Transferrin Receptor-Targeting Peptides: HAIYPRH, THRPPMWSPVWP, SPRPRHTLRLSL

Transferrin receptor (TfR), specifically TfR1 (CD71), is a crucial dimeric glycoprotein receptor on the cell surface. Its main physiological function is to mediate the endocytosis of iron-carrying transferrin (Tf) to provide cells with essential iron, and it exhibits a high expression profile on proliferating cells (e.g., tumor cells, activated immune cells), as well as on endothelial cells of the blood-brain barrier (BBB). This specific high expression pattern, together with its efficient internalization ability, makes TfR an attractive target for drug delivery. By designing ligands, such as small molecule peptides, that can specifically bind TfR, it is possible to achieve efficient and targeted delivery of therapeutic drugs (chemotherapeutic agents, nucleic acids, proteins, etc.) to specific cells or tissues, especially in the brain, overcoming the limitations of traditional drug delivery methods, such as systemic toxicity and low BBB penetration efficiency. In this paper, we will focus on three key TfR-targeting peptides, HAIYPRH, THRPPMWSPVWP, and SPRPRHTLRLSL, and delve into their properties, mechanisms of action, and cutting-edge applications in brain-targeted delivery and cancer therapy.

Transferrin Receptor as a Therapeutic Target

Transferrin receptors play an irreplaceable and central role in the maintenance of cellular iron homeostasis. The uptake of iron, a trace element essential for a variety of enzymatic reactions and cellular functions, is strictly dependent on the TfR-mediated endocytosis pathway. Understanding the basic biological functions of TfR and its regulation under pathological conditions is a cornerstone for the development of effective targeted delivery systems.

Role of Transferrin Receptors in Cellular Uptake

TfR1 initiates the internalization process by binding with high affinity to serum iron carrying transferrin (holo-transferrin). This specific binding triggers the formation of lattice protein-encapsulated follicles, leading to the uptake of ligand-receptor complexes into the cell interior via lattice protein-mediated endocytosis. Subsequently, the acidic environment within the endosomes prompts the dissociation and release of ferric ions from transferrin, and free ferric ions are translocated to the cytoplasmic solute for cellular utilization via divalent metal ion transporter 1 (DMT1). Dissociated ferric ions from apo-transferrin remain bound to TfR1 and eventually return to the surface of the cell membrane via recirculating endosomes. Under physiological neutral pH conditions, the affinity of desferrioxetransferrin for the receptor decreases dramatically, thus completing its release, and TfR1 re-enters the next round of the ligand binding and internalization cycle. This sophisticated cycling mechanism ensures the continuity and efficiency of cellular iron supply.

Advantages of Targeting Transferrin Receptors in Drug Delivery

TfR1 is overexpressed on the surface of a variety of malignant tumor cells to meet their high iron demand for rapid proliferation. In addition, brain capillary endothelial cells, which constitute the Blood-Brain Barrier (BBB), also highly express TfR1, which is critical for maintaining iron homeostasis in brain tissues. This selective high expression in pathological tissues and specific barrier sites provides an important molecular basis for targeted delivery. Modification of drug carriers or drug molecules with ligands that bind specifically to TfR1 (e.g., antibodies, transferrin itself, or the targeting peptides explored in this article) can enable active targeted enrichment of drugs to focal regions (e.g., tumor tissues or across the BBB into the brain parenchyma). This strategy not only significantly improves drug bioavailability at the target site and enhances therapeutic efficacy, but also effectively reduces the distribution of the drug in non-targeted healthy tissues, resulting in a substantial reduction in systemic toxicity and an improved therapeutic window.

Characterization of Transferrin-Targeting Peptides

Compared with larger targeting ligands such as antibodies or full-length transferrin, short peptide molecules have attracted much attention in the development of targeted delivery systems due to their small molecular weight, low immunogenicity, ease of chemical synthesis and modification, and better tissue penetration, etc. HAIYPRH, THRPPMWSPVWP, and SPRPRHTLRLSL are three representative peptide sequences that have been intensively investigated and demonstrated good TfR1 representative peptide sequences that have been intensively studied and demonstrated good TfR1 targeting ability, and each of them has unique binding properties and application potential.

HAIYPRH and Its Brain-Targeting Capabilities

The heptapeptide HAIYPRH (His-Ala-Ile-Tyr-Pro-Arg-His) was screened by phage display technology and specifically recognizes and binds to human TfR1. Uniquely, HAIYPRH binds to an epitope region of TfR1 that is distinct from the natural ligand transferrin. This non-competitive binding property is the core mechanism for efficient brain-targeted delivery. When HAIYPRH binds to TfR1, it mimics or triggers a process similar to the internalization and transcytosis of the transferrin-receptor complex. Numerous studies have demonstrated that HAIYPRH-modified nanocarriers or drug couplers can significantly enhance their efficiency in crossing the BBB and increase drug concentration in the brain parenchyma, providing a powerful tool for the treatment of central nervous system disorders (e.g., brain tumors, neurodegenerative diseases).

THRPPMWSPVWP: Structure and Binding Affinity

The dodecapeptide THRPPMWSPVWP (Thr-His-Arg-Pro-Pro-Met-Trp-Ser-Pro-Val-Trp-Pro), also derived from a phage display screen, also showed significant affinity for TfR1. The peptide sequence is long and its structural stability may be affected by the formation of internal disulfide bonds (e.g. Cys-Cys linkage). THRPPMWSPVWP was shown to bind TfR1 efficiently and its ability to mediate drug carrier-targeted delivery to TfR1-expressing cells was demonstrated in in vitro and in vivo models. Its binding properties and structure provide an important reference for the design of more stable or optimized TfR1-targeting peptides. In-depth study of its binding epitope and affinity will help to understand its mode of interaction with the receptor.

SPRPRHTLRLSL Peptide for Enhanced Delivery Efficiency

The peptide SPRPRHTLRLSL (Ser-Pro-Arg-Pro-Arg-His-Thr-Leu-Arg-Leu-Ser-Leu) is another important class of TfR1-targeting ligands. The core strength of this peptide is its efficient cell binding and internalization ability. It was found that SPRPRHTLRLSL-modified nanoparticles or liposomes can be rapidly taken up by TfR1-expressing cells, including tumor cells and endothelial cells. This efficient internalization property is critical for therapeutic strategies that require drug delivery into the cell interior, such as gene therapy or chemotherapeutic agents that require intracellular release. Targeted delivery mediated by SPRPRHTLRLSL can significantly increase the intracellular concentration of the loaded drug and overcome the cell membrane barrier, resulting in enhanced drug efficacy, which is particularly suitable for targeted therapy of tumors.

Applications in Brain Drug Delivery and Cancer Therapy

TfR-targeted peptides, due to their ability to specifically bind TfR1, have demonstrated great application value in the two key areas of overcoming biological barriers and achieving precision therapies, especially in brain drug delivery and tumor-targeted chemotherapy.

Crossing the Blood-Brain Barrier with Peptide-Mediated Delivery

The blood-brain barrier is the biggest physiological obstacle preventing the majority of therapeutic agents from entering the central nervous system. Based on the high expression of TfR1 on BBB endothelial cells, TfR-targeting peptides such as HAIYPRH have become a powerful weapon to break through this barrier. The core mechanism lies in mimicking the natural ligand-receptor pathway of transferrin, i.e., through TfR1-mediated receptor-mediated transcytosis (RMT). When the peptide binds to TfR1 on the apical membrane side of BBB endothelial cells, it triggers endocytosis to form vesicles, which carry the peptide and its coupled or loaded drug across the endothelial cell layer and are eventually released into the brain parenchyma on the basolateral side of the basement membrane. Using HAIYPRH-modified liposomes, polymer nanoparticles or directly coupling drugs with peptides, therapeutic drugs (e.g., chemotherapeutic agents, neurotrophic factors, nucleic acid drugs, etc.) have been successfully delivered to the brain in a variety of animal models, which has significantly increased the concentration of drugs in the brain foci, and has opened up a new avenue for the treatment of gliomas, Alzheimer's disease, Parkinson's disease, and other central nervous system diseases.

Targeted Chemotherapy Using Transferrin Receptor Peptides

In the field of tumor therapy, the application of TfR-targeting peptides has focused on improving tumor targeting and reducing systemic toxicity of chemotherapeutic agents. Overexpression of TfR1 on the surface of multiple malignant tumor cells provides the basis for peptide-mediated active targeting. Peptides such as THRPPMWSPVWP or SPRPRHTLRLSL are chemically bonded or physically encapsulated to nanocarriers (e.g., liposomes, polymeric micelles, gold nanoparticles) or directly coupled to chemotherapeutic agents (e.g., adriamycin, paclitaxel) to construct targeted delivery systems. These systems can promote the enrichment of drug carriers at the tumor site and efficient endocytosis by tumor cells through the specific binding of peptides to TfR1 on the surface of tumor cells. Studies have shown that these targeted delivery systems can significantly increase the accumulation concentration and prolong the retention time of chemotherapeutic drugs in tumor tissues, and at the same time reduce the distribution of the drugs in normal organs such as the heart, liver, and kidneys, which can enhance the efficacy of anti-tumor therapy and at the same time effectively alleviate the dose-limiting side effects such as myelosuppression, cardiotoxicity, and neurotoxicity.

Taken together, the transferrin receptor-targeting peptides HAIYPRH, THRPPMWSPVWP, and SPRPRHTLRLSL represent cutting-edge tools for overcoming critical biological barriers and enabling precise drug delivery. They significantly enhance the efficiency and specificity of drug delivery to brain foci and tumor tissues by specifically recognizing and binding to TfR1, which is highly expressed in pathological tissues (e.g., tumors) and on specific barriers (e.g., the blood-brain barrier), and by exploiting receptor-mediated transcytosis and receptor-mediated endocytosis, respectively. The unique binding properties of each of these peptides (e.g., non-competitive brain targeting of HAIYPRH, structure and affinity of THRPPMWSPVWP, and efficient internalization of SPRPRHTLRLSL) provide diversified choices for the design of delivery systems for different therapeutic needs (traversing the BBB or tumor cell targeting). With the in-depth analysis of the peptide-receptor interaction mechanism, the continuous optimization of peptide stability and pharmacokinetics, and the development of novel coupling technologies and carrier materials, TfR-targeted peptides have extremely broad application prospects in the clinical translational fields of neurological disease treatment and tumor precision chemotherapy, and are expected to bring breakthrough therapies for many intractable diseases.

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