In January 2024, a research paper titled "Remyelinating effect driven by transferrin-loaded extracellular vesicles" was included in the Scholar database [1]. The study explored using extracellular vesicles (EVs) as carriers for transferrin (TF/Tf) delivery to the central nervous system via the nasal route. Results showed that EV-delivered Tf entered neuroglia, promoting OPCs (oligodendrocyte precursor cells) maturation and indicating potential for myelin regeneration. This discovery aligns with the trend of using Serotransferrin/Tf-modified nano-novel drugs in cancer therapy. These drugs, employing carrier modes like exosomes, target biological markers highly expressed in cancer cells. Join us today to learn more about the significance of Serotransferrin/Tf and its applications in disease research!
Serotransferrin (TF, Tf, or Transferrin), is a beta-globulin in plasma, acting as the primary iron transport protein in the blood. Discovered by researchers Holmberg and Laurell, it consists of 679 amino acids, with an approximate molecular weight of 79 kD. Comprising two N-terminal (336 amino acid residues) and C-terminal (343 amino acid residues) structural domains, Tf displays a highly homologous structure. Each Tf molecule can bind two metal ions, including Fe3+, Cu2+, Co3+, Cr3+, with the strongest affinity for Fe3+. This binding involves two tyrosines, one aspartic acid, and one histidine in the structural domains, forming a stable octahedral structure (Figure 1) [2-4].
TF is a glycoprotein with a specific affinity for binding and transporting iron, widely distributed in various tissues and organs. While primarily synthesized by liver cells in the bloodstream, small amounts are also produced by support cells, ventricular membranes, oligodendrocytes, and other tissue cells. Beyond serum, transferrin is present in body fluids such as plasma, cerebrospinal fluid, bile, lymphatic fluid, amniotic fluid, and breast milk. The concentration of transferrin in serum remains stable without external stimulation [5-7].
TF is a key player in supplying iron to the body, facilitating its transport to erythropoietic cells for hemoglobin synthesis or delivering trivalent iron ions from absorption and storage sites to other iron-demanding locations. Maintaining iron ion homeostasis is crucial for sustaining life activities, as both deficiency and overload can harm tissues and organs. Tf plays a pivotal role in achieving iron ion homeostasis by coordinating with various proteins. Additionally, TF is implicated in numerous cellular processes, including nutrient metabolism, embryogenesis, cell proliferation, mitosis, chemotaxis, and angiogenesis [8-10].
Figure 1. TF structure [2]
TF binds to the Transferrin Receptor (TFR) on the cell membrane, enabling the iron-loaded TF-TFR complex to enter the cell via endocytosis. After internalization, the complex undergoes a conformational change triggered by a pH drop, releasing Fe3+ from TF. Intronic ferric reductase converts Fe3+ to Fe2+, which is efficiently transported into the cytoplasm by Divalent Metal Transporter 1 (DMT1). Inside the cell, Fe2+ associates with Ferritin Heavy Chain 1 (FTH1). Receptor-mediated endocytosis by the TF-TFR complex is the primary pathway for cellular iron uptake. This process is effective for delivering anticancer drugs or transporting therapeutic drugs to tumor cells overexpressing TFR (Figure 2) [11-12].
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Figure 2. TF mediates uptake of iron ions via the receptor [11]
Cellular iron-induced death relies on iron metabolism, where excess free iron ions can generate free radicals, causing oxidative stress, DNA damage, and lipid peroxidation, leading to cell death. In a study on myeloma patients, decreased transferrin and increased ferritin levels, despite normal iron levels, suggested reduced intracellular iron and non-toxic iron storage, respectively. Elevating transferrin levels and treating myeloma MM cells with Erastin increased sensitivity to Erastin, reducing cell proliferation. This heightened sensitivity correlated positively with intracellular iron levels. Thus, boosting transferrin levels enhances susceptibility of MM cells to Erastin-induced iron death [13-14].
Recently, TF has emerged as a key player in tumor-targeted therapies, particularly through the widespread utilization of Tf-modified nanocarriers in Drug Delivery Systems (DDS). DDS involves employing nanomaterials like polymers, liposomes, exosomes, and metal oxides as carriers for drug formulation, enabling controlled and sustained drug release. This strategy ensures that the drug remains in the target tissue or disease area for a specified duration, enhancing its effectiveness as a research tool for disease therapy.
A study found that using Transferrin T-modified adriamycin liposomes (Tf-SL-DOX) significantly increased adriamycin concentrations in target organs. In vitro tests revealed a significantly lower IC50 of 20.4μmol/L for Tf-SL-DOX compared to 166.2μmol/L for adriamycin liposomes (SL-DOX), with a notable difference (P<0.01). SL-DOX was highly effective in killing HepG2 hepatocellular carcinoma cells in vitro. Tail vein injection of Tf-SL-DOX notably slowed tumor growth compared to the model group, achieving a 67% tumor inhibition rate. These results suggest that Tf-SL-DOX effectively inhibits tumor tissue growth, indicating enhanced targeting of hepatocellular carcinoma cells with lower cardiotoxicity [15-18].
TF modification on green fluorescence-emitting carbon dots (GCD) resulted in GCD-PEG-Tf@DOX, a combination of adriamycin (DOX) with GCD. Treating breast cancer cells MCF-7 with GCD-PEG-Tf@DOX precisely targeted cancer cells overexpressing transferrin receptors (TfR). Confocal microscopy confirmed strong fluorescence in high TfR expression MCF-7 cells and weak fluorescence in low TfR expression CHO cells, indicating accurate targeting. Cytotoxicity experiments showed GCD-PEG-Tf@DOX had time- and concentration-dependent cytotoxicity similar to free DOX, preserving DOX's effectiveness. Injection into tumor-bearing mice significantly inhibited tumor growth without affecting body weight, suggesting GCD-PEG-Tf@DOX has minimal side effects and excellent targeting ability [19-22].
A study examined the expression of transferrin, clusterin, and transthyretin proteins in normal, hyperplastic, and cancerous prostate tissues. The findings showed significantly higher transferrin (Tf) expression in prostate cancer tissues compared to benign prostatic hyperplasia and normal prostate groups, reaching a positivity rate of 94%. Further investigation revealed a positive correlation between Tf expression and both the pathological grading and clinical stage of prostate cancer. This indicates that Tf is prominently expressed in prostate cancer tissues, consistent with serum Tf expression. The researchers concluded that Tf can be used as a differential indicator in prostate cancer serum, serving as a marker for disease progression and treatment evaluation [23-25].
Several studies have highlighted abnormal transferrin (Tf) expression in highly malignant and easily metastatic tumors such as glioma, lung adenocarcinoma, ovarian cancer, and chronic lymphocytic leukemia [26-29]. For instance, combining HP, Tf, and CEA has been shown to enhance the diagnostic specificity and sensitivity of early-stage ovarian epithelial cancer, improving the detection rate of CA125-negative cases [30]. In another study, researchers designed a Tf-5-ALA-PTX-NCs nanoplatform integrating chemo- and photodynamic therapy to enhance tumor targeting through magnetic and active targeting of transferrin receptors. The platform demonstrated effective tumor-specific targeting and synergistic anti-tumor effects both in vitro and in vivo [31].
Studies on peritoneal dialysis-associated peritonitis (PDAP) have identified prevalent disorders of iron metabolism in patients, with serum iron, ferritin, and transferrin identified as risk factors for PDAP development [32]. Low transferrin levels are linked to an increased incidence of anemia [33]. Furthermore, transferrin inhibits the growth of bacteria, viruses, and fungi by forming chelating complexes during infection, suggesting a potential method for anti-infective drug research [34].
Transferrin (TF), a glycoprotein crucial for binding and transporting iron, presents promising avenues in clinical drug research. It has been identified as a targeted ligand for tumor therapy, achieving specific treatment, and has shown effectiveness when combined with chemotherapy and photodynamic therapy to inhibit tumor growth and minimize side effects. TF-modified liposomes serve as improved drug carriers, addressing multidrug resistance and enabling targeted delivery of antitumor drugs, enhancing drug concentrations and reducing toxicity in normal tissues. TF also exhibits antimicrobial properties, suggesting potential for developing anti-infective drugs. Its association with lower transferrin levels is linked to an increased incidence of anemia. Overall, TF research holds multifaceted applications, especially in anti-infective and tumor studies.
Transferrin (TF) is pivotal in iron transport and holds promise in clinical drug research. It proves effective as a targeted ligand for tumor therapy, synergizing with chemotherapy and photodynamic therapy to inhibit tumor growth with reduced side effects. TF-modified liposomes enhance drug delivery, addressing multidrug resistance and minimizing toxicity in normal tissues. TF's antimicrobial properties open avenues for anti-infective drug development, while its association with lower transferrin levels correlates with an increased risk of anemia. In essence, TF research offers diverse disease research applications.
To fully support researchers and pharmaceutical companies in their research on Serotransferrin (TF) in anti-infective, anemia, tumor and other diseases, CUSABIO presents TF active proteins to support your research on the mechanism of TF or their potential clinical value.
CUSABIO Serotransferrin (TF) Protein
Recombinant Human Serotransferrin(TF) (Active) Code: CSB-MP023412HU
Purity was greater than 95% as determined by SDS-PAGE.
Immobilized TFRC (CSB-MP3648HU) at 2 μg/mL can bind Human TF. The EC50 is 58.72-77.84 ng/mL.
References
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