(4):883–890

    Article  CAS  PubMed  Google Scholar 

  • Calzolari A, Deaglio S, Sposi N, Petrucci E, Morsilli O, Gabbianelli M, Malavasi F, Peschle C, Testa U (2004) Transferrin receptor 2 protein is not expressed in normal erythroid cells. Biochem J 381(3):629–634

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Calzolari A, Oliviero I, Deaglio S, Mariani G, Biffoni M, Sposi N, Malavasi F, Peschle C, Testa U (2007) Transferrin receptor 2 is frequently expressed in human cancer cell lines. Blood Cells Mol Dis 39(1):82–91

    Article  CAS  PubMed  Google Scholar 

  • Calzolari A, Larocca L, Deaglio S, Finisguerra V, Boe A, Raggi C, Ricci Vitani L, Pierconti F, Malavasi F, De Maria R, Testa U, Pallini R (2010) Transferrin receptor 2 is frequently and highly expressed in glioblastomas. Transl Oncol 3(2):123–134

    Article  PubMed Central  PubMed  Google Scholar 

  • Carvalho FS, Burgeiro A, Garcia R, Moreno AJ, Carvalho RA, Oliveira PJ (2013) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med Res Rev. doi:10.1002/med.21280

    PubMed  Google Scholar 

  • Chang J, Paillard A, Passirani C, Morille M, Benoit J-P, Betbeder D, Garcion E (2012) Transferrin adsorption onto PLGA nanoparticles governs their interaction with biological systems from blood circulation to brain cancer cells. Pharm Res 29(6):1495–1505

    Article  CAS  PubMed  Google Scholar 

  • Chiu S-J, Liu S, Perrotti D, Marcucci G, Lee R (2006) Efficient delivery of a Bcl-2-specific antisense oligodeoxyribonucleotide (G3139) via transferrin receptor-targeted liposomes. J Control Release 112(2):199–207

    Article  CAS  PubMed  Google Scholar 

  • Choudhary S, Mathew M, Verma RS (2011) Therapeutic potential of anticancer immunotoxins. Drug Discov Today 16(11–12):495–503

    Article  CAS  PubMed  Google Scholar 

  • Ciechanover A, Schwartz AL, Dautry-Varsat A, Lodish HF (1983) Kinetics of internalization and recycling of transferrin and the transferrin receptor in a human hepatoma cell line. Effect of lysosomotropic agents. J Biol Chem 258(16):9681–9689

    CAS  PubMed  Google Scholar 

  • Cimini A, Mei S, Benedetti E, Laurenti G, Koutris I, Cinque B, Cifone MG, Galzio R, Pitari G, Di Leandro L, Giansanti F, Lombardi A, Fabbrini MS, Ippoliti R (2012) Distinct cellular responses induced by saporin and a transferrin–saporin conjugate in two different human glioblastoma cell lines. J Cell Physiol 227(3):939–951

    Article  CAS  PubMed  Google Scholar 

  • Conner S, Schmid S (2003) Regulated portals of entry into the cell. Nature 422(6927):37–44

    Article  CAS  PubMed  Google Scholar 

  • Daniels T, Delgado T, Rodriguez J, Helguera G, Penichet M (2006a) The transferrin receptor part I: biology and targeting with cytotoxic antibodies for the treatment of cancer. Clin Immunol 121(2):144–158

    Article  CAS  PubMed  Google Scholar 

  • Daniels TR, Delgado T, Helguera G, Penichet ML (2006b) The transferrin receptor part II: targeted delivery of therapeutic agents into cancer cells. Clinical Immunology 121(2):159–176. doi:10.1016/j.clim.2006.06.006

    Article  CAS  PubMed  Google Scholar 

  • Daniels TR, Ng PP, Delgado T, Lynch MR, Schiller G, Helguera G, Penichet ML (2007) Conjugation of an anti transferrin receptor IgG3-avidin fusion protein with biotinylated saporin results in significant enhancement of its cytotoxicity against malignant hematopoietic cells. Mol Cancer Ther 6(11):2995–3008

    Article  CAS  PubMed  Google Scholar 

  • Das Gupta A, Shah VI (1990) Correlation of transferrin receptor expression with histologic grade and immunophenotype in chronic lymphocytic leukemia and Non-Hodgkin’s lymphoma. Hematol Pathol 4(1):37–41

    CAS  PubMed  Google Scholar 

  • Dautry Varsat A, Ciechanover A, Lodish HF (1983) pH and the recycling of transferrin during receptor-mediated endocytosis. Proc Natl Acad Sci USA 80(8):2258–2262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Deaglio S, Capobianco A, Calı A, Bellora F, Alberti F, Righi L, Sapino A, Camaschella C, Malavasi F (2002) Structural, functional, and tissue distribution analysis of human transferrin receptor-2 by murine monoclonal antibodies and a polyclonal antiserum. Blood 100(10):3782–3789. doi:10.1182/blood-2002-01-0076

    Article  CAS  PubMed  Google Scholar 

  • Descamps L, Dehouck MP, Torpier G, Cecchelli R (1996) Receptor-mediated transcytosis of transferrin through blood–brain barrier endothelial cells. Am J Physiol 270(4):H1149–H1158

    CAS  PubMed  Google Scholar 

  • Dufes C, Al Robaian M, Somani S (2013) Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells. Therapeutic delivery 4(5):629–640

    Article  CAS  PubMed  Google Scholar 

  • El Hage Chahine J-M, Hémadi M, Ha-Duong N-T (1820) Hémadi M, Ha-Duong NT (2012) Uptake and release of metal ions by transferrin and interaction with receptor 1. Biochimica et Biophysica Acta (BBA) 3:334–347. doi:10.1016/j.bbagen.2011.07.008 General Subjects

    Google Scholar 

  • Elliott R, Head J (2006) Complete resolution of malignant ascites in stage IV breast cancer by peritoneal drainage and innovative chemoimmunotherapy: a case report. Cancer Biother Radiopharm 21(2):138–145

    Article  PubMed  Google Scholar 

  • Faulk WP, Hsi BL, Stevens PJ (1980) Transferrin and transferrin receptors in carcinoma of the breast. Lancet (Lond) 2(8191):390–392

    Article  CAS  Google Scholar 

  • Faulk WP, Taylor CG, Yeh CJ, McIntyre JA (1990) Preliminary clinical study of transferrin–adriamycin conjugate for drug delivery to acute leukemia patients. Mol Biother 2(1):57–60

    CAS  PubMed  Google Scholar 

  • Faulk WP, Barabas K, Sun IL, Crane FL (1991) Transferrin–adriamycin conjugates which inhibit tumor cell proliferation without interaction with DNA inhibit plasma membrane oxidoreductase and proton release in K562 cells. Biochem Int 25(5):815–822

    CAS  PubMed  Google Scholar 

  • Ferrara N, Hillan KJ, Novotny W (2005) Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333(2):328–335. doi:10.1016/j.bbrc.2005.05.132

    Article  CAS  PubMed  Google Scholar 

  • Friden PM, Walus LR, Musso GF, Taylor MA, Malfroy B, Starzyk RM (1991) Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood–brain barrier. Proc Natl Acad Sci USA 88(11):4771–4775

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Galbraith GM, Galbraith RM, Temple A, Faulk WP (1980) Demonstration of transferrin receptors on human placental trophoblast. Blood 55(2):240–242

    CAS  PubMed  Google Scholar 

  • Gatter KC, Brown G, Trowbridge IS, Woolston RE, Mason DY (1983) Transferrin receptors in human tissues: their distribution and possible clinical relevance. J Clin Pathol 36(5):539–545

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2(1):48–58

    Article  CAS  PubMed  Google Scholar 

  • Griffin TW, Stocl M, Collins J, Fernandes J, Maher VE (1992) Combined antitumor therapy with the chemotherapeutic drug doxorubicin and an anti-transferrin receptor immunotoxin: in vitro and in vivo studies. J Immunother 11(1):12–18

    Article  CAS  PubMed  Google Scholar 

  • Habeshaw JA, Lister TA, Stansfeld AG, Greaves MF (1983) Correlation of transferrin receptor expression with histological class and outcome in non-Hodgkin lymphoma. Lancet (Lond) 1(8323):498–501

    Article  CAS  Google Scholar 

  • Hamilton TA, Wada HG, Sussman HH (1979) Identification of transferrin receptors on the surface of human cultured cells. Proceedings of the National Academy of Sciences of the United States of America. Proc Natl Acad Sci USA 76(12):6406–6410

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hammarström ML, Axelsson B, Ivansen M, Hammarström S, Perlmann P (1982) Transferrin receptors on mitogen-stimulated human thymus-derived lymphocytes. Scand J Immunol 16(4):355–360

    Article  PubMed  Google Scholar 

  • Head JF, Wang F, Elliott RL (1997) Antineoplastic drugs that interfere with iron metabolism in cancer cells. Adv Enzyme Regul 37:147–169

    Article  CAS  PubMed  Google Scholar 

  • Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5):1011–1027. doi:10.1200/jco.2005.06.081

    Article  CAS  PubMed  Google Scholar 

  • Hopkins CR, Trowbridge IS (1983) Internalization and processing of transferrin and the transferrin receptor in human carcinoma A431 cells. J Cell Biol 97(2):508–521

    Article  CAS  PubMed  Google Scholar 

  • Hoshino T, Misaki M, Yamamoto M, Shimizu H, Ogawa Y, Toguchi H (1995) In vitro cytotoxicities and in vivo distribution of transferrin–platinum(II) complex. J Pharm Sci 84(2):216–221

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, He L, Liu W, Fan C, Zheng W, Wong Y-S, Chen T (2013) Selective cellular uptake and induction of apoptosis of cancer-targeted selenium nanoparticles. Biomaterials 34(29):7106–7116. doi:10.1016/j.biomaterials.2013.04.067

    Article  CAS  PubMed  Google Scholar 

  • Huebers HA, Finch CA (1987) The physiology of transferrin and transferrin receptors. Physiol Rev 67(2):520–582

    CAS  PubMed  Google Scholar 

  • Ippoliti R, Lendaro E, D’Agostino I, Fiani ML, Guidarini D, Vestri S, Benedetti PA, Brunori M (1995) A chimeric saporin–transferrin conjugate compared to ricin toxin: role of the carrier in intracellular transport and toxicity. FASEB J 9(12):1220–1225

    CAS  PubMed  Google Scholar 

  • Jain RK (2001) Delivery of molecular and cellular medicine to solid tumors. Adv Drug Deliv Rev 46(1–3):149–168

    Article  CAS  PubMed  Google Scholar 

  • Jefferies WA, Brandon MR, Hunt SV, Williams AF, Gatter KC, Mason DY (1984) Transferrin receptor on endothelium of brain capillaries. Nature 312(5990):162–163

    Article  CAS  PubMed  Google Scholar 

  • Jiang YY, Liu C, Hong MH, Zhu SJ, Pei YY (2007) Tumor cell targeting of transferrin–PEG–TNF-alpha conjugate via a receptor-mediated delivery system: design, synthesis, and biological evaluation. Bioconjug Chem 18(1):41–49

    Article  PubMed  CAS  Google Scholar 

  • Jiang W, KimBetty YS, Rutka JT, ChanWarren CW (2008) Nanoparticle-mediated cellular response is size-dependent. Nat Nano 3(3):145–150. http://www.nature.com/nnano/journal/v3/n3/suppinfo/nnano.2008.30_S1.html

    Google Scholar 

  • Jin M, Snider MD (1993) Role of microtubules in transferrin receptor transport from the cell surface to endosomes and the Golgi complex. J Biol Chem 268(24):18390–18397

    CAS  PubMed  Google Scholar 

  • Karagiannis T, Lobachevsky P, Martin R (2006a) DNA targeted UVA photosensitization: characterization of an extremely photopotent iodinated minor groove binding DNA ligand. J Photochem Photobiol B 83(3):195–204

    Article  CAS  PubMed  Google Scholar 

  • Karagiannis TC, Lobachevsky PN, Leung BK, White JM, Martin RF (2006b) Receptor-mediated DNA-targeted photoimmunotherapy. Cancer Res 66(21):10548–10552

    Article  CAS  PubMed  Google Scholar 

  • Kawabata H, Germain RS, Vuong PT, Nakamaki T, Said JW, Koeffler HP (2000) Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem 275(22):16618–16625

    Article  CAS  PubMed  Google Scholar 

  • Kersten S, Desvergne B, Wahli W (2000) Roles of PPARs in health and disease. Nature 405(6785):421–424

    Article  CAS  PubMed  Google Scholar 

  • Kim TH, Jo YG, Jiang HH, Lim SM, Youn YS, Lee S, Chen X, Byun Y, Lee KC (2012) PEG–transferrin conjugated TRAIL (TNF-related apoptosis-inducing ligand) for therapeutic tumor targeting. J Control Release 162(2):422–428. doi:10.1016/j.jconrel.2012.07.021

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kim S, Saha K, Kim C, Rotello V (2013) The role of surface functionality in determining nanoparticle cytotoxicity. Acc Chem Res 46(3):681–691

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Klausner RD, Ashwell G, van Renswoude J, Harford JB, Bridges KR (1983a) Binding of apotransferrin to K562 cells: explanation of the transferrin cycle. Proc Natl Acad Sci USA 80(8):2263–2266

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Klausner RD, Van Renswoude J, Ashwell G, Kempf C, Schechter AN, Dean A, Bridges KR (1983b) Receptor-mediated endocytosis of transferrin in K562 cells. J Biol Chem 258(8):4715–4724

    CAS  PubMed  Google Scholar 

  • Kondo K, Noguchi M, Mukai K, Matsuno Y, Sato Y, Shimosato Y, Monden Y (1990) Transferrin receptor expression in adenocarcinoma of the lung as a histopathologic indicator of prognosis. Chest 97(6):1367–1371

    Article  CAS  PubMed  Google Scholar 

  • Koppu S, Oh YJ, Edrada-Ebel R, Blatchford DR, Tetley L, Tate RJ, Dufès C (2010) Tumor regression after systemic administration of a novel tumor-targeted gene delivery system carrying a therapeutic plasmid DNA. J Control Release 143(2):215–221. doi:10.1016/j.jconrel.2009.11.015

    Article  CAS  PubMed  Google Scholar 

  • Kratz F, Beyer U, Roth T, Tarasova N, Collery P, Lechenault F, Cazabat A, Schumacher P, Unger C, Falken U (1998) Transferrin conjugates of doxorubicin: synthesis, characterization, cellular uptake, and in vitro efficacy. J Pharm Sci 87(3):338–346

    Article  CAS  PubMed  Google Scholar 

  • Kratz F, Roth T, Fichiner I, Schumacher P, Fiebig HH, Unger C (2000) In vitro and in vivo efficacy of acid-sensitive transferrin and albumin doxorubicin conjugates in a human xenograft panel and in the MDA-MB-435 mamma carcinoma model. J Drug Target 8(5):305–318

    Article  CAS  PubMed  Google Scholar 

  • Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei HY, van Hagen M, Postema PT, de Jong M, Reubi JC (1993) Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 20(8):716–731

    Article  CAS  PubMed  Google Scholar 

  • Lakadamyali M, Rust M, Zhuang X (2006) Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes. Cell 124(5):997–1009

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Laske DW, Ilercil O, Akbasak A, Youle RJ, Oldfield EH (1994) Efficacy of direct intratumoral therapy with targeted protein toxins for solid human gliomas in nude mice. J Neurosurg 80(3):520–526

    Article  CAS  PubMed  Google Scholar 

  • Laske DW, Muraszko KM, Oldfield EH, DeVroom HL, Sung C, Dedrick RL, Simon TR, Colandrea J, Copeland C, Katz D, Greenfield L, Groves ES, Houston LL, Youle RJ (1997a) Intraventricular immunotoxin therapy for leptomeningeal neoplasia. Neurosurgery 41(5):1039–1049

    Article  CAS  PubMed  Google Scholar 

  • Laske DW, Youle RJ, Oldfield EH (1997b) Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med 3(12):1362–1368

    Article  CAS  PubMed  Google Scholar 

  • Lemieux P, Page M (1994) Sensitivity of multidrug-resistant MCF-7 cells to a transferrin-doxorubicin conjugate. Anticancer Res 14(2A):397–403

    CAS  PubMed  Google Scholar 

  • Liu G, Mao J, Jiang Z, Sun T, Hu Y, Zhang C, Dong J, Huang Q, Lan Q (2013) Transferrin-modified doxorubicin-loaded biodegradable nanoparticles exhibit enhanced efficacy in treating brain glioma-bearing rats. Cancer Biother Radiopharma 28(9):691–696

    Article  CAS  Google Scholar 

  • Lubgan D, Jozwiak Z, Grabenbauer GG, Distel LV (2009) Doxorubicin–transferrin conjugate selectively overcomes multidrug resistance in leukaemia cells. Cell Mol Biol Lett 14(1):113–127

    Article  CAS  PubMed  Google Scholar 

  • Luck A, Mason A (2012) Transferrin-mediated cellular iron delivery. Curr Top Membr 69:3–35

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Madhumathi J, Verma RS (2012) Therapeutic targets and recent advances in protein immunotoxins. Curr Opin Microbiol 15(3):300–309. doi:10.1016/j.mib.2012.05.006

    Article  CAS  PubMed  Google Scholar 

  • Martell LA, Agrawal A, Ross DA, Muraszko KM (1993) Efficacy of transferrin receptor-targeted immunotoxins in brain tumor cell lines and pediatric brain tumors. Cancer Res 53(6):1348–1353

    CAS  PubMed  Google Scholar 

  • Martin RF, Murray V, D’Cunha G, Pardee M, Kampouris E, Haigh A, Kelly DP, Hodgson GS (1990) Radiation sensitization by an iodine-labelled DNA ligand. Int J Radiat Biol 57(5):939–946

    Article  CAS  PubMed  Google Scholar 

  • Matsui T, Fukuda M (2011) Small GTPase Rab12 regulates transferrin receptor degradation: implications for a novel membrane trafficking pathway from recycling endosomes to lysosomes. Cell Logist 1(4):155–158

    Article  PubMed Central  PubMed  Google Scholar 

  • Matsui T, Itoh T, Fukuda M (2011) Small GTPase Rab12 regulates constitutive degradation of transferrin receptor. Traffic 12(10):1432–1443

    Article  CAS  PubMed  Google Scholar 

  • Mattia E, Rao K, Shapiro DS, Sussman HH, Klausner RD (1984) Biosynthetic regulation of the human transferrin receptor by desferrioxamine in K562 cells. J Biol Chem 259(5):2689–2692

    CAS  PubMed  Google Scholar 

  • Mayle K, Le A, Kamei D (2012) The intracellular trafficking pathway of transferrin. Biochimica et biophysica acta 1820(3):264–281

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McCaffrey MW, Bielli A, Cantalupo G, Mora S, Roberti V, Santillo M, Drummond F, Bucci C (2001) Rab4 affects both recycling and degradative endosomal trafficking. FEBS Lett 495(1–2):21–30. doi:10.1016/S0014-5793(01)02359-6

    Article  CAS  PubMed  Google Scholar 

  • McClelland A, Kühn LC, Ruddle FH (1984) The human transferrin receptor gene: genomic organization, and the complete primary structure of the receptor deduced from a cDNA sequence. Cell 39(2):267–274

    Article  CAS  PubMed  Google Scholar 

  • Mendelsohn J, Baselga J (2000) The EGF receptor family as targets for cancer therapy. Oncogene 19(56):6550–6565

    Article  CAS  PubMed  Google Scholar 

  • Mendelsohn J, Trowbridge I, Castagnola J (1983) Inhibition of human lymphocyte proliferation by monoclonal antibody to transferrin receptor. Blood 62(4):821–826

    CAS  PubMed  Google Scholar 

  • Mout R, Moyano D, Rana S, Rotello V (2012) Surface functionalization of nanoparticles for nanomedicine. Chem Soc Rev 41(7):2539–2544

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Munns J, Yaxley J, Coomer J, Lavin MF, Gardiner RA, Watters D (1998) Evaluation of the potential of transferrin–adriamycin conjugates in the treatment of bladder cancer. Br J Urol 82(2):284–289

    Article  CAS  PubMed  Google Scholar 

  • Nam J-P, Park S-C, Kim T-H, Jang J-Y, Choi C, Jang M-K, Nah J-W (2013) Encapsulation of paclitaxel into lauric acid-O-carboxymethyl chitosan-transferrin micelles for hydrophobic drug delivery and site-specific targeted delivery. Int J Pharm 457(1):124–135

    Article  CAS  PubMed  Google Scholar 

  • Neckers LM, Trepel JB (1986) Transferrin receptor expression and the control of cell growth. Cancer Invest 4(5):461–470

    Article  CAS  PubMed  Google Scholar 

  • O’Keefe DO, Draper RK (1985) Characterization of a transferrin–diphtheria toxin conjugate. J Biol Chem 260(2):932–937

    PubMed  Google Scholar 

  • Panaccio M, Zalcberg JR, Thompson CH, Leyden MJ, Sullivan JR, Lichtenstein M, McKenzie IF (1987) Heterogeneity of the human transferrin receptor and use of anti-transferrin receptor antibodies to detect tumours in vivo. Immunol Cell Biol 65(6):461–472

    Article  PubMed  Google Scholar 

  • Paris-Robidas S, Emond V, Tremblay C, Soulet D, Calon F (2011) In vivo labeling of brain capillary endothelial cells after intravenous injection of monoclonal antibodies targeting the transferrin receptor. Mol Pharmacol 80(1):32–39. doi:10.1124/mol.111.071027

    Article  CAS  PubMed  Google Scholar 

  • Pirker R, FitzGerald DJP, Hamilton TC, Ozols RF, Willingham MC, Pastan I (1985) Anti-transferrin receptor antibody linked to Pseudomonas exotoxin as a model immunotoxin in human ovarian carcinoma cell lines. Cancer Res 45(2):751–757

    CAS  PubMed  Google Scholar 

  • Pirker R, FitzGerald DJP, Willingham MC, Pastan I (1988) Enhancement of the activity of immunotoxins made with either ricin a chain or pseudomonas exotoxin in human ovarian and epidermoid carcinoma cell lines. Cancer Res 48(14):3919–3923

    CAS  PubMed  Google Scholar 

  • Prior R, Reifenberger G, Wechsler W (1990) Transferrin receptor expression in tumours of the human nervous system: relation to tumour type, grading and tumour growth fraction. Virchows Archiv 416(6):491–496

    Article  CAS  PubMed  Google Scholar 

  • Prutki M, Poljak Blazi M, Jakopovic M, Tomas D, Stipancic I, Zarkovic N (2006) Altered iron metabolism, transferrin receptor 1 and ferritin in patients with colon cancer. Cancer Lett 238(2):188–196

    Article  CAS  PubMed  Google Scholar 

  • Raso V, Basala M (1984) A highly cytotoxic human transferrin–ricin A chain conjugate used to select receptor-modified cells. J Biol Chem 259(2):1143–1149

    CAS  PubMed  Google Scholar 

  • Recht L, Torres CO, Smith TW, Raso V, Griffin TW (1990) Transferrin receptor in normal and neoplastic brain tissue: implications for brain-tumor immunotherapy. J Neurosurg 72(6):941–945. doi:10.3171/jns.1990.72.6.0941

    Article  CAS  PubMed  Google Scholar 

  • Richardson DR, Ponka P (1997) The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim Biophys Acta 1331(1):1–40

    Article  CAS  PubMed  Google Scholar 

  • Rouault T, Rao K, Harford J, Mattia E, Klausner RD (1985) Hemin, chelatable iron, and the regulation of transferrin receptor biosynthesis. J Biol Chem 260(27):14862–14866

    CAS  PubMed  Google Scholar 

  • Rutledge EA, Mikoryak CA, Draper RK (1991) Turnover of the transferrin receptor is not influenced by removing most of the extracellular domain. J Biol Chem 266(31):21125–21130

    CAS  PubMed  Google Scholar 

  • Ryschich E, Huszty G, Knaebel HP, Hartel M, Büchler MW, Schmidt J (2004) Transferrin receptor is a marker of malignant phenotype in human pancreatic cancer and in neuroendocrine carcinoma of the pancreas. Eur J Cancer 40(9):1418–1422

    Article  CAS  PubMed  Google Scholar 

  • Sahoo SK, Labhasetwar V (2005) Enhanced antiproliferative activity of transferrin-conjugated paclitaxel-loaded nanoparticles is mediated via sustained intracellular drug retention. Mol Pharm 2(5):373–383. doi:10.1021/mp050032z

    Article  CAS  PubMed  Google Scholar 

  • Sahoo SK, Ma W, Labhasetwar V (2004) Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. Int J Cancer 112(2):335–340. doi:10.1002/ijc.20405

    Article  CAS  PubMed  Google Scholar 

  • Schneider C, Sutherland R, Newman R, Greaves M (1982) Structural features of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9. J Biol Chem 257(14):8516–8522

    CAS  PubMed  Google Scholar 

  • Schneider C, Owen MJ, Banville D, Williams JG (1984) Primary structure of human transferrin receptor deduced from the mRNA sequence. Nature 311(5987):675–678

    Article  CAS  PubMed  Google Scholar 

  • Schulman HM, Wilczynska A, Ponka P (1981) Transferrin and iron uptake by human lymphoblastoid and K-562 cells. Biochem Biophys Res Commun 100(4):1523–1530

    Article  CAS  PubMed  Google Scholar 

  • Scott CF Jr, Goldmacher VS, Lambert JM, Jackson JV, McIntyre GD (1987) An immunotoxin composed of a monoclonal antitransferrin receptor antibody linked by a disulfide bond to the ribosome-inactivating protein gelonin: potent in vitro and in vivo effects against human tumors. J Natl Cancer Inst 79(5):1163–1172

    CAS  PubMed  Google Scholar 

  • Seymour GJ, Walsh MD, Lavin MF, Strutton G, Gardiner RA (1987) Transferrin receptor expression by human bladder transitional cell carcinomas. Urol Res 15(6):341–344

    Article  CAS  PubMed  Google Scholar 

  • Shapira A, Benhar I (2010) Toxin-based therapeutic approaches. Toxins 2(11):2519–2583

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shinohara H, Fan D, Ozawa S, Yano S, Van Arsdell M, Viner JL, Beers R, Pastan I, Fidler IJ (2000) Site-specific expression of transferrin receptor by human colon cancer cells directly correlates with eradication by antitransferrin recombinant immunotoxin. Int J Oncol 17(4):643–651

    CAS  PubMed  Google Scholar 

  • Sieff C, Bicknell D, Caine G, Robinson J, Lam G, Greaves MF (1982) Changes in cell surface antigen expression during hemopoietic differentiation. Blood 60(3):703–713

    CAS  PubMed  Google Scholar 

  • Singh M (1999) Transferrin As A targeting ligand for liposomes and anticancer drugs. Curr Pharm Des 5(6):443–451

    CAS  PubMed  Google Scholar 

  • Singh M, Atwal H, Micetich R (1998) Transferrin directed delivery of adriamycin to human cells. Anticancer Res 18(3A):1423–1427

    CAS  PubMed  Google Scholar 

  • Singh M, Mugler K, Hailoo D, Burke S, Nemesure B, Torkko K, Shroyer K (2011) Differential expression of transferrin receptor (TfR) in a spectrum of normal to malignant breast tissues: implications for in situ and invasive carcinoma. Appl Immunohistochem Mol Morphol 19(5):417–423

    Article  CAS  PubMed  Google Scholar 

  • Speth PAJ, Hoesel QGCM, Haanen C (1988) Clinical pharmacokinetics of doxorubicin. Clin-Pharmacokinet 15(1):15–31. doi:10.2165/00003088-198815010-00002

    Article  CAS  PubMed  Google Scholar 

  • Steere A, Byrne S, Chasteen ND (1820) Mason A (2012) Kinetics of iron release from transferrin bound to the transferrin receptor at endosomal pH. Biochim Biophys Acta 3:326–333

    Google Scholar 

  • Stein BS, Sussman HH (1986) Demonstration of two distinct transferrin receptor recycling pathways and transferrin-independent receptor internalization in K562 cells. J Biol Chem 261(22):10319–10331

    CAS  PubMed  Google Scholar 

  • Sun IL, Sun EE, Crane FL, Morre DJ, Faulk WP (1992) Inhibition of transplasma membrane electron transport by transferrin–adriamycin conjugates. Biochim Biophys Acta 23(1):84–88

    Article  Google Scholar 

  • Sutherland R, Delia D, Schneider C, Newman R, Kemshead J, Greaves M (1981) Ubiquitous cell-surface glycoprotein on tumor cells is proliferation-associated receptor for transferrin. Proc Natl Acad Sci 78(7):4515–4519

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Szwed M, Matusiak A, Laroche-Clary A, Robert J, Marszalek I, Jozwiak Z (2013) Transferrin as a drug carrier: cytotoxicity, cellular uptake and transport kinetics of doxorubicin transferrin conjugate in the human leukemia cells. Toxicol Vitro. doi:10.1016/j.tiv.2013.09.013

    Google Scholar 

  • Taetle R, Honeysett JM, Trowbridge I (1983) Effects of anti-transferrin receptor antibodies on growth of normal and malignant myeloid cells. Int J Cancer 32(3):343–349

    Article  CAS  PubMed  Google Scholar 

  • Taetle R, Castagnola J, Mendelsohn J (1986) Mechanisms of growth inhibition by anti-transferrin receptor monoclonal antibodies. Cancer Res 46(4):1759–1763

    CAS  PubMed  Google Scholar 

  • Trinder D, Baker E (2003) Transferrin receptor 2: a new molecule in iron metabolism. Int J Biochem Cell Biol 35(3):292–296

    Article  CAS  PubMed  Google Scholar 

  • Trowbridge IS, Domingo DL (1981) Anti-transferrin receptor monoclonal antibody and toxin-antibody conjugates affect growth of human tumour cells. Nature 294(5837):171–173

    Article  CAS  PubMed  Google Scholar 

  • Trowbridge IS, Lopez F (1982) Monoclonal antibody to transferrin receptor blocks transferrin binding and inhibits human tumor cell growth in vitro. Proc Natl Acad Sci USA 79(4):1175–1179

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Trowbridge IS, Omary MB (1981) Human cell surface glycoprotein related to cell proliferation is the receptor for transferrin. Proc Natl Acad Sci 78(5):3039–3043

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ulbrich K, Hekmatara T, Herbert E, Kreuter J (2009) Transferrin- and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood–brain barrier (BBB). Eur J Pharma Biopharma 71(2):251–256. doi:10.1016/j.ejpb.2008.08.021

    Article  CAS  Google Scholar 

  • van der Meel R, Vehmeijer LJC, Kok RJ, Storm G, van Gaal EVB (2013) Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status. Adv Drug Deliv Rev 65(10):1284–1298. doi:10.1016/j.addr.2013.08.012

    Article  PubMed  CAS  Google Scholar 

  • Wang F, Jiang X, Yang DC, Elliott RL, Head JF (2000) Doxorubicin–gallium–transferrin conjugate overcomes multidrug resistance: evidence for drug accumulation in the nucleus of drug resistant MCF-7/ADR cells. Anticancer Res 20(2A):799–808

    CAS  PubMed  Google Scholar 

  • Ward JH, Jordan I, Kushner JP, Kaplan J (1984) Heme regulation of HeLa cell transferrin receptor number. J Biol Chem 259(21):13235–13240

    CAS  PubMed  Google Scholar 

  • Weaver M, Laske DW (2003) Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) therapy of malignant gliomas. J Neurooncol 65(1):3–13

    Article  PubMed  Google Scholar 

  • Whitesides GM (2003) The ‘right’ size in nanobiotechnology. Nat Biotechnol 21(10):1161–1165

    Article  CAS  PubMed  Google Scholar 

  • Woith W, Nüsslein I, Antoni C, Dejica DI, Winkler TH, Herrmann M, Pirner K, Kalden JR, Manger B (1993) A soluble form of the human transferrin receptor is released by activated lymphocytes in vitro. Clin Exp Immunol 92(3):537–542

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wrba F, Ritzinger E, Reiner A, Holzner JH (1986) Transferrin receptor (TrfR) expression in breast carcinoma and its possible relationship to prognosis. An immunohistochemical study. Virchows Archiv A 410(1):69–73

    Article  CAS  Google Scholar 

  • Wu J, Lu Y, Lee A, Pan X, Yang X, Zhao X, Lee R (2007) Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil. J Pharm Pharma Sci 10(3):350–357

    CAS  Google Scholar 

  • Wu L, Wu J, Zhou Y, Tang X, Du Y, Hu Y (2012) Enhanced antitumor efficacy of cisplatin by tirapazamine–transferrin conjugate. Int J Pharm 431(1–2):190–196. doi:10.1016/j.ijpharm.2012.04.032

    Article  CAS  PubMed  Google Scholar 

  • Yashunsky V, Shimron S, Lirtsman V, Weiss A, Melamed Book N, Golosovsky M, Davidov D, Aroeti B (2009) Real-time monitoring of transferrin-induced endocytic vesicle formation by mid-infrared surface plasmon resonance. Biophys J 97(4):1003–1012

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yeh CJ, Taylor CG, Faulk WP (1984) Transferrin binding by peripheral blood mononuclear cells in human lymphomas, myelomas and leukemias. Vox Sang 46(4):217–223

    Article  CAS  PubMed  Google Scholar 

  • Yoon D, Chu DSH, Ng C, Pham E, Mason A, Hudson D, Smith V, MacGillivray RTA, Kamei D (2009) Genetically engineering transferrin to improve its in vitro ability to deliver cytotoxins. J Control Release 133(3):178–184

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zerial M, Melancon P, Schneider C, Garoff H (1986) The transmembrane segment of the human transferrin receptor functions as a signal peptide. EMBO J 5(7):1543–1550

    PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The support of the Australian Institute of Nuclear Science and Engineering (AINSE) is acknowledged. TCK was the recipient of AINSE awards. TCK is supported by an Australian Research Council Future Fellowship and the Epigenomic Medicine Laboratory is supported by McCord Research. Supported in part by the Victorian Government’s Operational Infrastructure Support Program.

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Tortorella, S., Karagiannis, T.C. Transferrin Receptor-Mediated Endocytosis: A Useful Target for Cancer Therapy. J Membrane Biol 247, 291–307 (2014). https://doi.org/10.1007/s00232-014-9637-0

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