Theoretical study of the interaction of anti-cancer drugs with nanoporous materials

Cancer is an increasingly serious threat to global public health, according to the World Health Organization, which states that the number of cancer cases will reach 24 million a year by 2035. There is a list of chemotherapeutics that are widely used in cancer therapy, including busulfan, doxorubicin, 5-fluoracil, paclitaxel, cisplatin, gemcitabine, imatinib, tamoxifen, methotrexate and manyothers. Cancer chemotherapies are curbed by their unspecificity towards tumorcells, leading to high doses, rapid clearance, poor pharmacokinetics andserious side effects. Nanoparticle-therapeutics can reduce the risks associated with free drug therapeutics while improving the efficacy of conventional drugs. Recently,Metal-Organic Frameworks (MOFs) have been proposed as potential nanocarrier platforms for anti-cancer drug delivery, due to their low toxicity,biodegradability, high internal surface area, widely tunable composition, highpayloads and controlled drug release.In this thesis, we performed molecular simulations to study anti-cancer drug adsorption and diffusion in MOFs. Computational simulations can offer a unique insight into the drug adsorption and diffusion mechanisms in porous nanocarriers at the atomic level, since a clear molecular-level understanding is important for the development of novel drug delivery systems with better control of drug administration.In particular, we have applied a multi-scale methodology, comprising of DFT calculations and GCMC/MD simulations, to study the adsorption and diffusion properties of the anticancer drug Gemcitabine (GEM) in a series of IRMOFs.Our results indicated suitable drug/MOF interactions for drug adsorption with as low release. High drug loading capacities were calculated for all host materials, surpassing even ten times the amount of GEM storage in other conventional materials. The mobility of GEM in the IRMOFs’ pores was also investigated and a slow drug release rate was revealed, thus reducing the side effects of the traditional medicine and improving the life expectancy of patients suffering from cancer.This thesis underscores the molecular behavior of a drug in porous materials,which plays a key role in drug loading and release. Our results show that all the studied IRMOFs are promising nano encapsulators for storage of GEM which can be used as alternatives to conventional drug delivery systems and suggest further experimental testing.Ο καρκίνος αποτελεί παγκόσμια απειλή για τη δημόσια υγεία, σύμφωνα με τον Παγκόσμιο Οργανισμό Υγείας, ο οποίος αναφέρει ότι ο αριθμός των νέων περιστατικών καρκίνου θα φτάσει τα 24 εκατομμύρια ετησίως έως το 2035.Μεγάλη ποικιλία χημειοθεραπευτικών φαρμάκων χρησιμοποιούνται ευρέως στη φαρμακοβιομηχανία, και ιδιαίτερα γνωστά είναι η βουσουλφάνη, ηδοξορουβικίνη, η 5-φθοροουρακίλη, η πακλιταξέλη, η σισπλατίνη, ηγεμσιταμπίνη, η ιματινίμπη, η ταμοξιφαίνη, η μεθοτρεξάτη και πολλά άλλα. Οι διάφορες μέχρι τώρα χημειοθεραπείες περιορίζονται από τη μη εξειδίκευσή τους έναντι των καρκινικών κυττάρων, οδηγώντας έτσι σε υψηλές δόσεις, ταχεία κάθαρση, κακή φαρμακοκινητική και σοβαρές παρενέργειες.Ο σχεδιασμός νέων νάνο-συστημάτων χορήγησης αντικαρκινικών φαρμάκων έφερε νέα ελπίδα στην καταπολέμηση του καρκίνου, μειώνοντας αισθητά τις παρενέργειες των συμβατικών χημειοθεραπειών αλλά και βελτιώνοντας ταυτόχρονα την αποτελεσματικότητά τους. Πρόσφατα, τα πορώδη μέταλλο-οργανικά σκελετικά υλικά (Μetal-Organic-Frameworks, MOFs) έχουν προταθεί ως προσοδοφόροι νάνο-φορείς για τη μεταφορά αντικαρκινικών φαρμάκων, καθώς πολλά από αυτά παρουσιάζουν χαμηλή τοξικότητα, βιοσυμβατότητα και βιοαποικοδομησιμότητα, μεγάλη ειδική επιφάνεια και μεγάλο όγκο πόρων, καθώς και δυνατότητα μεγάλης αποθήκευσης και ελεγχόμενης αποδέσμευσης φαρμάκου. Σε αυτήν την μελέτη, εφαρμόσαμε διάφορες υπολογιστικές τεχνικές για να μελετήσουμε την αποθήκευση/μεταφορά αντικαρκινικών φαρμάκων σε MOFs.Οι υπολογιστικές προσομοιώσεις εξασφαλίζουν την εις βάθος κατανόηση των μηχανισμών προσρόφησης και διάχυσης φαρμάκων σε πορώδεις νανοδομές σε ατομικό επίπεδο, συμβάλλοντας έτσι στην ανάπτυξη νέων συστημάτων χορήγησης φαρμάκων με ελεγχόμενη αποδέσμευση και καλύτερο θεραπευτικό αποτέλεσμα. Ειδικότερα εφαρμόσαμε τη μεθοδολογία πολλαπλής κλίμακας, αποτελούμενη από υπολογισμούς DFT και προσομοιώσεις GCMC/MD, για να μελετήσουμε την προσρόφηση και διάχυση του αντικαρκινικού φαρμάκου Γεμσιταμπίνηςxx(GEM), σε υλικά τύπου IRMOFs. Tα αποτελέσματά μας έδειξαν ικανοποιητικές ενέργειες αλληλεπίδρασης φαρμάκου/ΜΟF έτσι ώστε το φάρμακο ναι μεν να μπορεί να προσροφηθεί ισχυρά στα host-MOFs, αλλά και να μπορεί να αποδεσμευτεί σταδιακά από αυτά. Παρατηρήθηκαν μεγάλα ποσοστά φόρτωσης του φαρμάκου για όλα τα υπό-μελέτη υλικά ξεπερνώντας ακόμα και δέκα φορές την ποσότητα αποθήκευσης της GEM σε άλλα συμβατικά υλικά.Tέλος, εξετάστηκε η κινητικότητα της GEM μέσα στους πόρους των IRMOFsκαι η υπολογισμοί μας αποκάλυψαν αργή απελευθέρωση του φαρμάκου από τα υπό εξέταση υλικά, μειώνοντας έτσι τις παρενέργειες και βελτιώνοντας σημαντικά το προσδόκιμο ζωής των ασθενών που πάσχουν από καρκίνο. Η μελέτη μας υπογραμμίζει ότι η μοριακή συμπεριφορά του φαρμάκου μέσα στα νανοπορώδη υλικά, παίζει σημαντικό ρόλο στην αποθήκευση και απελευθέρωση του φαρμάκου από αυτά. Τα αποτελέσματά μας δείχνουν ότι όλα τα υπό μελέτη IRMOFs αποτελούν ελπιδοφόρους νανοφορείς για τη χορήγηση της GEM και μπορούν να χρησιμοποιηθούν σαν εναλλακτικές λύσεις έναντι των συμβατικών συστημάτων μεταφοράς και έτσι προτείνεται περαιτέρω πειραματική μελέτη που θα επιβεβαιώσει τα ευρήματά μας

Sustainable Greenhouse Covering Materials with Nano- and Micro-Particle Additives for Enhanced Radiometric and Thermal Properties and Performance

This review aims to provide a comprehensive overview of nano- and microscopic materials that can provide thermal radiation insulation without reducing visible light transmittance, thereby reducing heat loss and conserving energy in greenhouses. We also reviewed the radial and thermal properties of greenhouse covering materials. Fillers, colorants, reinforcers, and additives, as well as glass, plastic film, and plastic sheet materials, were discussed. Additionally, by searching for keywords like insulation film, insulation agent, and infrared insulation, compounds based on graphene and fullerene as well as phase transition materials (PCMs) that may be used for radiation insulation, we proposed their potential use in greenhouse covers. They can be divided into semi-transparent photovoltaic (PV) materials, zinc oxide-based film fillers, and silica filter films. We discussed the radiation heat insulation and light transmission characteristics of these materials. Nano-synthesis techniques were also investigated. Based on latest advances in the literature, future developments in the micro- and macroscale synthesis of nanomaterials will enable additional innovations in covering materials for greenhouse structures. A limiting factor, though, was the high sensitivity of PVs to external climatic and meteorological variables. The ability of materials used to make greenhouse covers to control the microclimate, reduce CO2 emissions, use less energy, and increase agricultural productivity, however, cannot be disputed. Similar to this, a thorough examination of the uses of various greenhouse technologies reveals that the advancements also have financial advantages, particularly in terms of reducing greenhouse heating and cooling expenses. The PCMs, which decreased greenhouse-operating costs by maintaining constant ambient temperatures, provide ample evidence of this

Regiocontrolled Synthesis of γ‑Hydroxybutenolides via Singlet Oxygen-Mediated Oxidation of 2‑Thiophenyl Furans

Photooxygenation of 2-thiophenyl-substituted furans in ethanol leads to the rapid, regiocontrolled, and quantitative synthesis of γ-hydroxybutenolides. The carbonyl group in butenolide holds the position of thiophenyl moiety in reacting furans. Decomposition of the initially formed [4 + 2] endoperoxide into products through a radical chain mechanism is proposed, as the fate of thiophenyl moiety is its transformation into ethyl phenylsulfenate (PhS-OEt) and diphenyldisulfide. Under the reaction conditions, the sulfenate is fast oxidized into the corresponding sulfinate

Total Synthesis and Structural Revision of (+)-Yaoshanenolide B

(+)-Yaoshanenolide B was synthesized employing as a key step an endo- and face-selective Diels–Alder reaction between natural <i>R</i>-(−)-α-phellandrene and the exocyclic double bond of a 5-methylene-2­(5<i>H</i>)-furanone. The dienophile furanone was prepared by photooxygenation of a suitably substituted 2-thiophenylfuran followed by dehydration of the resulting γ-hydroxybutenolide. Through this synthesis, the initially proposed structure for (+)-yaoshanenolide B has been revised to the 1<i>R</i>,2<i>S</i>,4<i>R</i>,7<i>R</i>,1″<i>S</i> diastereomer

Livestock Agriculture Greenhouse Gases for Electricity Production: Recent Developments and Future Perspectives

The focus of this review paper was to investigate innovations currently employed to capture and use greenhouse gases produced within livestock farms for energy production and expected future directions. The methods considered for data collection regarded a systematic review of the literature, where 50 journal articles were critically reviewed. The main findings identified that the conventional method used in transforming livestock agriculture greenhouse gases into energy regards the combustion of biogas. However, emerging methods encompass microbial fuel cells, dry biogas reforming, steam biogas reforming, auto thermal Chemical Looping Reforming (CLRa), and gas-to-liquid methods that convert methane to liquid hydrocarbons. The conclusions from the review are that there is a potential to integrate these methods in livestock agriculture in order to generate energy from greenhouse emissions and reduce the reliance on fossil fuels

Machine learning predictions of concentration-specific aggregate hazard scores of inorganic nanomaterials in embryonic zebrafish

The possibility of employing computational approaches like nano-QSAR or nano-read-across to predict nanomaterial hazard is attractive from both a financial, and most importantly, where in vivo tests are required, ethical perspective. In the present work, we have employed advanced Machine Learning techniques, including stacked model ensembles, to create nano-QSAR tools for modeling the toxicity of metallic and metal oxide nanomaterials, both coated and uncoated and with a variety of different core compositions, tested at different dosage concentrations on embryonic zebrafish. Using both computed and experimental descriptors, we have identified a set of properties most relevant for the assessment of nanomaterial toxicity and successfully correlated these properties with the associated biological responses observed in zebrafish. Our findings suggest that for the group of metal and metal oxide nanomaterials, the core chemical composition, concentration and properties dependent upon nanomaterial surface and medium composition (such as zeta potential and agglomerate size) are significant factors influencing toxicity, albeit the ranking of different variables is sensitive to the exact analysis method and data modeled. Our generalized nano-QSAR ensemble models provide a promising framework for anticipating the toxicity potential of new nanomaterials and may contribute to the transition out of the animal testing paradigm. However, future experimental studies are required to generate comparable, similarly high quality data, using consistent protocols, for well characterized nanomaterials, as per the dataset modeled herein. This would enable the predictive power of our promising ensemble modeling approaches to be robustly assessed on large, diverse and truly external datasets