Pharmacology of Lactoferrin Formulations: History
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Contributor:
Fabiola Guzmán-Mejía
,
Marycarmen Godínez-Victoria
,
Daniel Efrain Molotla-Torres
,
Maria Elisa Drago-Serrano

Lactoferrin is an 80 kDa monomeric glycoprotein that exhibits multitask activities of interest in the pharmaceutical field for the design of products with therapeutic potential including nanoparticles, liposomes, among many others. Lactoferrin has been included in delivery systems to transport and protect drugs from enzymatic degradation in the intestine favoring the bioavailability for the treatment of inflammatory bowel disease and colon cancer. Moreover, nanoparticles loaded with lactoferrin have been formulated as delivery system to transport drugs for neurodegenerative diseases, which cannot cross the blood-brain barrier to enter toward the central nervous system. Pharmaceutical products containing lactoferrin as either bioactive or on those products formulated with lactoferrin as carrier have been designed considering their interaction with receptors expressed in tissues as targets of drugs delivered via parenteral or mucosal administration. These lactoferrin preparations may be sustainable approaches that may contributed decreasing resistance of antimicrobials and enhancing the bioavailability of first-hand drugs for intestinal chronic inflammation and neurodegenerative diseases.

  • lactoferrin
  • neurodegenerative diseases
  • intestinal bowel diseases

1. Introduction

Lactoferrin (Lf) is a monomeric glycoprotein with a molecular mass of 80 kDa belonging to the transferrin family. Lactoferrin is an iron chelator that binds reversibly two ferric (Fe3+) cations so that the iron free form is termed apolactoferrin (Apo-Lf), whereas fully saturated diferric Lf is known as hololactoferrin (Holo-Lf) [1][2]. Lactoferrin is a multifunctional glycoprotein that displays antimicrobial [3], antiviral [4][5], immunomodulatory [6], and antioxidant properties [2]. Antimicrobial actions of Lf entail its microbiostatic effect (i) by preventing the uptake of iron as an essential factor for the growth of some microbial species and (ii) by interacting with the surface components of bacteria, protozoans, and yeast, resulting in an increased permeability, disruption, and structural damage of the microbial surface [3]. Lactoferrin displays antiviral properties to influenza viruses, herpes simplex viruses, the hepatitis C virus, coronaviruses, and retroviruses [3][5]. Lf has antiviral action by inducing innate antiviral immunity to the norovirus causing gastroenteritis as documented in B cell culture assays [4]. The underlying mechanisms entail the ability of Lf to bind the virus envelope protein or the virus receptor and to block the virus entry to host cells or indirectly to prevent virus-induced apoptosis [3]. Experimental studies support the antiviral action of Lf, although the antiviral outcome of Lf is not so clear as documented in human trials [5].
Lactoferrin acts as a link between innate and adaptive immunity. Lf enhances the generation of the antibody response and modulates the interleukin generation and the activation of cells responsible for adaptive immunity, i.e., antigen-presenting cells. Lf modulation proceeds across the cell surface through receptor signaling and/or via internalization resulting in modulation of transcriptional nuclear factors [6]. Lactoferrin participates in the regulation of oxidative stress that either plays a critical role in protection against numerous microbial infections or has a detrimental impact on chronic degenerative processes [3]. Lactoferrin’s ability to bind reversibly free Fe3+ cations helps to balance iron levels in the body [6]. An excess of free Fe3+ cations can be toxic because they can donate electrons to diatomic oxygen (O2) necessary in the formation of reactive oxygen species (ROS). It is known that the rate and extent of ROS generation and removal are dependent on the enzymatic efficiency of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). Ferric cations drive the generation of ROS including superoxide radical (·O2−), hydroxyl radical (·OH−), and hydrogen peroxide (H2O2) via Fenton reaction; the latter encompasses the participation of the enzymes SOD, GPx, and CAT. Thus, by binding Fe3+ cations, Lf is able to prevent ROS production and avoid the deleterious effects of oxidative stress [2].
Lactoferrin can carry out some modulatory actions due to its interaction with multiple eukaryotic receptors expressed on a wide array of target cells. Receptors that bind to Lf include intelectin-1 (omentin-1), CD14, chemokine receptor 4 (CXCR4), and low-density lipoprotein receptor-related protein (LRP), among many others. Intelectin-1 is expressed in the small intestine and enables Lf uptake, that is, the binding and endocytosis of Lf; CD14 and CXCR4 are found in phagocytic cells; and LRP is distributed in the nervous system [7].

2. Pharmacology of Lactoferrin Formulations: General Aspects

Lactoferrin is used for many pharmaceutical and food applications, and their functions depend on structure and conformation. In this section we will address some pharmacokinetic (absorption and biodistribution) and pharmacodynamic aspects that have led to the use of Lf in the development of different carrier systems. These carrier systems are especially important for the use of formulations that require (i) improving the stability of Lf to be administered orally, alone or in combination with other drugs sensitive to degradation in the gastrointestinal tract (GIT) and (ii) driving drugs into the CNS that cannot cross the blood–brain barrier (BBB) by taking advantage of Lf receptor-mediated cellular capture processes.
The oral route of administration is the most convenient, safe, and economical route. To achieve therapeutic efficiency, an orally administered drug must be absorbed in the GIT to be bioavailable in plasma and be distributed through the bloodstream to target organs. Orally administered Lf and Lf-peptide derivatives experience numerous challenges such as inactivation by pH values and enzymatic degradation by GIT peptidases [8]. Therefore, carrier systems are used for improving the stability and bioavailability of Lf or different drugs that are sensitive to gastric degradation when they are administrated orally. The most important formulation approaches for bioactive proteins are lipid-based nanocarriers such as oil-in-water nanoemulsions, self-emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), liposomes, and micelles [9]. Proteins in combination with lipid components of carrier systems form highly lipophilic structures in which peptidases and hydrolases cannot act, thus protecting the bioactive protein [10][11]. For the intestinal absorption process, lipid-based nanocarriers are internalized by endocytosis and transcytosis via a clathrin-dependent endocytic pathway [9].
Many experimental approaches have been made to evaluate how different carrier systems, such as microparticles or nanoparticles and liposomes, can improve the stability of Lf. These oral delivery systems focused on the stability of Lf recently have been extensively reviewed [12][13][14]. Using an in vitro simulated digestive model, it has been shown that bLf is sensitive to gastric digestion [15], but when it is formulated in oral carriers, the systems’ proteolysis is decreased [16][17][18][19][20]. This oral delivery system showed high stability in gastric conditions and effectively protected Lf from digestion and improved the intestinal absorption. Lactoferrin absorption is mediated by the existence of receptors (LfR) expressed in different tissues [7]. In the GTI, intelectin-1 receptor is responsible for transporting Lf within enterocytes as it has been reported on Caco-2 epithelial cell cultures. Immunochemical assays showed the co-localization of Lf and intelectin receptor within endosomes marked with endosome antigen 1 (EEA1) [21]. Studies have shown that Lf in carrier systems improves the cell uptake vs. Lf native or non-formulated on Caco-2 cells cultures [22][23]. Once captured by epithelial cells, Lf can then be released intact or fragmented into the culture medium [24]. These findings suggested that at the intestinal level, lactoferrin is endocytosed to be released at the lamina propria.
Lf present in the lamina propria can be distributed to the blood circulation via the lymphatic system [25][26]. A study evaluated the amount of bLf or bLf liposomes administered intraduodenally to Wistar rats; it was found that both formulations had the same absorption profiles evaluated as plasma concentrations of Lf [26]. This assay indicates that Lf formulations do not alter the absorption process in epithelial cells, but the Lf administrated intraduodenally does not allow the observation of the effect of gastric degradation of Lf.
In vivo assays of biodistribution in mice fed Lf nanoparticles (Lf-NPs) in their diet showed that the amounts of Lf in different tissues such as the stomach, small intestine, large intestine, heart, liver, lung, and brain was found to be greater than in mice fed a diet without a delivery system [22][27][28]. Having in mind the efficient biodistribution of Lf NPs within the brain, experimental studies addressed the use of Lf as a drug carrier targeted to the CNS via LfR. Lactoferrin receptor low-density lipoprotein receptor-related protein 1 (LRP1) has been reported in the brain including the blood–brain barrier (BBB) [29][30]. Binding of Lf to the LRP induces the transport of Lf through brain endothelial cells within the central nervous system (CNS) [31]. Some Lf nanoformulations have been designed as transporters of drugs that do not cross the BBB to the CNS for Alzheimer’s and Parkinson’s treatment. Experimental biodistribution assays in mice treated intravenously or intranasally with fluorescent Lf–drug nanoparticles showed their accumulation in the brain [32][33]. The data suggested the efficient BBB crossing of Lf NPs and underlined their potential use for the transport of drugs in the CNS.

This entry is adapted from the peer-reviewed paper 10.3390/ph16020214

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