The Significance of Transferrin Receptors in Oncology: the Development of Functional Nano-based Drug Delivery Systems
Abstract
Anticancer therapeutic research aims to improve clinical management of the disease through the development of strategies that involve currently-relevant treatment options and targeted delivery. Tumour-specific and -targeted delivery of compounds to the site of malignancy allows for enhanced cellular uptake, increased therapeutic benefit with high intratumoural drug concentrations, and decreased systemic exposure. Due to the upregulation of transferrin receptor expression in a wide variety of cancers, its function and its highly efficient recycling pathway, strategies involving the selective targeting of the receptor are well documented. Direct conjugation and immunotoxin studies using the transferrin peptide or anti-transferrin receptor antibodies as the targeting moiety have established the capacity to enhance cellular uptake, cross the blood brain barrier, limit systemic toxicity and reverse multi-drug resistance. Limitations in direct conjugation, including the difficulty in linking an adequate amount of therapeutic compound to the ligand or antibody have identified the requirement to develop novel delivery methods. The application of nanoparticulate theory in the development of functional drug delivery systems has proven to be most promising, with the ability to selectively modify size-dependent properties and surface chemistry. The transferrin modification on a range of nanoparticle formulations enhances selective cellular uptake through transferrin-mediated processes, and increases therapeutic benefit through the ability to encapsulate high concentrations of relevant drug to the tumour site. Although ineffective in crossing the blood brain barrier in its free form, chemotherapeutic compounds including doxorubicin, may be loaded into transferrin-conjugated nanocarriers and impart cytotoxic effects in glioma cells in vitro and in vivo. Additionally, transferrin-targeted nanoparticles may be used in selective diagnostic applications with enhanced selectivity and sensitivity. Four transferrin-modified nano-based drug delivery systems are currently in early phases of human clinical trials. Despite the collective promise, inconsistencies in some studies have exposed some limitations in current formulations and the difficulty in translating preliminary studies into clinically-relevant therapeutic options. The main objective of this review is to investigate the development of transferrin targeted nano-based drug delivery systems in order to establish the use of transferrin as a cancer-targeted moiety, and to ultimately evaluate the progression of cancer therapeutic strategies for future research.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tf-modified drug delivery systems can achieve selective cellular uptake, cross the blood-brain barrier, limit systemic toxicity, and reverse multidrug resistance.
“Current drug delivery systems based on Tf modification can achieve selective cellular uptake, cross the blood-brain barrier, limit systemic toxicity, and reverse multidrug resistance.268”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [268]
Cited by
Sorted by citations
Smart nanoparticles for cancer therapy
Sun, L., Liu, H., Ye, Y., Lei, Y., Islam, R., Tan, S., Tong, R., Miao, Y.-B., & Cai, L. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01642-x · Cited by 1,073 · see citing works
Glioma: experimental models and reality
Lenting, K., Verhaak, R. G. W., ter Laan, M., Wesseling, P., & Leenders, W. P. J. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1671-4 · Cited by 286 · see citing works
“Numerous research efforts to get drugs over the BBB are ongoing, including active transport of peptide- or antibody-coated nanoparticles [50, 73, 145].”
Johnsen, K. B., & Moos, T. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.11.032 · Cited by 132 · see citing works
“The TfR system provides a way of entering the brain, hereby allowing for entrance of drug molecules and nanoparticles [5,75].”
BackgroundKaspler, P., Lazic, S., Forward, S., Arenas, Y., Mandel, A., & Lilge, L. D. (2016) · Photochemical & Photobiological Sciences · doi:10.1039/c5pp00450k · Cited by 131 · see citing works
Targeted Delivery to Tumors: Multidirectional Strategies to Improve Treatment Efficiency
Kutova, O. M., Guryev, E. L., Соколова, Е. А., Alzeibak, R., & Balalaeva, I. V. (2019) · Cancers · doi:10.3390/cancers11010068 · Cited by 113 · see citing works
Deshpande, P. P., Jhaveri, A. M., Pattni, B. S., Biswas, S., & Torchilin, V. P. (2018) · Drug Delivery · doi:10.1080/10717544.2018.1435747 · Cited by 115 · see citing works
“TfR targeting using Tf, has also emerged as a popular cancer-cell targeting approach based on recent published literature (Kolhatkar et al., 2011; Mehra et al., 2013; Tortorella & Karagiannis, 2014; Nogueira et al., 2015), also corroborated by results from our study.”
ResultCook, R. L., Householder, K. T., Chung, E. P., Prakapenka, A. V., DiPerna, D. M., & Sirianni, R. W. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.10.013 · Cited by 74 · see citing works
Tumor-Targeted and Clearable Human Protein-Based MRI Nanoprobes
Zhao, Y., Peng, J., Li, J., Huang, L. F., Yang, J., Huang, K., Li, H., Jiang, N., Zheng, S., Zhang, X., et al. (2017) · Nano Letters · doi:10.1021/acs.nanolett.7b00828 · Cited by 67 · see citing works
Targeting Receptors on Cancer Cells with Protein Toxins
Antignani, A., Ho, E. C. H., Bilotta, M. T., Qiu, R., Sarnvosky, R., & FitzGerald, D. J. (2020) · Biomolecules · doi:10.3390/biom10091331 · Cited by 58 · see citing works
“Further, the transferrin receptor is overexpressed in many cancers where increased expression is correlated with a poor prognosis [55].”
BackgroundGhanghoria, R., Kesharwani, P., Tekade, R. K., et al. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.11.002 · Cited by 55 · see citing works
Developments and future clinical outlook of taxane nanomedicines
Louage, B., Wever, O. D., Hennink, W. E., & Geest, B. G. D. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.03.027 · Cited by 49 · see citing works
Chen, B.-A., Bao, W., Liu, R., Wang, Y., Wang, F., Xia, G., Zhang, H., Li, X., & Yin, H. (2015) · International Journal of Nanomedicine · doi:10.2147/ijn.s75090 · Cited by 49 · see citing works
“16 Daunorubicin (DNR) is widely used in the treatment of leukemia.”
Zhang, Y., Huang, Q., Ma, C., et al. (2018) · Talanta · doi:10.1016/j.talanta.2018.06.002 · Cited by 42 · see citing works
Leitch, H. A., Fibach, E., & Rachmilewitz, E. A. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.03.002 · Cited by 39 · see citing works
Crossing the barrier: treatment of brain tumors using nanochain particles
Karathanasis, E., & Ghaghada, K. B. (2016) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1387 · Cited by 36 · see citing works
Tumor‐Targeted Catalytic Immunotherapy
Yang, E., Wang, W., Liu, Y., Yi, H., Lei, A., & Sun, Z. (2024) · Advanced Materials · doi:10.1002/adma.202413210 · Cited by 36 · see citing works
Plasmid pORF-hTRAIL targeting to glioma using transferrin-modified polyamidoamine dendrimer
Bing, H., Gao, S. T., Li, J., et al. (2015) · Drug Design Development and Therapy · doi:10.2147/dddt.s95843 · Cited by 33 · see citing works
“35,36 Thus, this system was introduced to facilitate Trail crossing the BBB and targeting to the tumor.”
Huang, Q., Wang, S., Zhou, J., et al. (2018) · RSC Advances · doi:10.1039/c7ra13454a · Cited by 29 · see citing works
Transferrin tagged lipid nanoemulsion of docetaxel for enhanced tumor targeting
Afzal, S. M., Shareef, M. Z., & Veerabrahma, K. (2016) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2016.10.008 · Cited by 26 · see citing works
Li, S., Zhao, H., Mao, X., et al. (2019) · Pharmaceutical Research · doi:10.1007/s11095-019-2688-2 · Cited by 27 · see citing works
Qi, S., Al-mashriqi, H. S., Salah, A., et al. (2022) · Microchemical Journal · doi:10.1016/j.microc.2021.107163 · Cited by 27 · see citing works
Shabani, L., Abbasi, M., Amini, M., Amani, A. M., & Vaez, A. (2022) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2022.120316 · Cited by 27 · see citing works
Nanomedicine and its applications to the treatment of prostate cancer
Oliveira, R. O. D., Maria, L. C. D. S., & BARRATT, G. M. (2014) · Annales Pharmaceutiques Françaises · doi:10.1016/j.pharma.2014.04.006 · Cited by 25 · see citing works
Blood-brain barrier amenable gold nanoparticles biofabrication in aged cell culture medium
Rehman, F. U., Bao, J., Muhammad, P., He, W., Hanif, S., & Rauf, M. A. (2020) · Materials Today Bio · doi:10.1016/j.mtbio.2020.100072 · Cited by 20 · see citing works
In vivo quantitative FRET small animal imaging: Intensity versus lifetime-based FRET
Smith, J. T., Sinsuebphon, N., Rudkouskaya, A., Michalet, X., Intes, X., & Barroso, M. (2023) · Biophysical Reports · doi:10.1016/j.bpr.2023.100110 · Cited by 17 · see citing works
“The Tf-TfR system was chosen as a model for in vivo FRET imaging of ligand-receptor engagement since transferrin has been used widely as a carrier for drug delivery (65).”
Zhang, L., Zhu, X., Wu, S., Chen, Y., Tan, S., Liu, Y., Jiang, W., & Huang, J. (2018) · International Journal of Nanomedicine · doi:10.2147/ijn.s181121 · Cited by 17 · see citing works
Kucheryavykh, Y. V., Davila, J., Ortiz-Rivera, J., et al. (2019) · Biomolecules · doi:10.3390/biom9040154 · Cited by 16 · see citing works
Nanotechnology Meets the Tumor Microenvironment: Unlocking New Horizons in Cancer Therapy
Yadav, P., Yadav, A. K., & Bhatia, D. D. (2025) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c01120 · Cited by 16 · see citing works
Gastrointestinal Tract Stabilized Protein Delivery Using Disulfide Thermostable Exoshell System
Sadeghi, S., Mavelli, G. V., Vaidya, S. S., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179856 · Cited by 11 · see citing works
“TfR1 is a transmembrane glycoprotein with a critical role in cellular iron uptake through endocytosis of iron-binding proteins, transferrin, and ferritin [57,59].”
BackgroundKasprzak, M. M., Fabijańska, M., Chęcińska, L., et al. (2016) · Inorganica Chimica Acta · doi:10.1016/j.ica.2016.11.021 · Cited by 11 · see citing works
Nicotra, S., Sorio, D., Filippi, G., et al. (2017) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-017-0616-z · Cited by 11 · see citing works
Liu, P., Zhou, S., Zhou, Z., Jin, Z., Chen, W., Li, Z., Xu, J., Chen, F., Li, Y., Wen, Y., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217582 · Cited by 8 · see citing works
Nanoparticles for Brain Tumor Delivery
Chaudhuri, T. R., & Straubinger, R. M. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813997-4.00012-8 · Cited by 7 · see citing works
Global view of a drug-sensitivity gene network
Yang, H., Zhang, Y., Wang, J., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.23229 · Cited by 5 · see citing works
“Tumor-targeted delivery of compounds to the site of malignancy allows for enhanced cellular uptake and increased therapeutic effects, so the development of targeted delivery greatly improved anticancer therapeutic research [29].”
BackgroundRudkouskaya, A., Faulkner, D. E., Sinsuebphon, N., Intes, X., & Barroso, M. (2020) · Elsevier eBooks · doi:10.1016/b978-0-08-102983-1.00012-0 · Cited by 4 · see citing works
Nanoparticles and prostate cancer
Garg, A., Garg, S., & Swarnakar, N. K. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819793-6.00012-6 · Cited by 6 · see citing works
Surface-decoration strategies in nanomedicine for cancer treatment
Parveen, S., Fatima, S., Quadri, S. N., et al. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-821095-6.00018-5 · Cited by 3 · see citing works
Kumari, N. U., Chigurupati, S. P. D., Rajana, N., Madan, J., & Mehra, N. K. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-33366-8.00013-0 · Cited by 2 · see citing works
Tripathi, A., Vaishnaw, B., Jaishwal, P., Samal, P. K., Verma, A., & Singh, N. (2025) · Current Materials Science · doi:10.2174/0126661454366845250618053301 · Cited by 2 · see citing works
Peptide and Protein Tags for the Half-Life Extension of Therapeutic Agents: A Review Article
Aboutalebi, S., Najafi, F., Yazdizadeh, N., & Shafiee, F. (2025) · The Protein Journal · doi:10.1007/s10930-025-10304-6 · Cited by 2 · see citing works
Emerging Polymer-Based Nanomaterials for Cancer Therapeutics
Gupta, C. R., Uthale, A., Teni, T. R., Ambre, P., & Coutinho, E. C. (2021) · Nanotechnology in the life sciences · doi:10.1007/978-3-030-74330-7_7 · Cited by 2 · see citing works
Functionalization of Nanosystems in Cancer Treatment
Luiz, M. T., Dutra, J. A. P., de Araújo, J. T. C., Filippo, L. D. D., Duarte, J. L., & Chorilli, M. (2022) · Springer eBooks · doi:10.1007/978-3-031-17831-3_3 · Cited by 1 · see citing works
Gyulkhandanyan, A. G., Zakoyana, A. A., Gyulkhandanyan, G. V., et al. (2018) · Biophotonics: Photonic Solutions for Better Health Care VI · doi:10.1117/12.2306577 · Cited by 1 · see citing works
“Due to increased needs of iron in a tumor development, the transferrin receptor (TfR) is highly expressed in tumor cells whereas it is usually presented at a low level in the surrounding normal adult tissue.(11,12) After the binding of transferrin to TfR on the cell membrane, the internalization of this complex occurs…”
BackgroundFabrication and Characterization of Sol-Gel Based Nanoparticles for Drug Delivery
Yadav, R. (2014) · CUNY Academic Works (City University of New York) · Cited by 1 · see citing works
Development and evaluation of nanoparticles for cancer treatment
de Oliveira, R. O. (2014) · theses.fr (ABES) · doi:10.70675/092ffb55zc3a7z4518za356zb7aada62be77 · Cited by 1 · see citing works
Qi, S., Al-mashriqi, H. S., Salah, A., et al. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3937170
Targeted Nanocarriers-based Approach For Prostate Cancer Therapy
Garg, A., Madamsetty, V. S., Ashique, S., Gauttam, V. K., & Mishra, N. (2023) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9789815080506123010008
An Insight into Mesoporous Silica Nanoparticles: Ray of Hope for Cancer Management
Chauhan, C., Garg, A., & Agrawal, R. (2023) · Current Cancer Therapy Reviews · doi:10.2174/0115733947242447231003035334
Liposomal nanomedicine: applications for drug delivery in cancer therapy
Kumar, M., Sil, D., Srivatava, S., et al. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-40443-6.00006-4
Nanocarrier-mediated immune microenvironment remodelling in osteosarcoma
Fu, J., Bi, Z., Wei, R., Lv, S., & Guo, Y. (2026) · Nano Today · doi:10.1016/j.nantod.2026.103181
- Authors
- Tortorella, S., & Karagiannis, T.
- Affiliations
- Baker Heart and Diabetes Institute (AU)
- ORCID
- Karagiannis, Tom
- Venue
- Current Drug Delivery
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2014-01-15
- Volume
- 11
- Issue
- 4
- Pages
- 427-443
- ISSN
- 1567-2018 (ISSN-L)
- OpenAlex
- W2315387567
- Cited by
- 51
- References
- 0
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 5 · 2015: 4 · 2014: 3
- FWCI
- 2.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Drug Delivery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Keywords
- transferrin receptor, nanoparticle drug delivery, targeted cancer therapy, blood-brain barrier penetration, glioma, doxorubicin, multidrug resistance, tumor targeting, nanoparticle surface modification, cancer theranostics
- MeSH terms
- Animals, Antineoplastic Agents, Drug Compounding, Humans, Neoplasm Proteins, Neoplasms, Receptors, Transferrin, Transferrin, Drug Delivery Systems, Nanostructures
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
