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.

Keywords: Anti-viral drugs; Bone engineering; Cancer therapy; Drug delivery; Immunomodulatory functions; Lactoferrin; Nanoparticles; Tumor targeting.

Graphical abstract

Fig. 1

The research progress timeline of Lf nanoparticles in cancer therapy field.

Fig. 2

A schematic diagram illustrating different pharmacological actions of Lf.

Fig. 3

Antiviral activity of Lf towards SARS-CoV. (A) SARS-Cov utilizes Heparan Sulfate Proteoglycans (HSPG) to roll on host cells and subsequently identify potential specific entry receptors. (B) Upregulation of Lf and allocations to HSPGs to prevent initial contact between virus particles and subsequent infection [44].

Fig. 4

Schematic representation of the major anti-cancer mechanisms of Lf.

Fig. 5

Proposed mechanisms of absorption of Fe-bLf loaded polymetric NPs in cancer therapy. Maximal Uptake was achieved through iron receptors; DMT1 in addition to LRP receptors. Through EPR mediated effect, the NPs reached cancer tissue and subsequently internalized through pinocytosis utilizing Tf and Lf receptors [14].

Fig. 6

Schematic illustration of the brain targeting mechanism of Lf.

Fig. 7

Schematic diagram illustrating the formation of inhalable PEM/RES-loaded liquid crystalline monoolein NPs for lung cancer targeting [196].

Fig. 8

Immuno-modulatory mechanisms of Lf. Lf triggers differentiation, maturation and activation of immune cells through NF-ĸB pathway, leading to enhanced activity of immune cell; NK and PMN cells.