Lactoferrin Receptor Research Articles

In Vitro and In Vivo Evaluation of Lactoferrin-Modified Liposomal Etomidate with Enhanced Brain-Targeting Effect for General Anesthesia.

Etomidate is a general anesthetic that has shown good hemodynamic stability without significant cardiovascular or respiratory depression. Despite several kinds of dosage forms having been reported for this drug, formulation types are very limited in clinical practice, and brain-targeted formulations for this central nervous system (CNS) drug have been rarely reported. Moreover, studies on the biocompatibility, toxicity, and anesthetic effects of the etomidate preparations in vivo were inadequate. The present study was to develop lactoferrin-modified liposomal etomidate (Eto-lip-LF) for enhanced drug distribution in the brain and improved anesthetic effects. Eto-lip-LF had good stability for storage and hemocompatibility for intravenous injection. Compared with the non-lactoferrin-containing liposomes, the lactoferrin-modified liposomes had notably enhanced brain-targeting ability in vivo, which was probably realized by the binding of transferrin with the transferrin and lactoferrin receptors highly distributed in the brain. Eto-lip-LF had a therapeutic index of about 25.3, higher than that of many other general anesthetics. Moreover, compared with the commercial etomidate emulsion, Eto-lip-LF could better achieve rapid onset of general anesthesia and rapid recovery from anesthesia, probably due to the enhanced drug delivery to the brain. The above results demonstrated the potential of this lactoferrin-modified liposomal etomidate to become an alternative preparation for clinical general anesthesia.

Targeting Intracellular Bacteria with Dual Drug-loaded Lactoferrin Nanoparticles.

Treatment of microbial infections is becoming daunting because of widespread antimicrobial resistance. The treatment challenge is further exacerbated by the fact that certain infectious bacteria invade and localize within host cells, protecting the bacteria from antimicrobial treatments and the host's immune response. To survive in the intracellular niche, such bacteria deploy surface receptors similar to host cell receptors to sequester iron, an essential nutrient for their virulence, from host iron-binding proteins, in particular lactoferrin and transferrin. In this context, we aimed to target lactoferrin receptors expressed by macrophages and bacteria; as such, we prepared and characterized lactoferrin nanoparticles (Lf-NPs) loaded with a dual drug combination of antimicrobial natural alkaloids, berberine or sanguinarine, with vancomycin or imipenem. We observed increased uptake of drug-loaded Lf-NPs by differentiated THP-1 cells with up to 90% proportion of fluorescent cells, which decreased to about 60% in the presence of free lactoferrin, demonstrating the targeting ability of Lf-NPs. The encapsulated antibiotic drug cocktail efficiently cleared intracellular Staphylococcus aureus (Newman strain) compared to the free drug combinations. However, the encapsulated drugs and the free drugs alike exhibited a bacteriostatic effect against the hard-to-treat Mycobacterium abscessus (smooth variant). In conclusion, the results of this study demonstrate the potential of lactoferrin nanoparticles for the targeted delivery of antibiotic drug cocktails for the treatment of intracellular bacteria.

Thermosensitive hydrogel with emodin-loaded triple-targeted nanoparticles for a rectal drug delivery system in the treatment of chronic non-bacterial prostatitis

BackgroundThe complex etiology and pathogenesis underlying Chronic Non-Bacterial Prostatitis (CNP), coupled with the existence of a Blood Prostate Barrier (BPB), contribute to a lack of specificity and poor penetration of most drugs. Emodin (EMO), a potential natural compound for CNP treatment, exhibits commendable anti-inflammatory, anti-oxidant, and anti-fibrosis properties but suffers from the same problems as other drugs.MethodsBy exploiting the recognition properties of lactoferrin (LF) receptors that target intestinal epithelial cells (NCM-460) and prostate epithelial cells (RWPE-1), a pathway is established for the transrectal absorption of EMO to effectively reach the prostate. Additionally, hyaluronic acid (HA) is employed, recognizing CD44 receptors which target macrophages within the inflamed prostate. This interaction facilitates the intraprostatic delivery of EMO, leading to its pronounced anti-inflammatory effects. A thermosensitive hydrogel (CS-Gel) prepared from chitosan (CS) and β-glycerophosphate disodium salt (β-GP) was used for rectal drug delivery with strong adhesion to achieve effective drug retention and sustained slow release. Thus, we developed a triple-targeted nanoparticle (NPs)/thermosensitive hydrogel (Gel) rectal drug delivery system. In this process, LF, with its positive charge, was utilized to load EMO through dialysis, producing LF@EMO-NPs. Subsequently, HA was employed to encapsulate EMO-loaded LF nanoparticles via electrostatic adsorption, yielding HA/LF@EMO-NPs. Finally, HA/LF@EMO-NPs lyophilized powder was added to CS-Gel (HA/LF@EMO-NPs Gel).ResultsCellular assays indicated that NCM-460 and RWPE-1 cells showed high uptake of both LF@EMO-NPs and HA/LF@EMO-NPs, while Raw 264.7 cells exhibited substantial uptake of HA/LF@EMO-NPs. For LPS-induced Raw 264.7 cells, HA/LF@EMO-NPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways. Tissue imaging corroborated the capacity of HA/LF-modified formulations to breach the BPB, accumulating within the gland's lumen. Animal experiments showed that rectal administration of HA/LF@EMO-NPs Gel significantly reduced inflammatory cytokine expression, oxidative stress levels and fibrosis in the CNP rats, in addition to exerting anti-inflammatory effects by inhibiting the NF-κB signaling pathway without obvious toxicity.ConclusionThis triple-targeted NPs/Gel rectal delivery system with slow-release anti-inflammatory, anti-oxidant, and anti-fibrosis properties shows great potential for the effective treatment of CNP.Graphical

Lactoferrin: neuroprotection against Parkinson's disease and secondary molecule for potential treatment.

Parkinson's disease (PD) is the second-most common neurodegenerative disease and is largely caused by the death of dopaminergic (DA) cells. Dopamine loss occurs in the substantia nigra pars compacta and leads to dysfunctions in motor functions. Death of DA cells can occur with oxidative stress and dysfunction of glial cells caused by Parkinson-related gene mutations. Lactoferrin (Lf) is a multifunctional glycoprotein that is usually known for its presence in milk, but recent research shows that Lf is also found in the brain regions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a known mitochondrial toxin that disturbs the mitochondrial electron transport chain (ETC) system and increases the rate of reactive oxygen species. Lf's high affinity for metals decreases the required iron for the Fenton reaction, reduces the oxidative damage to DA cells caused by MPTP, and increases their surveillance rate. Several studies also investigated Lf's effect on neurons that are treated with MPTP. The results pointed out that Lf's protective effect can also be observed without the presence of oxidative stress; thus, several potential mechanisms are currently being researched, starting with a potential HSPG-Lf interaction in the cellular membrane of DA cells. The presence of Lf activity in the brain region also showed that lactoferrin initiates receptor-mediated transcytosis in the blood-brain barrier (BBB) with the existence of lactoferrin receptors in the endothelial cells. The existence of Lf receptors both in endothelial cells and DA cells created the idea of using Lf as a secondary molecule in the transport of therapeutic agents across the BBB, especially in nanoparticle development.

Comparison of Whey Proteome and Glycoproteome in Bovine Colostrum and Mature Milk.

Milk samples were collected from 10 cows, in the colostrum (3-4 days) and mature (90 days) lactation stage, to assess the differential expression of all whey proteins and N-glycoproteins. In total, 240 whey proteins and 315 N-glycosylation sites on 214 glycoproteins were quantified. GO annotations, KEGG pathway analysis, and protein classification were performed to understand the similarities and differences of the biological functions of whey proteins and N-glycoproteins among different lactation stages in bovine milk. Furthermore, differential expression of whey proteins and whey N-glycosylated proteins was found between different lactation stages. The related changes of biological functions in differentially expressed proteins were discussed. For example, the increased frequency of glycosylation on lactoferrin and folate receptor alpha occurring in bovine colostrum may provide protection and stimulate development of the newborn calf. Our study thereby improves understanding of variations of glycosylation sites on milk glycoproteins among lactation stages.

Ferroportin1 in the brain

Despite years of research, it remains unclear why certain brain regions of patients with neurodegenerative diseases (NDs) have abnormally high levels of iron, although it has long been suggested that disrupted expression of iron-metabolizing proteins due to genetic or non-genetic factors is responsible for the enhancement in brain iron contents. In addition to the increased expression of cell-iron importers lactoferrin (lactotransferrin) receptor (LfR) in Parkinsonʼs disease (PD) and melanotransferrin (p97) in Alzheimerʼs disease (AD), some investigations have suggested that cell-iron exporter ferroportin 1 (Fpn1) may be also associated with the elevated iron observed in the brain. The decreased expression of Fpn1 and the resulting decrease in the amount of iron excreted from brain cells has been thought to be able to enhance iron levels in the brain in AD, PD and other NDs. Cumulative results also suggest that the reduction of Fpn1 can be induced by hepcidin-dependent and -independent pathways. In this article, we discuss the current understanding of Fpn1 expression in the brain and cell lines of rats, mice and humans, with emphasis on the potential involvement of reduced Fpn1 in brain iron enhancement in patients with AD, PD and other NDs.

Neuroprotective Effects of Lactoferrin in Alzheimer's and Parkinson's Diseases: A Narrative Review.

Recent advancements in lactoferrin research have uncovered that lactoferrin does function not only as an antimicrobial protein but also as an immunomodulatory, anticancer, and neuroprotective agent. Focusing on neuroprotection, this literature review delineates how lactoferrin interacts in the brain, specifically its neuroprotective effects and mechanisms against Alzheimer's and Parkinson's diseases (AD and PD), the two most common neurodegenerative diseases. The neuroprotective pathways involving surface receptors (heparan sulfate proteoglycan (HSPG) and lactoferrin receptor (LfR)), signaling pathways (extracellular regulated protein kinase-cAMP response element-binding protein (ERK-CREB) and phosphoinositide 3-kinase/Akt (PI3K/Akt)), and effector proteins (A disintegrin and metalloprotease10 (ADAM10) and hypoxia-inducible factor 1α (HIF-1α)) in cortical/hippocampal and dopaminergic neurons are described. These cellular effects of lactoferrin are likely responsible for attenuating cognitive and motor deficits, amyloid-β and α-synuclein accumulation, and neurodegeneration in animal and cellular models of AD and PD. This review also discusses the inconsistent findings related to the neuroprotective effects of lactoferrin against AD. Overall, this review contributes to the existing literature by clarifying the potential neuroprotective effects and mechanisms of lactoferrin in the context of AD and PD neuropathology.

Time to Kill and Time to Heal: The Multifaceted Role of Lactoferrin and Lactoferricin in Host Defense.

Lactoferrin is an iron-binding glycoprotein present in most human exocrine fluids, particularly breast milk. Lactoferrin is also released from neutrophil granules, and its concentration increases rapidly at the site of inflammation. Immune cells of both the innate and the adaptive immune system express receptors for lactoferrin to modulate their functions in response to it. On the basis of these interactions, lactoferrin plays many roles in host defense, ranging from augmenting or calming inflammatory pathways to direct killing of pathogens. Complex biological activities of lactoferrin are determined by its ability to sequester iron and by its highly basic N-terminus, via which lactoferrin binds to a plethora of negatively charged surfaces of microorganisms and viruses, as well as to mammalian cells, both normal and cancerous. Proteolytic cleavage of lactoferrin in the digestive tract generates smaller peptides, such as N-terminally derived lactoferricin. Lactoferricin shares some of the properties of lactoferrin, but also exhibits unique characteristics and functions. In this review, we discuss the structure, functions, and potential therapeutic uses of lactoferrin, lactoferricin, and other lactoferrin-derived bioactive peptides in treating various infections and inflammatory conditions. Furthermore, we summarize clinical trials examining the effect of lactoferrin supplementation in disease treatment, with a special focus on its potential use in treating COVID-19.

Gastrointestinally absorbable lactoferrin-heparin conjugate with anti-angiogenic activity for treatment of brain tumor.

Glioblastoma multiforme (GBM) is a central nervous system disease with poor prognosis. Curative treatments for GBM involve chemotherapy, radiotherapy, and surgical pathways. Recently, antiangiogenic therapy through medications has been tried to slow tumor growth, but the drugs can induce side effects. To overcome these limitations, we developed a new orally absorbable form of heparin that can attenuate angiogenic activity by binding to growth factors around the tumor tissue. We conjugated lactoferrin (Lf) to heparin because Lf can be orally absorbed, and it interacts with the lactoferrin receptor (Lf-R) expressed on the intestine, blood-brain barrier (BBB), and glioma tumor masses. We successfully conjugated Lf and heparin by amide bond formation, as evidenced by advanced physicochemical properties such as pharmacokinetics and stability in acidic condition. This new material inhibited angiogenesis in vitro without toxicity. In addition, Lf-heparin administered orally to GBM orthotopic mice was absorbed in the small intestine and delivered specifically to the brain tumor by receptor transcytosis (Lf-R). Lf-heparin further attenuated angiogenesis progression in GBM orthotopic mice. Based on these results, Lf-heparin shows potential as a new oral medication for treatment of glioblastoma.

Inhibition of DAMP actions in the tumoral microenvironment using lactoferrin-glycyrrhizin conjugate for glioblastoma therapy

BackgroundHigh-mobility group box-1 (HMGB1) released from the tumor microenvironment plays a pivotal role in the tumor progression. HMGB1 serves as a damaged-associated molecular pattern (DAMP) that induces tumor angiogenesis and its development. Glycyrrhizin (GL) is an effective intracellular antagonist of tumor released HMGB1, but its pharmacokinetics (PK) and delivery to tumor site is deficient. To address this shortcoming, we developed lactoferrin-glycyrrhizin (Lf-GL) conjugate.MethodsBiomolecular interaction between Lf-GL and HMGB1 was evaluated by surface plasmon resonance (SPR) binding affinity assay. Inhibition of tumor angiogenesis and development by Lf-GL attenuating HMGB1 action in the tumor microenvironment was comprehensively evaluated through in vitro, ex vivo, and in vivo. Pharmacokinetic study and anti-tumor effects of Lf-GL were investigated in orthotopic glioblastoma mice model.ResultsLf-GL interacts with lactoferrin receptor (LfR) expressed on BBB and GBM, therefore, efficiently inhibits HMGB1 in both the cytoplasmic and extracellular regions of tumors. Regarding the tumor microenvironment, Lf-GL inhibits angiogenesis and tumor growth by blocking HMGB1 released from necrotic tumors and preventing recruitment of vascular endothelial cells. In addition, Lf-GL improved the PK properties of GL approximately tenfold in the GBM mouse model and reduced tumor growth by 32%. Concurrently, various biomarkers for tumor were radically diminished.ConclusionCollectively, our study demonstrates a close association between HMGB1 and tumor progression, suggesting Lf-GL as a potential strategy for coping with DAMP-related tumor microenvironment.Graphical HMGB1 is a tumor-promoting DAMP in the tumor microenvironment. The high binding capability of Lf-GL to HMGB1 inhibits tumor progression cascade such as tumor angiogenesis, development, and metastasis. Lf-GL targets GBM through interaction with LfR and allows to arrest HMGB1 released from the tumor microenvironment. Therefore, Lf-GL can be a GBM treatment by modulating HMGB1 activity.

Folic acid-modified lactoferrin nanoparticles coated with a laminarin layer loaded curcumin with dual-targeting for ulcerative colitis treatment

Curcumin (CUR) is a promising natural compound in ulcerative colitis (UC) treatment, but limited by its low oral bioavailability and poor targeting ability. Therefore, given the targeting action of lactoferrin (LF) by binding to the LF receptors of intestinal epithelial cells (IECs) and of folic acid (FA) by binding to the FA receptors of macrophages, we developed an oral dual-targeting nanosystem. Laminarin (LA)-coated, FA-modified LF nanoparticles (NPs) were used to encapsulate CUR (LA/FA/CUR-NPs) with a food-grade, enzyme-sensitive, and dual-targeting capacity. For the generated NPs, LF improved the loading efficiency of CUR (95.08 %). The LA layer could improve the upper gastrointestinal tract stability of the NPs while improve drug release around colon lesion through β-glucanase digestion. Based on the cellular uptake evaluation, FA/CUR-NPs were capable of specifically targeting colonic epithelial cells and macrophages through LF and FA ligands, respectively, to enhance the uptake efficiency. Moreover, based on the advantage of the dual-targeting strategy, oral administration of FA/CUR-NPs obviously reduced colitis symptoms by alleviating inflammation, accelerating colonic mucosal barrier repair and restoring the balance of the intestinal microbiota. This dual-targeted nanodesign corresponded to the multi-bioresponsibilities of CUR, thus offering a promising approach in UC treatment.

Binding of Equine Seminal Lactoferrin/Superoxide Dismutase (SOD-3) Complex Is Biased towards Dead Spermatozoa

Sperm-neutrophil binding is an important facet of breeding and significantly impacts fertility. While a specific seminal plasma protein has been found to reduce this binding and improve fertility (CRISP-3), additional molecule(s) appear to promote binding between defective sperm and neutrophils. Recent work has suggested one of these proteins is lactoferrin (LF), an 80 kDa iron-binding protein found throughout the body, but the purity of the protein was not confirmed. It is unknown if LF binds to sperm selectively based on viability, and if receptors for LF are located on equine sperm. To evaluate this, we attempted to purify equine seminal LF from five stallions (n = 5), biotinylate LF, and evaluate potential binding site(s) on spermatozoa. LF was consistently associated with superoxide dismutase (SOD-3), and all attempts to separate the two proteins were unsuccessful. Flow cytometric and microscopic analyses were used to compare LF/SOD-3 binding to viable and nonviable spermatozoa. Additionally, various methods of biotinylation were assessed to optimize this methodology. Biotinylation of seminal plasma protein was an effective and efficient method to study seminal plasma protein properties, and the binding site for LF/SOD-3 was found to be broadly localized to the entire sperm cell surface as well as selective towards nonviable/defective sperm. Although we were not able to determine if the binding to equine spermatozoa was through LF or SOD-3, we can conclude that equine seminal LF is tightly bound to SOD-3 and this protein complex binds selectively to nonviable spermatozoa, possibly to mark them for elimination by neutrophil phagocytosis.

"Guide" of muscone modification enhanced brain-targeting efficacy and anti-glioma effect of lactoferrin modified DTX liposomes.

Glioma is one of the most aggressive malignant diseases for human health. It is difficult to resect completely due to their invasiveness. The targeted delivery, as a noninvasive approach, is a major strategy for the development of treatments for brain tumors. Lactoferrin (Lf) receptors are over-expressed in both brain endothelial cells and glioma cells. Macromolecular Lf modified nanoparticles have been shown to enhance the brain targeting. Muscone is a "guide" drug that have been demonstrated to promote liposomes into the brain by modification. To further enhance the brain-targeting efficacy of Lf modified carriers, we designed that Lf and muscone dual-modified liposomes cross blood-brain barrier (BBB) and target to brain for enhanced docetaxel (DTX) brain delivery. The results showed that we successfully prepared Lf and muscone dual-modified liposomes (Lf-LP-Mu-DTX), the number of Lf molecules connected to the surface of per liposome was 28. Lf-LP-Mu-DTX increased uptake in both U87-MG cells and hCMEC/D3 cells, enhanced penetration of U87-MG tumor spheroid and in vitro BBB model, had better in vitro and in vivo anti-tumor effects. In conclusion, "guide" of muscone modification enhanced brain-targeting efficacy of Lf modified liposomes, Lf and muscone dual-modified docetaxel loaded liposomes present a potential brain-targeting drug delivery system for use in the future treatment of gliomas.

Association of Lactoferrin and Toll-like Receptor 2 Genotypes with Mastitis and Milk Components in Vietnamese Holstein Cattle.

Simply SummaryMastitis disease causes huge losses for the dairy industry worldwide. The molecular markers have been shown to be a promising tool for the diagnosis of mastitis infections and the selection of animals with better mastitis resistance. In this study, we surveyed the mastitis incidence in Vietnamese Holstein cows. We also examined the association of polymorphisms in Lactoferrin (LTF) and Toll-like receptor 2 (TLR2) genes with mastitis score and milk component traits. Our results indicated that the interaction between TLR2 genotypes and diseases has a significant impact on the fat and protein percentage of mink. Therefore, TLR2 polymorphism could be used for the selection of cows with better milk compositions.Mastitis is one of the most widespread diseases in dairy cows and causes huge losses for the dairy industry. Molecular markers can be used for the quick diagnosis of mastitis infection, consequently reducing the loss caused by this disease. Lactoferrin (LTF) and Toll-like receptor 2 (TLR2) have been suggested as candidate genes for mastitis; however, their associations with the mastitis incidence and milk components have not been reported in Vietnamese Holstein cows. This study examined the association of TLR2 and LTF polymorphisms with subclinical mastitis and milk components in the Holstein breed raised in Vietnam. Among 192 samples, we identified 44 mastitis-positive samples (22.92%). The mastitis significantly reduced the fat and lactose components in milk (p < 0.001) but increased the protein concentration in milk. A total of 94 (49%) and 98 (51%) cows had AA and AB genotypes for the LTF gene, respectively. No significant association was found between the LTF genotypes and the milk component traits or mastitis incidence (p > 0.05). The interaction between LTF and mastitis incidence was significantly associated with the protein percentage (p = 0.01). A total of 78, 76, and 38 cows had genotypes GG, GT, and TT for the TLR2 gene, respectively. TLR2 genotypes were not significantly associated with mastitis incidence (p > 0.05) but were significantly associated with pH value (p = 0.03). The interaction between TLR2 and mastitis incidence was significantly associated with the fat (p = 0.02) and protein percentage (p = 0.04). Further studies are required to confirm the roles of LTF and TFL2 in mastitis in the Holstein breed in Vietnam.

Lactoferrin-Decorated Cerium Oxide Nanoparticles Prevent Renal Injury and Fibrosis.

Renal fibrosis is a hallmark feature of chronic kidney diseases (CKDs). However, despite the increased prevalence of renal fibrosis, there is no approved antifibrotic drug for the management of renal fibrosis. Cerium oxide nanoparticles (CONPs) have been demonstrated to possess a number of properties including antioxidant, anti-inflammatory and nephroprotective activity. As the kidneys are rich in lactoferrin (Lf) receptors, we synthesised the lactoferrin-CONP (Lf-CONP) system to be used for active targeting of the kidneys and provide antifibrotic effects of CONPs to the kidneys. We used the unilateral ureteral obstruction (UUO)-induced renal fibrosis model and treated the animals with Lf-CONP to observe the antifibrotic effects of Lf-CONP. Lf-CONP was found to inhibit the progression of renal fibrosis in a superior manner when compared to CONPs alone.

Targeting bacterial transferrin and lactoferrin receptors for vaccines.

A substantial disease burden in vertebrates is due to Gram-negative bacteria that exclusively inhabit the upper respiratory or genitourinary tracts of their hosts and rely on directly acquiring iron from the host iron-binding glycoproteins through surface receptor proteins. The receptors enable these bacteria to proliferate independently from their neighbors on the mucosal surface and during invasive infection of the host. The diversity in these receptors evolved over millions of years of evolution, which thus bodes well for long-lasting vaccine coverage. Experiments in food production animals provide proof of concept for the use of engineered antigens derived from the receptor proteins to prevent colonization and invasive infection in the natural host, strongly supporting development of these vaccines for use in humans.

Combined integrin \u03b1v\u03b23 and lactoferrin receptor targeted docetaxel liposomes enhance the brain targeting effect and anti-glioma effect

The integrin αvβ3 receptor and Lactoferrin receptor (LfR) are over-expressed in both cerebral microvascular endothelial cells and glioma cells. RGD tripeptide and Lf can specifically bind with integrin αvβ3 receptor and LfR, respectively. In our study, RGD and Lf dual-modified liposomes loaded with docetaxel (DTX) were designed to enhance the brain targeting effect and treatment of glioma. Our in vitro studies have shown that RGD-Lf-LP can significantly enhance the cellular uptake of U87 MG cells and human cerebral microvascular endothelial cells (hCMEC/D3) when compared to RGD modified liposomes (RGD-LP) and Lf modified liposomes (Lf-LP). Free RGD and Lf competitively reduced the cellular uptake of RGD-Lf-LP, in particular, free RGD played a main inhibitory effect on cellular uptake of RGD-Lf-LP in U87 MG cells, yet free Lf played a main inhibitory effect on cellular uptake of RGD-Lf-LP in hCMEC/D3 cells. RGD-Lf-LP can also significantly increase penetration of U87 MG tumor spheroids, and RGD modification plays a dominating role on promoting the penetration of U87 MG tumor spheroids. The results of in vitro BBB model were shown that RGD-Lf-LP-C6 obviously increased the transport of hCMEC/D3 cell monolayers, and Lf modification plays a dominating role on increasing the transport of hCMEC/D3 cell monolayers. In vivo imaging proved that RGD-Lf-LP shows stronger targeting effects for brain orthotopic gliomas than that of RGD-LP and Lf-LP. The result of tissue distribution confirmed that RGD-LF-LP-DTX could significantly increase brain targeting after intravenous injection. Furthermore, RGD-LF-LP-DTX (a dose of 5 mg kg−1 DTX) could significantly prolong the survival time of orthotopic glioma-bearing mice. In summary, RGD and LF dual modification are good combination for brain targeting delivery, RGD-Lf-LP-DTX could enhance brain targeting effects, and is thus a promising chemotherapeutic drug delivery system for treatment of glioma.Graphical abstract

Development of Encapsulation Strategies and Composite Edible Films to Maintain Lactoferrin Bioactivity: A Review.

Lactoferrin (LF) is a whey protein with various and valuable biological activities. For this reason, LF has been used as a supplement in formula milk and functional products. However, it must be considered that the properties of LF can be affected by technological treatments and gastrointestinal conditions. In this article, we have revised the literature published on the research done during the last decades on the development of various technologies, such as encapsulation or composite materials, to protect LF and avoid its degradation. Multiple compounds can be used to conduct this protective function, such as proteins, including those from milk, or polysaccharides, like alginate or chitosan. Furthermore, LF can be used as a component in complexes, nanoparticles, hydrogels and emulsions, to encapsulate, protect and deliver other bioactive compounds, such as essential oils or probiotics. Additionally, LF can be part of systems to deliver drugs or to apply certain therapies to target cells expressing LF receptors. These systems also allow improving the detection of gliomas and have also been used for treating some pathologies, such as different types of tumours. Finally, the application of LF in edible and active films can be effective against some contaminants and limit the increase of the natural microbiota present in meat, for example, becoming one of the most interesting research topics in food technology.

Медикаментозне обмеження доступності іонів заліза для патогенних бактерій (частина 1)

Більшість бактерій є мікроорганізмами, для забезпечення життєдіяльності яких необхідно залізо. Залізо є найважливішим макроелементом мікроорганізмів, діючи як переносник електронів і кофактор синтезу ДНК і РНК. Велика частина бактерій поглинає залізо за допомогою сидерофорів. Деякі бактерії продукують гемофори (аналогічні сидерофорам), призначені для отримання заліза з екзогенного гема (ферумпротопорфірину). Також частина представників бактеріального світу експресують рецептори до трансферину і лактоферину, що дозволяє їм використовувати залізо, пов’язане з даними протеїнами. Встановлено, що надлишок заліза в макроорганизмі асоційований з розвитком хронічного перебігу інфекційного процесу, оскільки високі рівні іонів заліза сприяють формуванню біоплівки патогенних бактерій. Порушення забезпечення залізом бактерії за рахунок зниження концентрації доступних іонів заліза; інгібування синтезу бактеріальних сидерофорів; застосування препаратів, що містять сидерофори, кон’юговані з антибіотиками; застосування препаратів, що містять галій, який конкурентно витісняє залізо, може викликати загибель патогенних мікроорганізмів і сприяти процесу одужання. На основі сидерофорів розроблені численні лікарські засоби, що захоплюють іони заліза. У певних клінічних випадках препарати, що зв’язують залізо, можуть відігравати ключову роль в ефективності антимікробної терапії.

Milk protein-shelled gold nanoparticles with gastrointestinally active absorption for aurotherapy to brain tumor

Orally absorbable gold nanoparticles (AuNP) having cancer ablation therapy is strongly demanded to treat glioblastoma multiforme (GBM) for patients with its highest incidence rate. Here, we develop a milk protein lactoferrin-conjugated AuNP for its oral absorption and targeting to the GBM through the interaction between lactoferrin (Lf) and lactoferrin receptor (LfR) that is highly expressed in the intestine, blood-brain barrier and GBM. For stability and long circulation of AuNP, glutathione and polyethylene glycol (PEG) is introduced, which is called to Lf-PEG-AuNP. When Lf-PEG-AuNP are orally administered to orthotopic GBM-bearing mice, 11-fold and 8-fold higher concentrations of AuNP are measured in bloodstreams and GBM in the brain, respectively, compared with unconjugated-AuNP. Therefore, orally administered Lf-PEG-AuNP exhibit an outstanding temperature rise in GBM by irradiating laser and significantly reduce tumor volume. Collectively, we suggest that the Lf-PEG-AuNP can fundamentally target GBM in the brain through oral absorption, and that its efficient photothermal therapy is possible.