Dissertation committee:
Αστέριος Πίσπας, Διευθυντής Ερευνών ΕΙΕ
Ερμόλαος Ιατρού, Καθηγητής, Τμήμα Χημείας ΕΚΠΑ
Μαρίνος Πιτσικάλης, Καθηγητής, Τμήμα Χημείας ΕΚΠΑ
Θωμάς Μαυρομούστακος, Καθηγητής, Τμήμα Χημείας ΕΚΠΑ
Γιώργος Σακελλαρίου, Αναπληρωτής Καθηγητής, Τμήμα Χημείας ΕΚΠΑ
Γιώργος Βουγιουκαλάκης, Αναπληρωτής Καθηγητής, Τμήμα Χημείας ΕΚΠΑ
Μαργαρίτα Χατζηχρηστίδη, Αναπληρώτρια Καθηγήτρια, Τμήμα Χημείας ΕΚΠΑ
Translated title:
Block copolymers, composed of one block randomly distributed with monomeric units. Synthesis, Characterization, Properties.
Summary:
In recent years the field of Polymer Science has seen great growth due to the multitude of applications of polymers in the fields of medicine, nanotechnology and biotechnology. The applications of polymers in nanotechnology are emmense. Especially those related to amphiphilic copolymers which through their property of self-assembly in aqueous media form nanostructures is of particular interest. Amphiphilic copolymers presenting different architectures such as block, random or statistical, star, graft copolymers form nanostructures of different morphological characteristics which can be used accordingly based on the requirements of each application in the field of nanotechnology. Also important is the possibility of modifying them after polymerization in order to incorporate additional functionalities and properties. Random or statistical copolymers were not used in the past in bio-applications due to poor control over polymer molecular mass and wide mass distributions. But the interweaving of polymerization techniques with modern methods such as living/controlled polymerization methods e.g Reversible Addition Fragmentation chain Transfer (RAFT) polymerization has overcome these obstacles. Random or statistical copolymers require fewer polymerization steps to incorporate two or more monomers, a feature that makes the polymerization process easier and less expensive. Amphiphilic copolymers that respond to stimuli such as changes in temperature, pH and ionic strength of the solution are a class of polymers which, due to the properties of their aqueous solutions, are commonly used in biomedical and nanotechnology applications. Their hydrophobic parts can be used to retain and transport pharmaceutical molecules as cargos, while due to their response to stimuli, they offer increased uptake and controlled release of drugs in target cells. The hydrophilic regions grant increased stability, water solubility and stealth properties of the polymeric system, extending their circulation time. Hydrophilic polyelectrolyte parts can also complex with nucleic acids and proteins forming bio-hybrid nanostructures, thus reducing their degradation rate with the ultimate goal of treating infected cells. The aim of the current doctoral dissertation is the synthesis of linear and star copolymers and their subsequent modification after polymerization in order to produce copolymers with a random distribution of monomeric units in a block or arm, respectively. The synthesis of copolymers that respond to changes in temperature, pH and ionic strength was carried out by the RAFT polymerization method and subsequently their self-assembly in aqueous media was studied. Μore specifically, the [poly(2-(dimethylamino)ethyl methacrylate)-b- poly(oligo(ethylene glycol) methyl ether methacrylate)] (PDMAEMA-b-POEGMA) diblock copolymers were synthesized, of which the PDMAEMA block was then partially modified with alkyl agents of different lengths through quaternization, resulting in the production of partially hydrophobic diblock copolymers where one block contains randomly distributed two types of monomer units P(DMAEMA-co-Q6/12DMAEMA)-b-POEGMA. Also, the PDMAEMA block was modified using 1-propanesultone in order to form copolymers of the type P(DMAEMA-co-sDMAEMA)-b-POEGMA possessing zwitterionic sulfobetaine groups. Then, the miktoarm star copolymers of the (PDMAEMA)x(POEGMA)y type were synthesized, where PDMAEMA arms were partially modified with alkyl agents of different lengths to finally produce the partially modified cationic miktoarm stars of the [P(DMAEMA-co-Q6/12DMAEMA)]x[POEGMA]y type with enhanced hydrophobic character. Modified copolymers through partial chemical modification of tertiary amine groups have been partially converted into cationic polyelectrolytes while simultaneously bearing long hydrophobic side groups with six and twelve carbon atoms. The molecular characterization of the synthesized polymers was performed using the techniques of size exclusion chromatography (SEC) to determine their molecular masses and molecular mass distributions, proton nuclear magnetic resonance (1H-NMR) spectroscopy for the determination of their composition and degree of chemical modification and FTIR spectroscopy for their chemical identification, confirming their successful synthesis. Subsequently, the self-organization of the synthesized polymers in aqueous solutions was studied as a function of temperature, pH and ionic strength of the solution using dynamic (DLS), static (SLS) and electrophoretic (ELS) light scattering techniques, fluorescence spectroscopy (FS) and cryo transmission electron microscopy (cryo-TEM). The evaluation of the physicochemical characteristics of the partially hydrophobic diblock copolymers of the P(DMAEMA-co-Q6/12DMAEMA)-b-POEGMA type in aqueous solutions led to the encapsulation and controlled release of the drug indomethacin as verified by the scattering techniques (DLS-SLS) and the spectra from UV-Vis and FTIR spectroscopies. Also, partial modification with alkyl agents in addition to the introduction of long hydrophobic chains simultaneously introduced positive charges to the amino groups of the P(DMAEMA-co-Q6/12DMAEMA) block resulting in the design and preparation of complexes with nucleic acids and proteins with the aim of developing bio-hybrid nanostructures. The ability of modified copolymers to complex biomacromolecules was studied by scattering techniques (DLS, SLS, ELS) and UV-Vis and FS spectroscopies. Additionally, the modified mikroarm stars [P(DMAEMA-co-Q6/12DMAEMA)]x[POEGMA]y were studied for their ability to form complexes with nucleic acids by using the corresponding techniques utilized for the linear analoques. Finally, simultaneous entrapment of the two drugs indomethacin and curcumin within the aggregates of the modified copolymers was carried out. The mixed nanostructures were studied by light scattering techniques (DLS, SLS), UV-Vis, FS and FTIR spectroscopies, while their morphologies were examined with the cryo-TEM technique.
Keywords:
RAFT polymerization, block copolymers with monomeric units randomly distributed in a block, aqueous solution studies, bio-hybrid nanostructures, complexes with nucleic acids, mixed drug/copolymer nanostructures
