Design of Molecularly Imprinted Polymers Using Supercritical Carbon Dioxide Technology.

The design and development of affinity polymeric materials through the use of green technology, such as supercritical carbon dioxide (scCO2), is a rapidly evolving field of research with vast applications across diverse areas, including analytical chemistry, pharmaceuticals, biomedicine, energy, food, and environmental remediation. These affinity polymeric materials are specifically engineered to interact with target molecules, demonstrating high affinity and selectivity. The unique properties of scCO2, which present both liquid- and gas-like properties and an accessible critical point, offer an environmentally-friendly and highly efficient technology for the synthesis and processing of polymers. The design and the synthesis of affinity polymeric materials in scCO2 involve several strategies. Commonly, the incorporation of functional groups or ligands into the polymer matrix allows for selective interactions with target compounds. The choice of monomer type, ligands, and synthesis conditions are key parameters of material performance in terms of both affinity and selectivity. In addition, molecular imprinting allied with co-polymerization and surface modification are commonly used in these strategies, enhancing the materials' performance and versatility. This review aims to provide an overview of the key strategies and recent advancements in the design of affinity polymeric materials using scCO2.

The ribonuclease PNPase is a key regulator of biofilm formation in Listeria monocytogenes and affects invasion of host cells.

Biofilms provide an environment that protects microorganisms from external stresses such as nutrient deprivation, antibiotic treatments, and immune defences, thereby creating favorable conditions for bacterial survival and pathogenesis. Here we show that the RNA-binding protein and ribonuclease polynucleotide phosphorylase (PNPase) is a positive regulator of biofilm formation in the human pathogen Listeria monocytogenes, a major responsible for food contamination in food-processing environments. The PNPase mutant strain produces less biofilm biomass and exhibits an altered biofilm morphology that is more susceptible to antibiotic treatment. Through biochemical assays and microscopical analysis, we demonstrate that PNPase is a previously unrecognized regulator of the composition of the biofilm extracellular matrix, greatly affecting the levels of proteins, extracellular DNA, and sugars. Noteworthy, we have adapted the use of the fluorescent complex ruthenium red-phenanthroline for the detection of polysaccharides in Listeria biofilms. Transcriptomic analysis of wild-type and PNPase mutant biofilms reveals that PNPase impacts many regulatory pathways associated with biofilm formation, particularly by affecting the expression of genes involved in the metabolism of carbohydrates (e.g., lmo0096 and lmo0783, encoding PTS components), of amino acids (e.g., lmo1984 and lmo2006, encoding biosynthetic enzymes) and in the Agr quorum sensing-like system (lmo0048-49). Moreover, we show that PNPase affects mRNA levels of the master regulator of virulence PrfA and PrfA-regulated genes, and these results could help to explain the reduced bacterial internalization in human cells of the ΔpnpA mutant. Overall, this work demonstrates that PNPase is an important post-transcriptional regulator for virulence and adaptation to the biofilm lifestyle of Gram-positive bacteria and highlights the expanding role of ribonucleases as critical players in pathogenicity.

Using Machine Learning and Molecular Docking to Leverage Urease Inhibition Data for Virtual Screening.

Urease is a metalloenzyme that catalyzes the hydrolysis of urea, and its modulation has an important role in both the agricultural and medical industry. Even though numerous molecules have been tested against ureases of different species, their clinical translation has been limited due to chemical and metabolic stability as well as side effects. Therefore, screening new compounds against urease would be of interest in part due to rising concerns regarding antibiotic resistance. In this work, we collected and curated a diverse set of 2640 publicly available small-molecule inhibitors of jack bean urease and developed a classifier using a random forest machine learning method with high predictive performance. In addition, the physicochemical features of compounds were paired with molecular docking and protein-ligand fingerprint analysis to gather insight into the current activity landscape. We observed that the docking score could not differentiate active from inactive compounds within each chemical family, but scores were correlated with compound activity when all compounds were considered. Additionally, a decision tree model was built based on 2D and 3D Morgan fingerprints to mine patterns of the known active-class compounds. The final machine learning model showed good prediction performance against the test set (81% and 77% precision for active and inactive compounds, respectively). Finally, this model was employed, as a proof-of-concept, on an in-house library to predict new hits that were then tested against urease and found to be active. This is, to date, the largest, most diverse dataset of compounds used to develop predictive in silico models. Overall, the results highlight the usefulness of using machine learning classifiers and molecular docking to predict novel urease inhibitors.

A Novel Strategy for Enhanced Sequestration of Protein-Bound Uremic Toxins Using Smart Hybrid Membranes.

Currently available hemodialysis (HD) membranes are unable to safely remove protein-bound uremic toxins (PBUTs), especially those bonded to human serum albumin (HSA). To overcome this issue, the prior administration of high doses of HSA competitive binders, such as ibuprofen (IBF), has been proposed as a complementary clinical protocol to increase HD efficiency. In this work, we designed and prepared novel hybrid membranes conjugated with IBF, thus avoiding its administration to end-stage renal disease (ESRD) patients. Two novel silicon precursors containing IBF were synthesized and, by the combination of a sol-gel reaction and the phase inversion technique, four monophasic hybrid integral asymmetric cellulose acetate/silica/IBF membranes in which silicon precursors are covalently bonded to the cellulose acetate polymer were produced. To prove IBF incorporation, methyl red dye was used as a model, thus allowing simple visual color control of the membrane fabrication and stability. These smart membranes may display a competitive behavior towards HSA, allowing the local displacement of PBUTs in future hemodialyzers.

Biomolecular Fishing: Design, Green Synthesis, and Performance of l-Leucine-Molecularly Imprinted Polymers.

Biopurification is a challenging and growing market. Despite great efforts in the past years, current purification strategies still lack specificity, efficiency, and cost-effectiveness. The development of more sustainable functional materials and processes needs to address pressing environmental goals, efficiency, scale-up, and cost. Herein, l-leucine (LEU)-molecularly imprinted polymers (MIPs), LEU-MIPs, are presented as novel biomolecular fishing polymers for affinity sustainable biopurification. Rational design was performed using quantum mechanics calculations and molecular modeling for selecting the most appropriate monomers. LEU-MIPs were synthesized for the first time by two different green approaches, supercritical carbon dioxide (scCO2) technology and mechanochemistry. A significant imprinting factor of 12 and a binding capacity of 27 mg LEU/g polymer were obtained for the LEU-MIP synthesized in scCO2 using 2-vinylpyridine as a functional monomer, while the LEU-MIP using acrylamide as a functional monomer synthesized by mechanochemistry showed an imprinting factor of 1.4 and a binding capacity of 18 mg LEU/g polymer, both systems operating at a low binding concentration (0.5 mg LEU/mL) under physiological conditions. As expected, at a higher concentration (1.5 mg LEU/mL), the binding capacity was considerably increased. Both green technologies show high potential in obtaining ready-to-use, stable, and low-cost polymers with a molecular recognition ability for target biomolecules, being promising materials for biopurification processes.

A Glimpse into Dendrimers Integration in Cancer Imaging and Theranostics.

Cancer is a result of abnormal cell proliferation. This pathology is a serious health problem since it is a leading cause of death worldwide. Current anti-cancer therapies rely on surgery, radiation, and chemotherapy. However, these treatments still present major associated problems, namely the absence of specificity. Thus, it is urgent to develop novel therapeutic strategies. Nanoparticles, particularly dendrimers, have been paving their way to the front line of cancer treatment, mostly for drug and gene delivery, diagnosis, and disease monitoring. This is mainly derived from their high versatility, which results from their ability to undergo distinct surface functionalization, leading to improved performance. In recent years, the anticancer and antimetastatic capacities of dendrimers have been discovered, opening new frontiers to dendrimer-based chemotherapeutics. In the present review, we summarize the intrinsic anticancer activity of different dendrimers as well as their use as nanocarriers in cancer diagnostics and treatment.

H2S-Synthesizing Enzymes Are Putative Determinants in Lung Cancer Management toward Personalized Medicine.

Lung cancer is a lethal disease with no truly efficient therapeutic management despite the progresses, and metabolic profiling can be a way of stratifying patients who may benefit from new therapies. The present study is dedicated to profiling cysteine metabolic pathways in NSCLC cell lines and tumor samples. This was carried out by analyzing hydrogen sulfide (H2S) and ATP levels, examining mRNA and protein expression patterns of cysteine catabolic enzymes and transporters, and conducting metabolomics analysis using nuclear magnetic resonance (NMR) spectroscopy. Selenium-chrysin (SeChry) was tested as a therapeutic alternative with the aim of having an effect on cysteine catabolism and showed promising results. NSCLC cell lines presented different cysteine metabolic patterns, with A549 and H292 presenting a higher reliance on cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE) to maintain H2S levels, while the PC-9 cell line presented an adaptive behavior based on the use of mercaptopyruvate sulfurtransferase (MST) and cysteine dioxygenase (CDO1), both contributing to the role of cysteine as a pyruvate source. The analyses of human lung tumor samples corroborated this variability in profiles, meaning that the expression of certain genes may be informative in defining prognosis and new targets. Heterogeneity points out individual profiles, and the identification of new targets among metabolic players is a step forward in cancer management toward personalized medicine.

Gas Permeability and Mechanical Properties of Polyurethane-Based Membranes for Blood Oxygenators.

The production of medical devices follows strict guidelines where bio- and hemocompatibility, mechanical strength, and tear resistance are important features. Segmented polyurethanes (PUs) are an important class of polymers that fulfill many of these requirements, thus justifying the investigation of novel derivatives with enhanced properties, such as modulated carbon dioxide and oxygen permeability. In this work, three segmented polyurethane-based membranes, containing blocks of hard segments (HSs) dispersed in a matrix of soft segment (SS) blocks, were prepared by reacting a PU prepolymer (PUR) with tris(hydroxymethyl)aminomethane (TRIS), Congo red (CR) and methyl-ß-cyclodextrin (MBCD), rendering PU/TRIS, PU/CR and PU/MBCD membranes. The pure (control) PU membrane exhibited the highest degree of phase segregation between HSs and SSs followed by PU/TRIS and PU/MBCD membranes, and the PU/CR membrane displayed the highest degree of mixing. Pure PU and PU/CR membranes exhibited the highest and lowest values of Young's modulus, tangent moduli and ultimate tensile strength, respectively, suggesting that the introduction of CR increases molecular mobility, thus reducing stiffness. The CO2 permeability was highest for the PU/CR membrane, 347 Barrer, and lowest for the pure PU membrane, 278 Barrer, suggesting that a higher degree of mixing between HSs and SSs leads to higher CO2 permeation rates. The permeability of O2 was similar for all membranes, but ca. 10-fold lower than the CO2 permeability.

Core-shell polycationic polyurea pharmadendrimers: new-generation of sustainable broad-spectrum antibiotics and antifungals.

The efficacy of conventional antimicrobials is falling to critical levels and raising alarming concerns around the globe. In this scenery, engineered nanoparticles emerged as a solid strategy to fight growing deadly infections. Here, we show the in vitro and in vivo performance of pharmadendrimers, a novel class of engineered polyurea dendrimers that are synthetic mimics of antibacterial peptides, against a collection of both Gram-positive and Gram-negative bacteria and fungi. These nanobiomaterials are stable solids prepared by low-cost and green processes, display a dense positively charged core-shell, and are biocompatible and hemocompatible drugs. Mechanistic data, corroborated by coarse-grained molecular dynamics simulations, points towards a fast-killing mechanism via membrane disruption, triggered by electrostatic interactions. Altogether this study provides strong evidence and support for the future use of polyurea pharmadendrimers in antibacterial and antifungal nanotherapeutics.

Exploring the Chemical Space of Urease Inhibitors to Extract Meaningful Trends and Drivers of Activity.

Blocking the catalytic activity of urease has been shown to have a key role in different diseases as well as in different agricultural applications. A vast array of molecules have been tested against ureases of different species, but the clinical translation of these compounds has been limited due to challenges of potency, chemical and metabolic stability as well as promiscuity against other proteins. The design and development of new compounds greatly benefit from insights from previously tested compounds; however, no large-scale studies surveying the urease inhibitors' chemical space exist that can provide an overview of developed compounds to data. Therefore, given the increasing interest in developing new compounds for this target, we carried out a comprehensive analysis of the activity landscape published so far. To do so, we assembled and curated a data set of compounds tested against urease. To the best of our knowledge, this is the largest data set of urease inhibitors to date, composed of 3200 compounds of diverse structures. We characterized the data set in terms of chemical space coverage, molecular scaffolds, distribution with respect to physicochemical properties, as well as temporal trends of drug development. Through these analyses, we highlighted different substructures and functional groups responsible for distinct activity and inactivity against ureases. Furthermore, activity cliffs were assessed, and the chemical space of urease inhibitors was compared to DrugBank. Finally, we extracted meaningful patterns associated with activity using a decision tree algorithm. Overall, this study provides a critical overview of urease inhibitor research carried out in the last few decades and enabled finding underlying SAR patterns such as under-reported chemical functional groups that contribute to the overall activity. With this work, we propose different rules and practical implications that can guide the design or selection of novel compounds to be screened as well as lead optimization.

Lipid Droplets in Cancer: From Composition and Role to Imaging and Therapeutics.

Cancer is the second most common cause of death worldwide, having its origin in the abnormal growth of cells. Available chemotherapeutics still present major drawbacks, usually associated with high toxicity and poor distribution, with only a small fraction of drugs reaching the tumour sites. Thus, it is urgent to develop novel therapeutic strategies. Cancer cells can reprogram their lipid metabolism to sustain uncontrolled proliferation, and, therefore, accumulate a higher amount of lipid droplets (LDs). LDs are cytoplasmic organelles that store neutral lipids and are hypothesized to sequester anti-cancer drugs, leading to reduced efficacy. Thus, the increased biogenesis of LDs in neoplastic conditions makes them suitable targets for anticancer therapy and for the development of new dyes for cancer cells imaging. In recent years, cancer nanotherapeutics offered some exciting possibilities, including improvement tumour detection and eradication. In this review we summarize LDs biogenesis, structure and composition, and highlight their role in cancer theranostics.

The Activation of Endothelial Cells Relies on a Ferroptosis-Like Mechanism: Novel Perspectives in Management of Angiogenesis and Cancer Therapy.

The activation of endothelial cells (ECs) is a crucial step on the road map of tumor angiogenesis and expanding evidence indicates that a pro-oxidant tumor microenvironment, conditioned by cancer metabolic rewiring, is a relevant controller of this process. Herein, we investigated the contribution of oxidative stress-induced ferroptosis to ECs activation. Moreover, we also addressed the anti-angiogenic effect of Propranolol. We observed that a ferroptosis-like mechanism, induced by xCT inhibition with Erastin, at a non-lethal level, promoted features of ECs activation, such as proliferation, migration and vessel-like structures formation, concomitantly with the depletion of reduced glutathione (GSH) and increased levels of oxidative stress and lipid peroxides. Additionally, this ferroptosis-like mechanism promoted vascular endothelial cadherin (VE-cadherin) junctional gaps and potentiated cancer cell adhesion to ECs and transendothelial migration. Propranolol was able to revert Erastin-dependent activation of ECs and increased levels of hydrogen sulfide (H2S) underlie the mechanism of action of Propranolol. Furthermore, we tested a dual-effect therapy by promoting ECs stability with Propranolol and boosting oxidative stress to induce cancer cell death with a nanoformulation comprising selenium-containing chrysin (SeChry) encapsulated in a fourth generation polyurea dendrimer (SeChry@PUREG4). Our data showed that novel developments in cancer treatment may rely on multi-targeting strategies focusing on nanoformulations for a safer induction of cancer cell death, taking advantage of tumor vasculature stabilization.

Intrinsic acetamide brush-off by polyurea biodendrimers.

The presence of genotoxic impurities in active pharmaceutical ingredients (APIs) is a major concern for the pharmaceutical industry. Acetamide is a common genotoxic byproduct found in synthetic routes of many APIs, mainly due to acetonitrile hydrolysis, and selective scavenging is a still a challenging task. Herein, as a proof-of-concept, we evaluate polyurea (PURE) biodendrimers as strategic nanopolymers to prepare safe drug nanoformulations from mixtures containing acetamide, using (S)-ibuprofen (IBF) as a model drug. Furthermore, computational molecular dynamics (MD) simulations were conducted to rationalize in vitro results and to identify the key intermolecular interactions within mixtures. Experimental data were corroborated by MD simulations which showed that acetamide, IBF and carboxyfluorescein interactions with PURE biodendrimers are mostly at the surface. Also, PURE nanoformulations appear to be driven by hydrogen bonding, electrostatic and hydrophobic interactions.

Conventional vs. Microwave- or Mechanically-Assisted Synthesis of Dihomooxacalix[4]arene Phthalimides: NMR, X-ray and Photophysical Analysis.

Direct O-alkylation of p-tert-butyldihomooxacalix[4]arene (1) with N-(bromopropyl)- or N-(bromoethyl)phthalimides and K2CO3 in acetonitrile was conducted under conventional heating (reflux) and using microwave irradiation and ball milling methodologies. The reactions afforded mono- and mainly distal di-substituted derivatives in the cone conformation, in a total of eight compounds. They were isolated by column chromatography, and their conformations and the substitution patterns were established by NMR spectroscopy (1H, 13C, COSY and NOESY experiments). The X-ray structures of four dihomooxacalix[4]arene phthalimide derivatives (2a, 3a, 3b and 5a) are reported, as well as their photophysical properties. The microwave (MW)-assisted alkylations drastically reduced the reaction times (from days to less than 45 min) and produced higher yields of both 1,3-di-substituted phthalimides (3a and 6a) with higher selectivity. Ball milling did not reveal to be a good method for this kind of reaction.

Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates: In Vivo Virulence Assessment in Galleria mellonella and Potential Therapeutics by Polycationic Oligoethyleneimine.

Klebsiella pneumoniae, one of the most common pathogens found in hospital-acquired infections, is often resistant to multiple antibiotics. In fact, multidrug-resistant (MDR) K. pneumoniae producing KPC or OXA-48-like carbapenemases are recognized as a serious global health threat. In this sense, we evaluated the virulence of K. pneumoniae KPC(+) or OXA-48(+) aiming at potential antimicrobial therapeutics. K. pneumoniae carbapenemase (KPC) and the expanded-spectrum oxacillinase OXA-48 isolates were obtained from patients treated in medical care units in Lisbon, Portugal. The virulence potential of the K. pneumonia clinical isolates was tested using the Galleria mellonella model. For that, G. mellonella larvae were inoculated using patients KPC(+) and OXA-48(+) isolates. Using this in vivo model, the KPC(+) K. pneumoniae isolates showed to be, on average, more virulent than OXA-48(+). Virulence was found attenuated when a low bacterial inoculum (one magnitude lower) was tested. In addition, we also report the use of a synthetic polycationic oligomer (L-OEI-h) as a potential antimicrobial agent to fight infectious diseases caused by MDR bacteria. L-OEI-h has a broad-spectrum antibacterial activity and exerts a significantly bactericidal activity within the first 5-30 min treatment, causing lysis of the cytoplasmic membrane. Importantly, the polycationic oligomer showed low toxicity against in vitro models and no visible cytotoxicity (measured by survival and health index) was noted on the in vivo model (G. mellonella), thus L-OEI-h is foreseen as a promising polymer therapeutic for the treatment of MDR K. pneumoniae infections.

Cysteine metabolic circuitries: druggable targets in cancer.

To enable survival in adverse conditions, cancer cells undergo global metabolic adaptations. The amino acid cysteine actively contributes to cancer metabolic remodelling on three different levels: first, in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, a reversible post-translational modification; second, as a substrate for the production of hydrogen sulphide (H2S), which feeds the mitochondrial electron transfer chain and mediates per-sulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, finally, as a carbon source for epigenetic regulation, biomass production and energy production. This review will provide a systematic portrayal of the role of cysteine in cancer biology as a source of carbon and sulphur atoms, the pivotal role of cysteine in different metabolic pathways and the importance of H2S as an energetic substrate and signalling molecule. The different pools of cysteine in the cell and within the body, and their putative use as prognostic cancer markers will be also addressed. Finally, we will discuss the pharmacological means and potential of targeting cysteine metabolism for the treatment of cancer.

Ovarian Cancer Biomarkers: Moving Forward in Early Detection.

Ovarian cancer is a silent cancer which rate survival mainly relays in early stage detection. The discovery of reliable ovarian cancer biomarkers plays a crucial role in the disease management and strongly impact in patient's prognosis and survival. Although having many limitations CA125 is a classical ovarian cancer biomarker, but current research using proteomic or metabolomic methodologies struggles to find alternative biomarkers, using non-invasive our relatively non-invasive sources such as urine, serum, plasma, tissue, ascites or exosomes. Metabolism and metabolites are key players in cancer biology and its importance in biomarkers discovery cannot be neglected. In this chapter we overview the state of art and the challenges facing the use and discovery of biomarkers and focus on ovarian cancer early detection.

Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance.

: Ovarian cancer is a highly lethal disease, mainly due to chemoresistance. Our previous studies on metabolic remodeling in ovarian cancer have supported that the reliance on glutathione (GSH) bioavailability is a main adaptive metabolic mechanism, also accounting for chemoresistance to conventional therapy based on platinum salts. In this study, we tested the effects of the in vitro inhibition of GSH synthesis on the restoration of ovarian cancer cells sensitivity to carboplatin. GSH synthesis was inhibited by exposing cells to l-buthionine sulfoximine (l-BSO), an inhibitor of -glutamylcysteine ligase (GCL). Given the systemic toxicity of l-BSO, we developed a new formulation using polyurea (PURE) dendrimers nanoparticles (l-BSO@PUREG4-FA2), targeting l-BSO delivery in a folate functionalized nanoparticle.

Osteogenic Differentiation of Human Mesenchymal Stem Cells by the Single Action of Luminescent Polyurea Oxide Biodendrimers.

Polyurea oxide (PURO) biodendrimers are a class of dendrimers that can trigger osteogenic differentiation of human mesenchymal stem cells (hMSCs). PURO biodendrimers are prepared by simple, solventless oxidation of polyurea dendrimers using hydrogen peroxide as the oxidant in quantitative yield, retaining both biocompatibility (up to 10 mg/mL for higher generations) and the non-traditional intrinsic luminescence. The effect of PURO biodendrimers in the differentiation of hMSCs was found by the single addition to a standard growth medium for MSCs differentiation (without differentiation inducers). After 21 days of incubation, the formation of osteoblasts was confirmed by the alizarin red staining assay and alkaline phosphatase activity. This is the first report of in vitro osteodifferentiation fully regulated by synthetic soft polymers such as dendrimers. Current osteogenic differentiation protocols rely on an in vitro inducing formulation (including dexamethasone, ascorbic acid, and ß-glycerophosphate), which lacks therapeutic potential in vivo. The outstanding role of dendrimers in nanomedicine, under clinic translation, combined with this feature is envisaged to foster PURO dendrimers as an important strategy in cell therapy and regenerative medicine.

Targeting Glutathione and Cystathionine ß-Synthase in Ovarian Cancer Treatment by Selenium-Chrysin Polyurea Dendrimer Nanoformulation.

Ovarian cancer is the main cause of death from gynecological cancer, with its poor prognosis mainly related to late diagnosis and chemoresistance (acquired or intrinsic) to conventional alkylating and reactive oxygen species (ROS)-generating drugs. We and others reported that the availability of cysteine and glutathione (GSH) impacts the mechanisms of resistance to carboplatin in ovarian cancer. Different players in cysteine metabolism can be crucial in chemoresistance, such as the cystine/glutamate antiporter system Xc (xCT) and the H2S-synthesizing enzyme cystathionine ß-synthase (CBS) in the pathway of cysteine catabolism. We hypothesized that, by disrupting cysteine metabolic flux, chemoresistance would be reverted. Since the xCT transporter is also able to take up selenium, we used selenium-containing chrysin (SeChry) as a plausible competitive inhibitor of xCT. For that, we tested the effects of SeChry on three different ovarian cancer cell lines (ES2, OVCAR3, and OVCAR8) and in two non-malignant cell lines (HaCaT and HK2). Results showed that, in addition to being highly cytotoxic, SeChry does not affect the uptake of cysteine, although it increases GSH depletion, indicating that SeChry might induce oxidative stress. However, enzymatic assays revealed an inhibitory effect of SeChry toward CBS, thus preventing production of the antioxidant H2S. Notably, our data showed that SeChry and folate-targeted polyurea dendrimer generation four (SeChry@PUREG4-FA) nanoparticles increased the specificity for SeChry delivery to ovarian cancer cells, reducing significantly the toxicity against non-malignant cells. Collectively, our data support SeChry@PUREG4-FA nanoparticles as a targeted strategy to improve ovarian cancer treatment, where GSH depletion and CBS inhibition underlie SeChry cytotoxicity.