Effects of folate-chicory acid liposome on macrophage polarization and TLR4/NF-κB signaling pathway in ulcerative colitis mouse.

BACKGROUND: Chichoric acid (CA) is a major active ingredient found in chicory and Echinacea. As a derivative of caffeic acid, it has various pharmacological effects. PURPOSE: Due to the unclear etiology and disease mechanisms, effective treatment methods for ulcerative colitis (UC) are currently lacking. The study investigated the therapeutic effects of the folate-chicory acid liposome on both LPS-induced macrophage inflammation models and dextran sulfate sodium (DSS)-induced mouse UC models. METHODS: Folate-chicory acid liposome was prepared using the double emulsion ultrasonic method with the aim of targeting folate receptors specifically expressed on macrophages. The study investigated the therapeutic effects of the folate-chicory acid liposome on both LPS-induced macrophage inflammation models and DSS -induced mouse UC models. Furthermore, the effects of the liposomes on macrophage polarization and their underlying mechanisms in UC were explored. RESULTS: The average particle size of folate-chicory acid liposome was 120.4 ± 0.46 nm, with an encapsulation efficiency of 77.32 ± 3.19 %. The folate-chicory acid liposome could alleviate macrophage apoptosis induced by LPS, decrease the expression of inflammatory factors in macrophages, enhance the expression of anti-inflammatory factors, inhibit macrophage polarization towards the M1 phenotype, and mitigate cellular inflammation in vetro. In vivo test, folate-chicory acid liposome could attenuate clinical symptoms, increased colon length, reduced DAI scores, CMDI scores, and alleviated the severity of colonic histopathological damage in UC mice. Furthermore, it inhibited the polarization of macrophages towards the M1 phenotype in the colon and downregulated the TLR4/NF-κB signaling pathway, thereby ameliorating UC in mice. CONCLUSION: Folate-chicory acid liposome exhibited a uniform particle size distribution and high encapsulation efficiency. It effectively treated UC mice by inhibiting the polarization of macrophages towards the M1 phenotype in the colon and downregulating the TLR4/NF-κB signaling pathway.

Raman spectroscopy study of 7,8-dihydrofolate inhibition on the Wuhan strain SARS-CoV-2 binding to human ACE2 receptor.

Emerging evidence suggests that elevated levels of folic acid in the bloodstream may confer protection against Wuhan-SARS-CoV-2 infection and mitigate its associated symptoms. Notably, two comprehensive studies of COVID-19 patients in Israel and UK uncovered a remarkable trend, wherein individuals with heightened folic acid levels exhibited only mild symptoms and necessitated no ventilatory support. In parallel, research has underscored the potential connection between decreased folic acid levels and the severity of Covid-19 among hospitalized patients. Yet, the underlying mechanisms governing this intriguing inhibition remain elusive. In a quest to elucidate these mechanisms, we conducted a molecular dynamics simulation approach followed by a Raman spectroscopy study to delve into the intricate interplay between the folic acid metabolite, 7,8-dihydrofolate (DHF), and the angiotensin-converting enzyme ACE2 receptor, coupled with its interaction with the receptor-binding domain (RBD) of the Wuhan strain of SARS-CoV-2. Through a meticulous exploration, we scrutinized the transformation of the ACE2 + RBD complex, allowing these reactants to form bonds. This was juxtaposed with a similar investigation where ACE2 was initially permitted to react with DHF, followed by the exposure of the ACE2 + DHF complex to RBD. We find that DHF, when bonded to ACE2, functions as a physical barrier, effectively inhibiting the binding of the Wuhan strain RBD. This physicochemical process offers a cogent explanation for the observed inhibition of host cell infection in subjects receiving supplementary folic acid doses, as epidemiologically substantiated in multiple studies. This study not only sheds light on a potential avenue for mitigating SARS-CoV-2 infection but also underscores the crucial role of folic acid metabolites in host-virus interactions. This research paves the way for novel therapeutic strategies in the battle against COVID-19 and reinforces the significance of investigating the molecular mechanisms underlying the protective effects of folic acid in the context of viral infections.

Preoperative predictors of successful tumour localization by intraoperative molecular imaging with pafolacianine in lung cancer to create predictive nomogram.

OBJECTIVES: Intraoperative molecular imaging (IMI) uses cancer-targeted fluorescent probe to locate nodules. Pafolacianine is a Food and Drug Administration-approved fluorescent probe for lung cancer. However, it has a 8-12% false negative rate for localization. Our goal is to define preoperative predictors of tumour localization by IMI. METHODS: We performed a retrospective review of patients who underwent IMI using pafolacianine for lung lesions from June 2015 to August 2019. Candidate predictors including sex, age, body mass index, smoking history, tumour size, distance of tumour from surface, use of neoadjuvant therapy and positron emission tomography avidity were included. The outcome was fluorescence in vivo and comprehensively included those who were true or false positives negatives. Multiple imputation was used to handle the missing data. The final model was evaluated using the area under the receiver operating characteristic curve. RESULTS: Three hundred nine patients were included in our study. The mean age was 64 (standard deviation 13) and 68% had a smoking history. The mean distance of the tumours from the pleural surface was 0.4 cm (standard deviation 0.6). Smoking in pack-years and distance from pleura had an odds ratio of 0.99 [95% confidence interval: 0.98-0.99; P = 0.03] and 0.46 [95% confidence interval: 0.27-0.78; P = 0.004], respectively. The final model had an area under the receiver operating characteristic curve of 0.68 and was used to create a nomogram that gives a probability of fluorescence in vivo. CONCLUSIONS: Primary tumours that are deeper from the pleural surface, especially in patients with a higher pack-years, are associated with a decreased likelihood of intraoperative localization. We identified a nomogram to predict the likelihood of tumour localization with IMI with pafolacianine.

Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens.

Two plasmid-encoded dihydrofolate reductase (DHFR) isoforms, DfrA1 and DfrA5, that give rise to high levels of resistance in Gram-negative bacteria were structurally and biochemically characterized to reveal the mechanism of TMP resistance and to support phylogenic groupings for drug development against antibiotic resistant pathogens. Preliminary screening of novel antifolates revealed related chemotypes that showed high levels of inhibitory potency against Escherichia coli chromosomal DHFR (EcDHFR), DfrA1, and DfrA5. Kinetics and biophysical analysis, coupled with crystal structures of trimethoprim bound to EcDHFR, DfrA1 and DfrA5, and two propargyl-linked antifolates (PLA) complexed with EcDHFR, DfrA1 and DfrA5, were determined to define structural features of the substrate binding pocket and guide synthesis of pan-DHFR inhibitors.

The bioaccessibility of folate in breads and the stability of folate vitamers during in vitro digestion.

Both the liberation and stability of endogenous folate are relevant to the bioaccessibility of folate. Since folates are unstable, in addition to studying the natural folate content in foods, bioaccessibility should be considered. To understand folate changes during digestion, a mixture of standard folate compounds was subjected to a static in vitro gastrointestinal digestion assay. Next, different types of bread were analysed to study how food matrices influence folate bioaccessibility. Folates were identified and quantitated by a UHPLC-PDA/FL method. Folic acid and 10-formylfolic acid were stable throughout the digestion, and the conversions among formyl folates and 5,10-methenyltetrahydrofolate were triggered at the gastric phase. Tetrahydrofolate began to degrade during the oral phase and was lost completely during the gastric phase. During the intestinal phase, 5-methyltetrahydrofolate began to degrade and suffered a 60% loss. With bread matrices, folate conversions and the decrease of reduced folates were also common, but the extent of changes varied. Generally, rye breads had the highest (80-120%) bioaccessibility of folate, while oat breads had the lowest (31-102%). The high proportion of 5-methyltetrahydrofolate could result in low bioaccessibility because of its relatively low stability during digestion in bread matrices. An increase in 10-formylfolic acid content was observed for all the breads, but 10-formyldihydrofolate seemed to be more stable in rye breads than in oat and wheat breads. The results showed that folates undergo significant changes during digestion and that food matrices could be modified to affect these changes towards better folate bioaccessibility.

Enhanced ROS-Boosted Phototherapy against Pancreatic Cancer via Nrf2-Mediated Stress-Defense Pathway Suppression and Ferroptosis Induction.

In situ oxygen generation is the most common strategy to boost reactive oxygen species (ROS) for enhancing the efficacy of phototherapy in cancer, including photodynamic therapy (PDT) and photothermal therapy (PTT). However, hyperoxidation or hyperthermia often triggers stress-defense pathways and promotes tumor cell survival, thus severely limiting the therapeutic efficacy. To overcome the tumor hypoxia and thermal resistance existing in phototherapy, we constructed a self-synergistic nanoplatform for tumors by incorporating brusatol, a nuclear factor erythroid 2-related factor (Nrf2) inhibitor, into the silica nanonetwork. It was then sequentially decorated with MnO2 and the photosensitizer chlorin e6 (Ce6) and then coated with poly(ethylene glycol)-folate (PEG-FA)-functionalized polydopamine (PDA) (designated as brusatol/silica@MnO2/Ce6@PDA-PEG-FA). As an oxygen generator, MnO2 can promote ROS production, which not only directly enhances Ce6-mediated PDT but also strengthens PDA-mediated PTT by attacking heat shock proteins (HSPs). Particularly, brusatol could efficiently inhibit the activation of Nrf2 defense pathway under hyperoxidation and hyperthermia and cause glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH) inactivation, thereby inducing ferroptosis and ultimately enhancing the phototherapeutic effects. By exploiting these features, brusatol/silica@MnO2/Ce6@PDA-PEG-FA exhibited excellent antitumor efficacy with enhanced PDT and PTT both in in vitro and in vivo studies. Overall, our work highlights a promising strategy against hypoxia- and hyperthermia-associated resistance in phototherapy via suppressing stress-defense system and inducing ferroptosis.

Synthesis of biocompatible nanocrystalline cellulose against folate receptors as a novel carrier for targeted delivery of doxorubicin.

We designed amine-functionalized nanocrystalline cellulose grafted folic acid/magnetic nanoparticles (AF-NCC/Fe3O4 NPs) against folate receptors for targeted delivery of doxorubicin (DOX). Toxicity is a major side effect of DOX, damaging vital organs such as the heart, kidney, and liver; for example, it causes dilated cardiomyopathy and hepatotoxicity. Accordingly, we aimed to reduce this adverse effect and increase the targeted delivery of DOX to the right point of cancer cells by using the unique features of cancer cells. The characterizations were approved in each step using Fourier transform infrared (FTIR), scanning electron microscope (SEM), X-ray diffraction (XRD), transmission electron microscopy (TEM), energy dispersive X-ray (EDX), zeta potential, and dynamic light scattering (DLS) analysis techniques. Encapsulation efficacy of AF-NCC/Fe3O4 NPs was 99.6%; drug release investigations showed excellent stability in physiological conditions (pH âˆ¼ 7.4) and a high release rate in the low pH condition of cancer environments (pH âˆ¼ 5.0). The hemolysis assay and Masson's trichrome and hematoxylin and eosin (H&E) staining results showed that the nanocarrier was entirely biocompatible. In vitro cell viability study approved that the designed nanocarrier increased the therapeutic effects of DOX on Saos-2 cells. The cellular internalization results displayed a high percentage of uptake within 2 h. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was applied for the evaluation of tumor protein p53 (p53), p21, and Bcl-2-associated X protein (Bax). DOX exerted its effects through DNA damage and oxidative stress that led to p53 upregulation, and p53 inhibited cell cycle progression. This arrest initiated apoptosis and inhibited cell migration. In summary, encapsulating DOX in AF-NCC/Fe3O4 NPs dramatically decreases the toxic effects of this chemotherapeutic agent on vital organs, especially on the heart. This smart nanocarrier increases the delivery of DOX using acid folic on its surface and also enhances the DOX release in the acidic environment of cancer cells. DOX exerts its therapeutic effects by the initiation of apoptosis and inhibition of migration.

Folate-Guided Protein Degradation by Immunomodulatory Imide Drug-Based Molecular Glues and Proteolysis Targeting Chimeras.

Molecular glues and proteolysis targeting chimeras (PROTACs) are promising new therapeutic modalities. However, the lack of specificity for molecular glue- or PROTAC-mediated proteolysis in cancer cells versus normal cells raises potential toxicity concerns that will likely limit their clinical applications. Here, we developed a general strategy to deliver immunomodulatory imide drug (IMiD)-based molecular glues and PROTACs to folate receptor α (FOLR1)-positive cancer cells. Specifically, we designed a folate-caged pomalidomide prodrug, FA-S2-POMA, by incorporating a folate group as a caging and guiding element and validated its degradation effect on its neo-substrates in FOLR1-positive cancer cells in a FOLR1-dependent manner. We also developed a folate-caged pomalidomide-based anaplastic lymphoma kinase (ALK) PROTAC, FA-S2-MS4048, which effectively degraded ALK fusion proteins in cancer cells, again in a FOLR1-dependent manner. This novel approach provides a generalizable platform for the targeted delivery of IMiD-based molecular glues and PROTACs to FOLR1-expressing cancer cells with the potential to ameliorate toxicity.

Efficient Design to Monitor the Site-specific Sustained Release of a Non-Emissive Anticancer Drug.

A pH-responsive smart nanocarrier with significant components was synthesized by conjugating the non-emissive anticancer drug methyl orange and polyethylene glycol derived folate moiety to the backbone of polynorbornene. Complete synthesis procedure and characterization methods of three monomers included in the work: norbornene-derived Chlorambucil (Monomer 1), norbornene grafted with polyethylene glycol, and folic acid (Monomer 2) and norbornene attached methyl orange (Monomer 3) connected to the norbornene backbone through ester linkage were clearly discussed. Finally, the random copolymer CHO PEG FOL METH was synthesized by ring-opening metathesis polymerization (ROMP) using Grubbs' second-generation catalyst. Advanced polymer chromatography (APC) was used to find the final polymer's molecular weight and polydispersity index (PDI). Dynamic light scattering, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were utilized to explore the prodrug's size and morphology. Release experiments of the anticancer drug, Chlorambucil and the coloring agent, methyl orange, were performed at different pH and time. Cell viability assay was carried out for determining the rate of survived cells, followed by the treatment of our final polymer named CHO PEG FOL METH.

Novel Multifunctional Stimuli-Responsive Nanoparticles for Synergetic Chemo-Photothermal Therapy of Tumors.

In this study, a novel class of multifunctional responsive nanoparticles is designed and fabricated as drug nanocarriers for synergetic chemo-photothermal therapy of tumors. The proposed nanoparticles are composed of a thermo-/pH-responsive poly(N-isopropylacrylamide-co-acrylic acid) (PNA) nanogel core, a polydopamine (PDA) layer for photothermal conversion, and an outer folic acid (FA) layer as a targeting agent for the folate receptors on tumor cells. The fabricated nanoparticles show good biocompatibility and outstanding photothermal conversion efficiency. The proposed nanoparticles loaded with doxorubicin (DOX) drug molecules are stable under physiological conditions with low leakage of drugs, while rapidly release drugs in environments with low pH conditions and at high temperature. The experimental results show that the drug release process is mainly governed by Fickian diffusion. In vitro cell experimental results demonstrate that the PNA-DOX@PDA-FA nanoparticles can be phagocytized by 4T1 tumor cells and release drugs in tumor cell acidic environments, and confirm that the combined chemo and photothermal therapeutic efficacy of PNA-DOX@PDA-FA nanoparticles is higher than the photothermal therapeutic efficacy or the chemotherapeutic efficacy alone. The proposed multifunctional responsive nanoparticles in this study provide a novel class of drug nanocarriers as a promising tool for synergetic chemo-photothermal therapy of tumors.

A multiple environment-sensitive prodrug nanomicelle strategy based on chitosan graftomer for enhanced tumor therapy of gambogic acid.

A novel multiple environment-sensitive polymeric prodrug of gambogic acid (GA) based on chitosan graftomer was fabricated for cancer treatment. Folic acid-chitosan conjugates was complexed with thermosensitive amine terminated poly-N-isopropylacrylamide (NH2-PNIPAM) to develop FA-CSPN. Gambogic acid was conjugated with the graftomer via esterification to achieve high drug-loading capacity and controlled drug release. The resulting amphiphilic prodrug, O-(gambogic acid)-N-(folic acid)-N'-(NH2-PNIPAM) chitosan graftomer (GFCP), could self-assemble into micelles. As expected, the micelles were stable and biocompatible, featuring pH-, esterase- and temperature-dependent manner of drug release. Moreover, the anticancer effect studies of GFCP micelles were performed using a tumor-bearing mouse model and cellular assays (tumor cell uptake assay, cytotoxicity and tumor-sphere penetration). Collectively, GFCP micelles show both potential in vivo and in vitro in improving the anticancer effectiveness of GA owing to high loading capacity, targeted tumor accumulation, and multiple tumor microenvironmental responsiveness.

Sonochemical preparation of folate-decorated reductive-responsive carboxymethylcellulose-based nanocapsules for targeted drug delivery.

In this study, a biocompatible folate-decorated reductive-responsive carboxymethylcellulose-based nanocapsules (FA-RCNCs) were designed and prepared via sonochemical method for targeted delivery and controlled release of hydrophobic drugs. The shell of FA-RCNCs was cross-linked by disulfide bonds formed from hydrosulfuryl groups on the thiolated carboxymethylcellulose (TCMC) and encapsulated hydrophobic drug dispersed in the oil phase into nanocapsules. Moreover, the size and morphology of drug loaded FA-RCNCs were characterized by DLS, SEM and CLSM which indicated that the synthesized nanocapsules have suitable size range and excellent stability for circulating in the bloodstream. The drug release rate of FA-RCNCs could be controlled by adjusting their sizes and shell thickness, which could be dominated by the concentration of TCMC and sonochemical conditions. Furthermore, the obtained FA-RCNCs could be ingested into Hela cells via folate-receptor (FR)-mediated endocytosis and quickly release drugs under reductive environment, which demonstrated that FA-RCNCs could become potential hydrophobic drugs carries for cancer therapy.

Folic Acid-Peptide Conjugates Combine Selective Cancer Cell Internalization with Thymidylate Synthase Dimer Interface Targeting.

Drug-target interaction, cellular internalization, and target engagement should be addressed to design a lead with high chances of success in further optimization stages. Accordingly, we have designed conjugates of folic acid with anticancer peptides able to bind human thymidylate synthase (hTS) and enter cancer cells through folate receptor α (FRα) highly expressed by several cancer cells. Mechanistic analyses and molecular modeling simulations have shown that these conjugates bind the hTS monomer-monomer interface with affinities over 20 times larger than the enzyme active site. When tested on several cancer cell models, these conjugates exhibited FRα selectivity at nanomolar concentrations. A similar selectivity was observed when the conjugates were delivered in synergistic or additive combinations with anticancer agents. At variance with 5-fluorouracil and other anticancer drugs that target the hTS catalytic pocket, these conjugates do not induce overexpression of this protein and can thus help combating drug resistance associated with high hTS levels.

Relationship of several serum folate forms with the risk of mortality: A prospective cohort study.

OBJECTIVE: We aim to examine the relation of several folate forms (5-methyltetrahydrofolate [5-mTHF], unmetabolized folic acid [UMFA], non-methyl folate, and MeFox [pyrazino-s-triazine derivative of 4α-hydroxy-5-methyltetrahydrofolate]) with the risk of mortality. METHODS: Using data from National Health and Nutrition Examination Survey 2011-2014, a total of 10,661 people with folate forms data were recruited. Death information was obtained from the National Death Index until 2015. Cox proportional hazards regression models were developed to evaluate the relationship between folate forms and mortality. RESULTS: During 2.99 years of follow-up, 344 (2.6%) deaths occurred. Overall, significantly higher risks of all-cause mortality were found in participants with higher level of serum 5-mTHF (≥51.3 nmol/L [quartile 4] vs. 23.9-51.3 nmol/L [quartile 2-3]; HR, 1.61; 95% CI: 1.03-2.53), UMFA (≥1.1 nmol/L [quartile 4] vs. <1.1 nmol/L [quartile 1-3]; HR, 1.55; 95% CI: 1.15-2.09), non-methyl folate (≥1.7 nmol/L [quartile 4] vs. 1.2-1.7 nmol/L [quartile 3]; HR, 1.62; 95% CI: 1.06-2.48), or MeFox (≥2.5 nmol/L [quartile 4] vs. <2.5 nmol/L [quartile 1-3]; HR, 1.54; 95% CI: 1.11-2.12). In addition, there was an increased risk of all-cause mortality for those with low level of serum 5-mTHF (<23.9 nmol/L [quartile 1] vs. 23.9-51.3 nmol/L [quartile 2-3]; HR, 1.66; 95% CI: 1.12-2.47). Most importantly, none of any folate forms significantly modified the association between other folate forms and mortality (all P for interactions >0.05). CONCLUSION: Higher levels of serum folate forms (5-mTHF, UMFA, non-methyl folate, and MeFox) were associated with higher risk of mortality while 5-mTHF insufficiency also showed a negative impact on mortality. Our findings emphasized the importance of monitoring the folate forms concentrations and may help counsel future related clinical trials.

Modelling folates reaction kinetics during cowpea seed germination in comparison with soaking.

Folate is a fundamental vitamin for metabolism in plants and humans. A modelling approach has been developed to characterize the reactivity of folates in cowpea seeds during germination at 30 °C, using a water-to-seed ratio of 1:1 (w/w). For this purpose, the concentrations of folic acid, 10-formylfolic acid, 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and tetrahydrofolate were determined in seeds during germination times up to 96 h. Two reaction models were sequentially built and adjusted to experimental data to describe changes in concentration in cowpea seed during two germination phases: before 14 h and after 48 h. Results showed intense enzymatic interconversion of all folate vitamers into 5-methyltetrahydrofolate before 14 h of germination and high enzymatic production of 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and tetrahydrofolate after 48 h of germination. This study suggests that a long germination process could be more beneficial than soaking to increase the production of bioavailable folates within the seed for human consumption.

The 1316T>C missenses mutation in MTHFR contributes to MTHFR deficiency by targeting MTHFR to proteasome degradation.

5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare hereditary disease characterized by defects in folate and homocysteine metabolism. Individuals with inherited MTHFR gene mutations have a higher tendency to develop neurodegeneration disease as Alzheimer' disease and atherosclerosis. MTHFR is a rate-limiting enzyme catalyzing folate production, various SNPs/mutations in the MTHFR gene have been correlated to MTHFR deficiency. However, the molecular mechanisms underpinning the pathogenic effects of these SNPs/mutations have not been clearly understood. In the present study, we reported a severe MTHFR deficiency patient with late-onset motor dysfunction and sequenced MTHFR gene exons of the family. The patient carries an MD-associating SNP (rs748289202) in one MTHFR allele and the rs545086633 SNP with unknown disease relevance in the other. The rs545086633 SNP (p.Leu439Pro) results in an L439P substitution in MTHFR protein, and drastically decreases mutant protein expression by promoting proteasomal degradation. L439 in MTHFR is highly conserved in vertebrates. Our study demonstrated that p.Leu439Pro in MTHFR is the first mutation causing significant intracellular defects of MTHFR, and rs545086633 should be examined for the in-depth diagnosis and treatment of MD.

Preparation and characterization of lutein loaded folate conjugated polymeric nanoparticles.

AIM: To prepare and characterise lutein-loaded polylactide-co-glycolide-polyethylene glycol-folate (PLGA-PEG-FOLATE) nanoparticles and evaluate enhanced uptake in SK-N-BE(2) cells. METHODS: Nanoparticles were prepared using O/W emulsion solvent evaporation and characterised using DLS, SEM, DSC, FTIR and in-vitro release. Lutein-uptake in SK-N-BE(2) cells was determined using flow-cytometry, confocal-microscopy and HPLC. Control was lutein PLGA nanoparticles. RESULTS: The size of lutein-loaded PLGA and PLGA-PEG-FOLATE nanoparticles were 189.6 ± 18.79 nm and 188.0 ± 4.06 nm, respectively. Lutein entrapment was ∼61%(w/w) and ∼73%(w/w) for PLGA and PLGA-PEG-FOLATE nanoparticles, respectively. DSC and FTIR confirmed encapsulation of lutein into nanoparticles. Cellular uptake studies showed ∼1.6 and ∼2-fold enhanced uptake of lutein from PLGA-PEG-FOLATE nanoparticles compared to PLGA nanoparticles and lutein, respectively. Cumulative release of lutein was higher in PLGA nanoparticles (100% (w/w) within 24 h) compared to PLGA-PEG-FOLATE nanoparticles (∼80% (w/w) in 48 h). CONCLUSION: Lutein-loaded PLGA-PEG-FOLATE nanoparticles could be a potential treatment for hypoxic ischaemic encephalopathy.