Lactoferrin, a multi-functional glycoprotein: Active therapeutic, drug nanocarrier & targeting ligand

Abstract

Recent progress in protein-based nanomedicine, inspired by the success of Abraxane® albumin-paclitaxel nanoparticles, have resulted in novel therapeutics used for treatment of challenging diseases like cancer and viral infections. However, absence of specific drug targeting, poor pharmacokinetics, premature drug release, and off-target toxicity are still formidable challenges in the clinic. Therefore, alternative protein-based nanomedicines were developed to overcome those challenges. In this regard, lactoferrin (Lf), a glycoprotein of transferrin family, offers a promising biodegradable well tolerated material that could be exploited both as an active therapeutic and drug nanocarrier. This review highlights the major pharmacological actions of Lf including anti-cancer, antiviral, and immunomodulatory actions. Delivery technologies of Lf to improve its pries and enhance its efficacy were also reviewed. Moreover, different nano-engineering strategies used for fabrication of drug-loaded Lf nanocarriers were discussed. In addition, the use of Lf for functionalization of drug nanocarriers with emphasis on tumor-targeted drug delivery was illustrated. Besides its wide application in oncology nano-therapeutics, we discussed the recent advances of Lf-based nanocarriers as efficient platforms for delivery of anti-parkinsonian, anti-Alzheimer, anti-viral drugs, immunomodulatory and bone engineering applications.

A Review on Lactoferrin and Central Nervous System Diseases

“…Increasing numbers of studies indirectly suggest that the Lf-mediated neuroprotection against neurodegenerative disorders is attributed to its biological characteristics. (1) In inflamed tissues, the content of Lf is significantly increased [60], and Lf can reduce the expression of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 to exert its anti-inflammatory effects [61]; (2) Lf can significantly increase the content of superoxide dismutase (SOD) and reduce the generation of ROS by inhibiting the Fenton reaction [16], thereby exerting ROS modulator effects; (3) Lf can regulate the expression of proteins involved in lipid degradation by controlling the activity of the cAMP/extracellular regulatory protein kinase (ERK) signaling pathway via LRP1 [28], thereby regulating lipid metabolism; (4) increased LfR expression in the brains of patients with neurodegenerative diseases suggests that Lf may play a significant role in the pathogenesis and prevention of neurodegenerative diseases [62]; (5) Lf acts as a normoxic mimetic of hypoxia that is capable of stabilizing hypoxia-inducible factor 1α (HIF-1α) [63] (6); Lf elevates the mRNA and protein levels of brain-derived neurotrophic factor (BDNF) and components of its signaling pathway [64].…”

“…Lactoferrin (Lf) was first identified in bovine milk by Sorensen in 1939, and Lf was subsequently isolated from human milk in 1960 [ 1 , 2 ]. Lf is an iron-binding glycoprotein with a molecular weight of approximately 80 kDa.…”

“…Lf is a multifunctional protein. In addition to its well-known function of regulating iron homeostasis [ 14 ], Lf also exerts multiple important biological effects, such as anti-inflammatory, antibacterial, reactive oxygen species (ROS) modulator, antiviral, and antitumor immunity effects [ 1 , 2 , 4 , 5 , 12 , 15 , 16 ]. These activities are largely mediated by the capacity of Lf to bind iron [ 7 , 17 , 18 , 19 ] and the binding constant [ 20 , 21 , 22 ].…”

Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective

“…Finally, while antibodies are most commonly associated with antigen targeting, ADCs are also being developed to conjugate cytotoxic drugs to tumor-specific receptor ligands. While these targeting modalities are not covered in this review, we point readers to these recently published reviews [191][192][193][194][195].…”

Stability-Indicating Analytical Approach for Stability Evaluation of Lactoferrin

“…Due to its positive effects, it is commercially purified from milk and added as an active ingredient to infant milk formulas, food supplements, food products, beverages, cosmetics, and pet foods [ 1 , 2 , 3 ]. Several clinical studies showed its potential to be used as a primary or adjuvant agent in the treatment of infections, cancers, sepsis, and other diseases [ 3 , 4 , 5 ].…”