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Identifier 000460203
Title Responsive polymer nanostructures and hydrogels with photo/acid sensitive linkages for biomedical applications
Alternative Title Αποκρίσιμες πολυμερικές νανοδομές και υδρογέλες με δεσμούς ευαίσθητους φως/οξύ για βιοιατρικές εφαρμογές
Author Ψαρρού, Μαρία
Thesis advisor Βαμβακάκη, Μαρία
Reviewer Χατζηνικολαϊδου, Μαρία
Αλεξίου-Χατζάκη Αικατερίνη
Βλασσόπουλος, Δημήτρης
Αναστασιάδης, Σπύρος
Fernando Carlos Giacomelli
Remzi Becer
Abstract Stimuli–sensitive or “smart” polymers have been on the focal point of many research groups, as exceptionally unique candidates for applications in rapidly burgeoning research fields, including biotechnology and nanomedicine, electronic devices, sensors and actuators and others. The present PhD thesis focuses on the synthesis of novel, stimuli–degradable polymers, polymer networks and polymer–drug conjugates and investigates their potential use as drug delivery devices. After a general introduction in Chapter 1, the second Chapter of this thesis focuses on the investigation of thioketal and thioacetal bonds as a new family of photolabile linkages. Linear main–chain poly(thioketals) were synthesized via a polycondensation reaction based on an acetal exchange mechanism. The chemical and macromolecular characteristics of the synthesized polymers were characterized by SEC and 1H NMR and ATR–FTIR spectroscopies. Next, the main chain photodegradation mechanism of the polymers upon UV irradiation (λ = 254 nm, 0.063 mW cm–1) was examined. It was found that the photolysis process proceeded in a chain–length dependent fashion, leading to the production of dithiol and ketone as the main photoproducts. Next, a facile chemical platform for the synthesis of photodegradable and thermo–reversible, model hydrogels comprising poly(ethylene glycol) (PEG) as the elastic chains and a dithioacetal at the cross–links will be presented. Hydrogels were synthesized via an acid–catalyzed step–growth reaction of a difunctional PEG–thiol macromer with a wisely selected aromatic dialdehyde molecule. Introduction of the photosensitive dithioacetal bonds rendered the hydrogels photodegradable to obtain the initial comonomers as the main photoproducts, which endowed the material with thermo– reversible properties. The viscoelastic properties of the water swollen gels, their photodegradation under UV exposure at λ = 254 nm with very low intensity (0.063 mW cm–1), and the reversible formation of the hydrogel upon heating were investigated by dynamic shear rheology. Mechanistic insights into the photodegradation mechanism of the hydrogels were gained by 1H NMR spectroscopy kinetic studies on a model, small molecule thioacetal compound. Finally, the photo–induced release of loaded cargo from the synthesized hydrogels was investigated. In the third Chapter of this thesis, we are focused on the investigation of light–sensitive poly(acylhydrazones). A novel water soluble, light– and acid–cleavable, main–chain 6 poly(acylhydrazone) copolymer was synthesized via a step–growth reaction of a dihydrazide monomer, adipic acid dihydrazide (AA), with a dibenzaldehyde modified poly(ethylene glycol) (PEGAld) affording a hydrophilic PEGAld–adipic acid (PEGAld– AA) copolymer. Photodegradation studies revealed a backbone photolysis process attributed to the cleavage of the labile acylhydrazone bonds along the polymer chain. The water–soluble poly(acylhydrazone) was conjugated with a hydrophobic anticancer drug, doxorubicin (DOX), affording an amphiphilic polymeric prodrug which formed spherical nanostructures in water. The synergistic effect of light–mediated degradation and acid–induced hydrolysis of the acylhydrazone bonds along the polymer chains, as well as the release kinetics of DOX from the polymeric prodrug were investigated. In Chapter 4, encouraged by our findings regarding the light–sensitivity of the acylhydrazone bonds, the synthesis, characterization and photochemical properties of different main–chain photodegradable poly(acylhydrazones) with regularly inserted photocleavable groups, with photo–sensitivity ranging from the UV to the visible light range was investigated. Poly(acylhydrazones) were synthesized using a PEG acylhydrazide macromonomer of Mn = 4000 g mol‒1 or 1500 g mol‒1, and judiciously selected aromatic dialdehydes or diketones as the comonomers. The dialdehyde monomers used in this study were terepthaldehyde (TPA) and dibenzaldehyde tetraphenyl ethylene (TPEAld), whereas the diketone monomers were 1,4– diacetylbenzene (DCB) and anthraquinone (ANQ). In addition, the synthesis of photodegradable alternating poly(acylhydrazone) multiblock copolymers comprising hydrophilic PEG blocks and hydrophobic PDMS blocks was pursued via the step– growth reaction of dialdehyde–terminated PDMS with diacylhydrazide–terminated PEG. The effect of the carbonyl group, aldehyde vs ketone, on the polymerization kinetics, the self–assembly as well as the photodegradation kinetics of the copolymers was investigated. Moreover, the influence of the chromophore on the self–assembly, the photophysical properties and the photodegradation of the poly(acylhydrazones) was examined. Mechanistic insights into the photodegradation mechanism of the PEG4kHy– TPE copolymer were gained via 1H NMR spectroscopy, whereas, the aggregation induced emission (AIE) properties, the photo–triggered drug release and the in vitro cytotoxicity of PEG4kHyd–TPE copolymer nanoparticles in water were investigated, rendering them attractive theranostic agents. 7 Finally, in Chapter 5, a hybrid (organic–inorganic) mRNA delivery system comprising polymer coated superparamagnetic iron oxide nanoparticles (SPIONs) is presented. The SPIONs were coated with modified natural polymers, namely oxidized dextran and quaternized chitosan, to bearing aldehyde and cationic quaternary ammonium groups, respectively, on their surface. The physicochemical and morphological characteristics of the hybrid particles were determined by ATR–FTIR spectroscopy, TGA analysis, DLS, SEM and TEM, whereas their biocompatibility in the presence and absence of a magnetic field was tested on T49D breast cancer cells. Owning to the presence of the cationic (quaternized chitosan) or aldehyde (oxidized dextran) groups on the particle surface, mRNA chains were bound via electrostatic interactions or covalent (imine) bonds, respectively. The binding and transfection efficiency of mRNA was examined using of a Green Fluorescent Protein–mRNA (GFP–mRNA) construct in preliminary in vitro studies. Chapter 6 summarizes the main Conclusions of the work carried out in this thesis and provides some future perspectives and the open questions derived from the study.
Language English
Subject Controlled drug delivery
PH degradable polymers
PH-διασπώμενα πολυμερή
Photodegradable polymeric materials
Smart polymers
Έξυπνα πολυμερή
Αποκρίσιμα πολυμερή
Ελεγχόμενη μεταφορά φαρμάκων
Φωτο-αποικοδομίσιμα πολυμερικά υλικά
Φωτοευαίσθητα πολυμέρα υλικά
Issue date 2023-11-29
Collection   School/Department--School of Sciences and Engineering--Department of Materials Science and Technology--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/1/7/b/metadata-dlib-1699271537-861673-27726.tkl Bookmark and Share
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